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## Science Has A Systemic Problem, Not an Innovation Problem

### Science Has A Systemic Problem, Not an Innovation Problem

Curator: Stephen J. Williams, Ph.D.

A recent email, asking me to submit a survey, got me thinking about the malaise that scientists and industry professionals frequently bemoan: that innovation has been stymied for some reason and all sorts of convuluted processes must be altered to spur this mythical void of great new discoveries…..  and it got me thinking about our current state of science, and what is the perceived issue… and if this desert of innovation actually exists or is more a fundamental problem which we have created.

The email was from an NIH committee asking for opinions on recreating the grant review process …. now this on the same day someone complained to me about a shoddy and perplexing grant review they received.

The following email, which was sent out to multiple researchers, involved in either NIH grant review on both sides, as well as those who had been involved in previous questionnaires and studies on grant review and bias.  The email asked for researchers to fill out a survey on the grant review process, and how to best change it to increase innovation of ideas as well as inclusivity.  In recent years, there have been multiple survey requests on these matters, with multiple confusing procedural changes to grant format and content requirements, adding more administrative burden to scientists.

The email from Center for Scientific Review (one of the divisions a grant will go to before review {they set up review study sections and decide what section a grant should be  assigned to} was as follows:

Update on Simplifying Review Criteria: A Request for Information

https://www.csr.nih.gov/reviewmatters/2022/12/08/update-on-simplifying-review-criteria-a-request-for-information/

NIH has issued a request for information (RFI) seeking feedback on revising and simplifying the peer review framework for research project grant applications. The goal of this effort is to facilitate the mission of scientific peer review – identification of the strongest, highest-impact research. The proposed changes will allow peer reviewers to focus on scientific merit by evaluating 1) the scientific impact, research rigor, and feasibility of the proposed research without the distraction of administrative questions and 2) whether or not appropriate expertise and resources are available to conduct the research, thus mitigating the undue influence of the reputation of the institution or investigator.

Currently, applications for research project grants (RPGs, such as R01s, R03s, R15s, R21s, R34s) are evaluated based on five scored criteria: Significance, Investigators, Innovation, Approach, and Environment (derived from NIH peer review regulations 42 C.F.R. Part 52h.8; see Definitions of Criteria and Considerations for Research Project Grant Critiques for more detail) and a number of additional review criteria such as Human Subject Protections.

NIH gathered input from the community to identify potential revisions to the review framework. Given longstanding and often-heard concerns from diverse groups, CSR decided to form two working groups to the CSR Advisory Council—one on non-clinical trials and one on clinical trials. To inform these groups, CSR published a Review Matters blog, which was cross-posted on the Office of Extramural Research blog, Open Mike. The blog received more than 9,000 views by unique individuals and over 400 comments. Interim recommendations were presented to the CSR Advisory Council in a public forum (March 2020 videoslides; March 2021 videoslides). Final recommendations from the CSRAC (report) were considered by the major extramural committees of the NIH that included leadership from across NIH institutes and centers. Additional background information can be found here. This process produced many modifications and the final proposal presented below. Discussions are underway to incorporate consideration of a Plan for Enhancing Diverse Perspectives (PEDP) and rigorous review of clinical trials RPGs (~10% of RPGs are clinical trials) within the proposed framework.

Simplified Review Criteria

NIH proposes to reorganize the five review criteria into three factors, with Factors 1 and 2 receiving a numerical score. Reviewers will be instructed to consider all three factors (Factors 1, 2 and 3) in arriving at their Overall Impact Score (scored 1-9), reflecting the overall scientific and technical merit of the application.

• Factor 1: Importance of the Research (Significance, Innovation), numerical score (1-9)
• Factor 2: Rigor and Feasibility (Approach), numerical score (1-9)
• Factor 3: Expertise and Resources (Investigator, Environment), assessed and considered in the Overall Impact Score, but not individually scored

Within Factor 3 (Expertise and Resources), Investigator and Environment will be assessed in the context of the research proposed. Investigator(s) will be rated as “fully capable” or “additional expertise/capability needed”. Environment will be rated as “appropriate” or “additional resources needed.” If a need for additional expertise or resources is identified, written justification must be provided. Detailed descriptions of the three factors can be found here.

Now looking at some of the Comments were very illuminating:

I strongly support streamlining the five current main review criteria into three, and the present five additional criteria into two. This will bring clarity to applicants and reduce the workload on both applicants and reviewers. Blinding reviewers to the applicants’ identities and institutions would be a helpful next step, and would do much to reduce the “rich-getting-richer” / “good ole girls and good ole boys” / “big science” elitism that plagues the present review system, wherein pedigree and connections often outweigh substance and creativity.

I support the proposed changes. The shift away from “innovation” will help reduce the tendency to create hype around a proposed research direction. The shift away from Investigator and Environment assessments will help reduce bias toward already funded investigators in large well-known institutions.

As a reviewer for 5 years, I believe that the proposed changes are a step in the right direction, refocusing the review on whether the science SHOULD be done and whether it CAN BE DONE WELL, while eliminating burdensome and unhelpful sections of review that are better handled administratively. I particularly believe that the de-emphasis of innovation (which typically focuses on technical innovation) will improve evaluation of the overall science, and de-emphasis of review of minor technical details will, if implemented correctly, reduce the “downward pull” on scores for approach. The above comments reference blinded reviews, but I did not see this in the proposed recommendations. I do not believe this is a good idea for several reasons: 1) Blinding of the applicant and institution is not likely feasible for many of the reasons others have described (e.g., self-referencing of prior work), 2) Blinding would eliminate the potential to review investigators’ biosketches and budget justifications, which are critically important in review, 3) Making review blinded would make determination of conflicts of interest harder to identify and avoid, 4) Evaluation of “Investigator and Environment” would be nearly impossible.

Most of the Comments were in favor of the proposed changes, however many admitted that it adds additional confusion on top of many administrative changes to formats and content of grant sections.

Being a Stephen Covey devotee, and just have listened to  The Four Principles of Execution, it became more apparent that issues that hinder many great ideas coming into fruition, especially in science, is a result of these systemic or problems in the process, not at the level of individual researchers or small companies trying to get their innovations funded or noticed.  In summary, Dr. Covey states most issues related to the success of any initiative is NOT in the strategic planning, but in the failure to adhere to a few EXECUTION principles.  Primary to these failures of strategic plans is lack of accounting of what Dr. Covey calls the ‘whirlwind’, or those important but recurring tasks that take us away from achieving the wildly important goals.  In addition, lack of  determining lead and lag measures of success hinder such plans.

In this case a lag measure in INNOVATION.  It appears we have created such a whirlwind and focus on lag measures that we are incapable of translating great discoveries into INNOVATION.

In the following post, I will focus on issues relating to Open Access, publishing and dissemination of scientific discovery may be costing us TIME to INNOVATION.  And it appears that there are systemic reasons why we appear stuck in a rut, so to speak.

The first indication is from a paper published by Johan Chu and James Evans in 2021 in PNAS:

### Slowed canonical progress in large fields of science

Chu JSG, Evans JA. Slowed canonical progress in large fields of science. Proc Natl Acad Sci U S A. 2021 Oct 12;118(41):e2021636118. doi: 10.1073/pnas.2021636118. PMID: 34607941; PMCID: PMC8522281

## Abstract

In many academic fields, the number of papers published each year has increased significantly over time. Policy measures aim to increase the quantity of scientists, research funding, and scientific output, which is measured by the number of papers produced. These quantitative metrics determine the career trajectories of scholars and evaluations of academic departments, institutions, and nations. Whether and how these increases in the numbers of scientists and papers translate into advances in knowledge is unclear, however. Here, we first lay out a theoretical argument for why too many papers published each year in a field can lead to stagnation rather than advance. The deluge of new papers may deprive reviewers and readers the cognitive slack required to fully recognize and understand novel ideas. Competition among many new ideas may prevent the gradual accumulation of focused attention on a promising new idea. Then, we show data supporting the predictions of this theory. When the number of papers published per year in a scientific field grows large, citations flow disproportionately to already well-cited papers; the list of most-cited papers ossifies; new papers are unlikely to ever become highly cited, and when they do, it is not through a gradual, cumulative process of attention gathering; and newly published papers become unlikely to disrupt existing work. These findings suggest that the progress of large scientific fields may be slowed, trapped in existing canon. Policy measures shifting how scientific work is produced, disseminated, consumed, and rewarded may be called for to push fields into new, more fertile areas of study.

So the Summary of this paper is

• The authors examined 1.8 billion citations among 90 million papers over 241 subjects
• found the corpus of papers do not lead to turnover of new ideas in a field, but rather the ossification or entrenchment of canonical (or older ideas)
• this is mainly due to older paper cited more frequently than new papers with new ideas, potentially because authors are trying to get their own papers cited more frequently for funding and exposure purposes
• The authors suggest that “fundamental progress may be stymied if quantitative growth of scientific endeavors is not balanced by structures fostering disruptive scholarship and focusing attention of novel ideas”

The authors note that, in most cases, science policy reinforces this “more is better” philosophy”,  where metrics of publication productivity are either number of publications or impact measured by citation rankings.  However, using an analysis of citation changes occurring in large versus smaller fields, it becomes apparent that this process is favoring the older, more established papers and a recirculating of older canonical ideas.

“Rather than resulting in faster turnover of field paradigms, the massive amounts of new publications entrenches the ideas of top-cited papers.”  New ideas are pushed down to the bottom of the citation list and potentially lost in the literature.  The authors suggest that this problem will intensify as the “annual mass” of new publications in each field grows, especially in large fields.  This issue is exacerbated by the deluge on new online ‘open access’ journals, in which authors would focus on citing the more highly cited literature.

We maybe at a critical junction, where if many papers are published in a short time, new ideas will not be considered as carefully as the older ideas.  In addition,

with proliferation of journals and the blurring of journal hierarchies due to online articles-level access can exacerbate this problem

As a counterpoint, the authors do note that even though many molecular biology highly cited articles were done in 1976, there has been extremely much innovation since then however it may take a lot more in experiments and money to gain the level of citations that those papers produced, and hence a lower scientific productivity.

##### This issue is seen in the field of economics as well

Ellison, Glenn. “Is peer review in decline?” Economic Inquiry, vol. 49, no. 3, July 2011, pp. 635+. Gale Academic OneFile, link.gale.com/apps/doc/A261386330/AONE?u=temple_main&sid=bookmark-AONE&xid=f5891002. Accessed 12 Dec. 2022.

Abstract

Over the past decade, there has been a decline in the fraction of papers in top economics journals written by economists from the highest-ranked economics departments. This paper documents this fact and uses additional data on publications and citations to assess various potential explanations. Several observations are consistent with the hypothesis that the Internet improves the ability of high-profile authors to disseminate their research without going through the traditional peer-review process. (JEL A14, 030)

The facts part of this paper documents two main facts:

1. Economists in top-ranked departments now publish very few papers in top field journals. There is a marked decline in such publications between the early 1990s and early 2000s.

2. Comparing the early 2000s with the early 1990s, there is a decline in both the absolute number of papers and the share of papers in the top general interest journals written by Harvard economics department faculty.

Although the second fact just concerns one department, I see it as potentially important to understanding what is happening because it comes at a time when Harvard is widely regarded (I believe correctly) as having ascended to the top position in the profession.

The “decline-of-peer-review” theory I allude to in the title is that the necessity of going through the peer-review process has lessened for high-status authors: in the old days peer-reviewed journals were by far the most effective means of reaching readers, whereas with the growth of the Internet high-status authors can now post papers online and exploit their reputation to attract readers.

Many alternate explanations are possible. I focus on four theories: the decline-in-peer-review theory and three alternatives.

1. The trends could be a consequence of top-school authors’ being crowded out of the top journals by other researchers. Several such stories have an optimistic message, for example, there is more talent entering the profession, old pro-elite biases are being broken down, more schools are encouraging faculty to do cutting-edge research, and the Internet is enabling more cutting-edge research by breaking down informational barriers that had hampered researchers outside the top schools. (2)

2. The trends could be a consequence of the growth of revisions at economics journals discussed in Ellison (2002a, 2002b). In this more pessimistic theory, highly productive researchers must abandon some projects and/or seek out faster outlets to conserve the time now required to publish their most important works.

3. The trends could simply reflect that field journals have declined in quality in some relative sense and become a less attractive place to publish. This theory is meant to encompass also the rise of new journals, which is not obviously desirable or undesirable.

The majority of this paper is devoted to examining various data sources that provide additional details about how economics publishing has changed over the past decade. These are intended both to sharpen understanding of the facts to be explained and to provide tests of auxiliary predictions of the theories. Two main sources of information are used: data on publications and data on citations. The publication data include department-level counts of publications in various additional journals, an individual-level dataset containing records of publications in a subset of journals for thousands of economists, and a very small dataset containing complete data on a few authors’ publication records. The citation data include citations at the paper level for 9,000 published papers and less well-matched data that is used to construct measures of citations to authors’ unpublished works, to departments as a whole, and to various journals.

##### Inside Job or Deep Impact? Extramural Citations and the Influence of Economic Scholarship

Josh Angrist, Pierre Azoulay, Glenn Ellison, Ryan Hill, Susan Feng Lu. Inside Job or Deep Impact? Extramural Citations and the Influence of Economic Scholarship.

JOURNAL OF ECONOMIC LITERATURE

VOL. 58, NO. 1, MARCH 2020

(pp. 3-52)

#### Why Isn’t Innovation Helping Reduce Health Care Costs?

National health care expenditures (NHEs) in the United States continue to grow at rates outpacing the broader economy: Inflation- and population-adjusted NHEs have increased 1.6 percent faster than the gross domestic product (GDP) between 1990 and 2018. US national health expenditure growth as a share of GDP far outpaces comparable nations in the Organization for Economic Cooperation and Development (17.2 versus 8.9 percent).

Multiple recent analyses have proposed that growth in the prices and intensity of US health care services—rather than in utilization rates or demographic characteristics—is responsible for the disproportionate increases in NHEs relative to global counterparts. The consequences of ever-rising costs amid ubiquitous underinsurance in the US include price-induced deferral of care leading to excess morbidity relative to comparable nations.

These patterns exist despite a robust innovation ecosystem in US health care—implying that novel technologies, in isolation, are insufficient to bend the health care cost curve. Indeed, studies have documented that novel technologies directly increase expenditure growth.

Why is our prolific innovation ecosystem not helping reduce costs? The core issue relates to its apparent failure to enhance net productivity—the relative output generated per unit resource required. In this post, we decompose the concept of innovation to highlight situations in which inventions may not increase net productivity. We begin by describing how this issue has taken on increased urgency amid resource constraints magnified by the COVID-19 pandemic. In turn, we describe incentives for the pervasiveness of productivity-diminishing innovations. Finally, we provide recommendations to promote opportunities for low-cost innovation.

### Net Productivity During The COVID-19 Pandemic

The issue of productivity-enhancing innovation is timely, as health care systems have been overwhelmed by COVID-19. Hospitals in Italy, New York City, and elsewhere have lacked adequate capital resources to care for patients with the disease, sufficient liquidity to invest in sorely needed resources, and enough staff to perform all of the necessary tasks.

The critical constraint in these settings is not technology: In fact, the most advanced technology required to routinely treat COVID-19—the mechanical ventilator—was invented nearly 100 years ago in response to polio (the so-called iron lung). Rather, the bottleneck relates to the total financial and human resources required to use the technology—the denominator of net productivity. The clinical implementation of ventilators has been illustrative: Health care workers are still required to operate ventilators on a nearly one-to-one basis, just like in the mid-twentieth century.

High levels of resources required for implementation of health care technologies constrain the scalability of patient care—such as during respiratory disease outbreaks such as COVID-19. Thus, research to reduce health care costs is the same kind of research we urgently require to promote health care access for patients with COVID-19.

### Types Of Innovation And Their Relationship To Expenditure Growth

The widespread use of novel medical technologies has been highlighted as a central driver of NHE growth in the US. We believe that the continued expansion of health care costs is largely the result of innovation that tends to have low productivity (exhibit 1). We argue that these archetypes—novel widgets tacked on to existing workflows to reinforce traditional care models—are exactly the wrong properties to reduce NHEs at the systemic level.

### Exhibit 1: Relative productivity of innovation subtypes

Source: Authors’ analysis.

### Content Versus Process Innovation

Content (also called technical) innovation refers to the creation of new widgets, such as biochemical agents, diagnostic tools, or therapeutic interventions. Contemporary examples of content innovation include specialty pharmaceuticalsmolecular diagnostics, and advanced interventions and imaging.

These may be contrasted with process innovations, which address the organized sequences of activities that implement content. Classically, these include clinical pathways and protocols. They can address the delivery of care for acute conditions, such as central line infections, sepsis, or natural disasters. Alternatively, they can target chronic conditions through initiatives such as team-based management of hypertension and hospital-at-home models for geriatric care. Other processes include hiring staffdelegating labor, and supply chain management.

### Performance-Enhancing Versus Cost-Reducing Innovation

Performance-enhancing innovations frequently create incremental outcome gains in diagnostic characteristics, such as sensitivity or specificity, or in therapeutic characteristics, such as biomarkers for disease status. Their performance gains often lead to higher prices compared to existing alternatives.

Performance-enhancing innovations can be compared to “non-inferior” innovations capable of achieving outcomes approximating those of existing alternatives, but at reduced cost. Industries outside of medicine, such as the computing industry, have relied heavily on the ability to reduce costs while retaining performance.

In health care though, this pattern of innovation is rare. Since passage of the 2010 “Biosimilars” Act aimed at stimulating non-inferior innovation and competition in therapeutics markets, only 17 agents have been approved, and only seven have made it to market. More than three-quarters of all drugs receiving new patents between 2005 and 2015 were “reissues,” meaning they had already been approved, and the new patent reflected changes to the previously approved formula. Meanwhile, the costs of approved drugs have increased over time, at rates between 4 percent and 7 percent annually.

### Sustaining Versus Disruptive Innovation

Competitive market theory suggests that incumbents and disruptors innovate differently. Incumbents seek sustaining innovations capable of perpetuating their dominance, whereas disruptors pursue innovations capable of redefining traditional business models.

In health care, while disruptive innovations hold the potential to reduce overall health expenditures, often they run counter to the capabilities of market incumbents. For example, telemedicine can deliver care asynchronously, remotely, and virtually, but large-scale brick-and-mortar medical facilities invest enormous capital in the delivery of synchronous, in-house, in-person care (incentivized by facility fees).

The connection between incumbent business models and the innovation pipeline is particularly relevant given that 58 percent of total funding for biomedical research in the US is now derived from private entities, compared with 46 percent a decade prior. It follows that the growing influence of eminent private organizations may favor innovations supporting their market dominance—rather than innovations that are societally optimal.

### Incentives And Repercussions Of High-Cost Innovation

Taken together, these observations suggest that innovation in health care is preferentially designed for revenue expansion rather than for cost reduction. While offering incremental improvements in patient outcomes, therefore creating theoretical value for society, these innovations rarely deliver incremental reductions in short- or long-term costs at the health system level.

For example, content-based, performance-enhancing, additive, sustaining innovations tend to add layers of complexity to the health care system—which in turn require additional administration to manage. The net result is employment growth in excess of outcome improvement, leading to productivity losses. This gap leads to continuously increasing overall expenditures in turn passed along to payers and consumers.

Nonetheless, high-cost innovations are incentivized across health care stakeholders (exhibit 2). From the supply side of innovation, for academic researchers, “breakthrough” and “groundbreaking” innovations constitute the basis for career advancement via funding and tenure. This is despite stakeholders’ frequent inability to generalize early successes to become cost-effective in the clinical setting. As previously discussed, the increasing influence of private entities in setting the medical research agenda is also likely to stimulate innovation benefitting single stakeholders rather than the system.

### Exhibit 2: Incentives promoting low-value innovation

Source: Authors’ analysis adapted from Hofmann BM. Too much technology. BMJ. 2015 Feb 16.

From the demand side of innovation (providers and health systems), a combined allure (to provide “cutting-edge” patient care), imperative (to leave “no stone unturned” in patient care), and profit-motive (to amplify fee-for-service reimbursements) spur participation in a “technological arms-race.” The status quo thus remains as Clay Christensen has written: “Our major health care institutions…together overshoot the level of care actually needed or used by the vast majority of patients.”

Christensen’s observations have been validated during the COVID-19 epidemic, as treatment of the disease requires predominantly century-old technology. By continually adopting innovation that routinely overshoots the needs of most patients, layer by layer, health care institutions are accruing costs that quickly become the burden of society writ large.

### Recommendations To Reduce The Costs Of Health Care Innovation

Henry Aaron wrote in 2002 that “…the forces that have driven up costs are, if anything, intensifying. The staggering fecundity of biomedical research is increasing…[and] always raises expenditures.” With NHEs spiraling ever-higher, urgency to “bend the cost curve” is mounting. Yet, since much biomedical innovation targets the “flat of the [productivity] curve,” alternative forms of innovation are necessary.

The shortcomings in net productivity revealed by the COVID-19 pandemic highlight the urgent need for redesign of health care delivery in this country, and reevaluation of the innovation needed to support it. Specifically, efforts supporting process redesign are critical to promote cost-reducing, substitutive innovations that can inaugurate new and disruptive business models.

Process redesign rarely involves novel gizmos, so much as rejiggering the wiring of, and connections between, existing gadgets. It targets operational changes capable of streamlining workflows, rather than technical advancements that complicate them. As described above, precisely these sorts of “frugal innovations” have led to productivity improvements yielding lower costs in other high-technology industries, such as the computing industry.

Shrank and colleagues recently estimated that nearly one-third of NHEs—almost $1 trillion—were due to preventable waste. Four of the six categories of waste enumerated by the authors—failure in care delivery, failure in care coordination, low-value care, and administrative complexity—represent ripe targets for process innovation, accounting for$610 billion in waste annually, according to Shrank.

Health systems adopting process redesign methods such as continuous improvement and value-based management have exhibited outcome enhancement and expense reduction simultaneously. Internal processes addressed have included supply chain reconfiguration, operational redesign, outlier reconciliation, and resource standardization.

Despite the potential of process innovation, focus on this area (often bundled into “health services” or “quality improvement” research) occupies only a minute fraction of wallet- or mind-share in the biomedical research landscape, accounting for 0.3 percent of research dollars in medicine. This may be due to a variety of barriers beyond minimal funding. One set of barriers is academic, relating to negative perceptions around rigor and a lack of outlets in which to publish quality improvement research. To achieve health care cost containment over the long term, this dimension of innovation must be destigmatized relative to more traditional manners of innovation by the funders and institutions determining the conditions of the research ecosystem.

Another set of barriers is financial: Innovations yielding cost reduction are less “reimbursable” than are innovations fashioned for revenue expansion. This is especially the case in a fee-for-service system where reimbursement is tethered to cost, which creates perverse incentives for health care institutions to overlook cost increases. However, institutions investing in low-cost innovation will be well-positioned in a rapidly approaching future of value-based care—in which the solvency of health care institutions will rely upon their ability to provide economically efficient care.

### Innovating For Cost Control Necessitates Frugality Over Novelty

Restraining US NHEs represents a critical step toward health promotion. Innovation for innovation’s sake—that is content-based, incrementally effective, additive, and sustaining—is unlikely to constrain continually expanding NHEs.

In contrast, process innovation offers opportunities to reduce costs while maintaining high standards of patient care. As COVID-19 stress-tests health care systems across the world, the importance of cost control and productivity amplification for patient care has become apparent.

As such, frugality, rather than novelty, may hold the key to health care cost containment. Redesigning the innovation agenda to stem the tide of ever-rising NHEs is an essential strategy to promote widespread access to care—as well as high-value preventive care—in this country. In the words of investors across Silicon Valley: Cost-reducing innovation is no longer a “nice-to-have,” but a “need-to-have” for the future of health and overall well-being this country.

#### So Do We Need A New Way of Disseminating Scientific Information?  Can Curation Help?

We had high hopes for Science 2.0, in particular the smashing of data and knowledge silos. However the digital age along with 2.0 platforms seemed to excaccerbate this somehow. We still are critically short on analysis!

Old Science 1.0 is still the backbone of all scientific discourse, built on the massive amount of experimental and review literature. However this literature was in analog format, and we moved to a more accesible digital open access format for both publications as well as raw data. However as there was a structure for 1.0, like the Dewey decimal system and indexing, 2.0 made science more accesible and easier to search due to the newer digital formats. Yet both needed an organizing structure; for 1.0 that was the scientific method of data and literature organization with libraries as the indexers. In 2.0 this relied on an army mostly of volunteers who did not have much in the way of incentivization to co-curate and organize the findings and massive literature.

The Intenet and the Web is rapidly adopting a new “Web 3.0” format, with decentralized networks, enhanced virtual experiences, and greater interconnection between people. Here we start the discussion what will the move from Science 2.0, where dissemination of scientific findings was revolutionized and piggybacking on Web 2.0 or social media, to a Science 3.0 format. And what will it involve or what paradigms will be turned upside down?

We have discussed this in other posts such as

Will Web 3.0 Do Away With Science 2.0? Is Science Falling Behind?

and

Curation Methodology – Digital Communication Technology to mitigate Published Information Explosion and Obsolescence in Medicine and Life Sciences

For years the pharmaceutical industry has toyed with the idea of making innovation networks and innovation hubs

It has been the main focus of whole conferences

Tales from the Translational Frontier – Four Unique Approaches to Turning Novel Biology into Investable Innovations @BIOConvention #BIO2018

However it still seems these strategies have not worked

Is it because we did not have an Execution plan? Or we did not understand the lead measures for success?

### Other Related Articles on this Open Access Scientific Journal Include:

Old Industrial Revolution Paradigm of Education Needs to End: How Scientific Curation Can Transform Education

Analysis of Utilizing LPBI Group’s Scientific Curation Platform as an Educational Tool: New Paradigm for Student Engagement

Global Alliance for Genomics and Health Issues Guidelines for Data Siloing and Sharing

Multiple Major Scientific Journals Will Fully Adopt Open Access Under Plan S

eScientific Publishing a Case in Point: Evolution of Platform Architecture Methodologies and of Intellectual Property Development (Content Creation by Curation) Business Model

### Will Web 3.0 Do Away With Science 2.0? Is Science Falling Behind?

Curator: Stephen J. Williams, Ph.D.

UPDATED 4/06/2022

A while back (actually many moons ago) I had put on two posts on this site:

Scientific Curation Fostering Expert Networks and Open Innovation: Lessons from Clive Thompson and others

Twitter is Becoming a Powerful Tool in Science and Medicine

Each of these posts were on the importance of scientific curation of findings within the realm of social media and the Web 2.0; a sub-environment known throughout the scientific communities as Science 2.0, in which expert networks collaborated together to produce massive new corpus of knowledge by sharing their views, insights on peer reviewed scientific findings. And through this new media, this process of curation would, in itself generate new ideas and new directions for research and discovery.

The platform sort of looked like the image below:

This system lied above a platform of the original Science 1.0, made up of all the scientific journals, books, and traditional literature:

Previous image source: PeerJ.com

To index the massive and voluminous research and papers beyond the old Dewey Decimal system, a process of curation was mandatory. The dissemination of this was a natural for the new social media however the cost had to be spread out among numerous players. Journals, faced with the high costs of subscriptions and their only way to access this new media as an outlet was to become Open Access, a movement first sparked by journals like PLOS and PeerJ but then begrudingly adopted throughout the landscape. But with any movement or new adoption one gets the Good the Bad and the Ugly (as described in my cited, above, Clive Thompson article). The bad side of Open Access Journals were

1. costs are still assumed by the individual researcher not by the journals
2. the arise of the numerous Predatory Journals

Even PeerJ, in their column celebrating an anniversary of a year’s worth of Open Access success stories, lamented the key issues still facing Open Access in practice

• which included the cost and the rise of predatory journals.

In essence, Open Access and Science 2.0 sprung full force BEFORE anyone thought of a way to defray the costs

### Can Web 3.0 Finally Offer a Way to Right the Issues Facing High Costs of Scientific Publishing?

What is Web 3.0?

From Wikipedia: https://en.wikipedia.org/wiki/Web3

Web 1.0 and Web 2.0 refer to eras in the history of the Internet as it evolved through various technologies and formats. Web 1.0 refers roughly to the period from 1991 to 2004, where most websites were static webpages, and the vast majority of users were consumers, not producers, of content.[6][7] Web 2.0 is based around the idea of “the web as platform”,[8] and centers on user-created content uploaded to social-networking services, blogs, and wikis, among other services.[9] Web 2.0 is generally considered to have begun around 2004, and continues to the current day.[8][10][4]

### Terminology

The term “Web3”, specifically “Web 3.0”, was coined by Ethereum co-founder Gavin Wood in 2014.[1] In 2020 and 2021, the idea of Web3 gained popularity[citation needed]. Particular interest spiked towards the end of 2021, largely due to interest from cryptocurrency enthusiasts and investments from high-profile technologists and companies.[4][5] Executives from venture capital firm Andreessen Horowitz travelled to Washington, D.C. in October 2021 to lobby for the idea as a potential solution to questions about Internet regulation with which policymakers have been grappling.[11]

Web3 is distinct from Tim Berners-Lee‘s 1999 concept for a semantic web, which has also been called “Web 3.0”.[12] Some writers referring to the decentralized concept usually known as “Web3” have used the terminology “Web 3.0”, leading to some confusion between the two concepts.[2][3] Furthermore, some visions of Web3 also incorporate ideas relating to the semantic web.[13][14]

## Concept

Web3 revolves around the idea of decentralization, which proponents often contrast with Web 2.0, wherein large amounts of the web’s data and content are centralized in the fairly small group of companies often referred to as Big Tech.[4]

Specific visions for Web3 differ, but all are heavily based in blockchain technologies, such as various cryptocurrencies and non-fungible tokens (NFTs).[4] Bloomberg described Web3 as an idea that “would build financial assets, in the form of tokens, into the inner workings of almost anything you do online”.[15] Some visions are based around the concepts of decentralized autonomous organizations (DAOs).[16] Decentralized finance (DeFi) is another key concept; in it, users exchange currency without bank or government involvement.[4] Self-sovereign identity allows users to identify themselves without relying on an authentication system such as OAuth, in which a trusted party has to be reached in order to assess identity.[17]

## Reception

Technologists and journalists have described Web3 as a possible solution to concerns about the over-centralization of the web in a few “Big Tech” companies.[4][11] Some have expressed the notion that Web3 could improve data securityscalability, and privacy beyond what is currently possible with Web 2.0 platforms.[14] Bloomberg states that sceptics say the idea “is a long way from proving its use beyond niche applications, many of them tools aimed at crypto traders”.[15] The New York Times reported that several investors are betting $27 billion that Web3 “is the future of the internet”.[18][19] Some companies, including Reddit and Discord, have explored incorporating Web3 technologies into their platforms in late 2021.[4][20] After heavy user backlash, Discord later announced they had no plans to integrate such technologies.[21] The company’s CEO, Jason Citron, tweeted a screenshot suggesting it might be exploring integrating Web3 into their platform. This led some to cancel their paid subscriptions over their distaste for NFTs, and others expressed concerns that such a change might increase the amount of scams and spam they had already experienced on crypto-related Discord servers.[20] Two days later, Citron tweeted that the company had no plans to integrate Web3 technologies into their platform, and said that it was an internal-only concept that had been developed in a company-wide hackathon.[21] Some legal scholars quoted by The Conversation have expressed concerns over the difficulty of regulating a decentralized web, which they reported might make it more difficult to prevent cybercrimeonline harassmenthate speech, and the dissemination of child abuse images.[13] But, the news website also states that, “[decentralized web] represents the cyber-libertarian views and hopes of the past that the internet can empower ordinary people by breaking down existing power structures.” Some other critics of Web3 see the concept as a part of a cryptocurrency bubble, or as an extension of blockchain-based trends that they see as overhyped or harmful, particularly NFTs.[20] Some critics have raised concerns about the environmental impact of cryptocurrencies and NFTs. Others have expressed beliefs that Web3 and the associated technologies are a pyramid scheme.[5] Kevin Werbach, author of The Blockchain and the New Architecture of Trust,[22] said that “many so-called ‘web3’ solutions are not as decentralized as they seem, while others have yet to show they are scalable, secure and accessible enough for the mass market”, adding that this “may change, but it’s not a given that all these limitations will be overcome”.[23] David Gerard, author of Attack of the 50 Foot Blockchain,[24] told The Register that “web3 is a marketing buzzword with no technical meaning. It’s a melange of cryptocurrencies, smart contracts with nigh-magical abilities, and NFTs just because they think they can sell some monkeys to morons”.[25] ##### Below is an article from MarketWatch.com Distributed Ledger series about the different forms and cryptocurrencies involved #### by Frances Yue, Editor of Distributed Ledger, Marketwatch.com Clayton Gardner, co-CEO of crypto investment management firm Titan, told Distributed Ledger that as crypto embraces broader adoption, he expects more institutions to bypass bitcoin and invest in other blockchains, such as Ethereum, Avalanche, and Terra in 2022. which all boast smart-contract features. Bitcoin traditionally did not support complex smart contracts, which are computer programs stored on blockchains, though a major upgrade in November might have unlocked more potential. “Bitcoin was originally seen as a macro speculative asset by many funds and for many it still is,” Gardner said. “If anything solidifies its use case, it’s a store of value. It’s not really used as originally intended, perhaps from a medium of exchange perspective.” For institutions that are looking for blockchains that can “produce utility and some intrinsic value over time,” they might consider some other smart contract blockchains that have been driving the growth of decentralized finance and web 3.0, the third generation of the Internet, according to Gardner. Bitcoin is still one of the most secure blockchains, but I think layer-one, layer-two blockchains beyond Bitcoin, will handle the majority of transactions and activities from NFT (nonfungible tokens) to DeFi,“ Gardner said. “So I think institutions see that and insofar as they want to put capital to work in the coming months, I think that could be where they just pump the capital.” ### Decentralized social media？ The price of Decentralized Social, or DeSo, a cryptocurrency powering a blockchain that supports decentralized social media applications, surged roughly 74% to about$164 from $94, after Deso was listed at Coinbase Pro on Monday, before it fell to about$95, according to CoinGecko.

In the eyes of Nader Al-Naji, head of the DeSo foundation, decentralized social media has the potential to be “a lot bigger” than decentralized finance.

“Today there are only a few companies that control most of what we see online,” Al-Naji told Distributed Ledger in an interview. But DeSo is “creating a lot of new ways for creators to make money,” Al-Naji said.

“If you find a creator when they’re small, or an influencer, you can invest in that, and then if they become bigger and more popular, you make money and they make and they get capital early on to produce their creative work,” according to AI-Naji.

BitClout, the first application that was created by AI-Naji and his team on the DeSo blockchain, had initially drawn controversy, as some found that they had profiles on the platform without their consent, while the application’s users were buying and selling tokens representing their identities. Such tokens are called “creator coins.”

AI-Naji responded to the controversy saying that DeSo now supports more than 200 social-media applications including Bitclout. “I think that if you don’t like those features, you now have the freedom to use any app you want. Some apps don’t have that functionality at all.”

But Before I get to the “selling monkeys to morons” quote,

THE GOOD, THE BAD, AND THE UGLY

#### THE GOOD

My foray into Science 2.0 and then pondering what the movement into a Science 3.0 led me to an article by Dr. Vladimir Teif, who studies gene regulation and the nucleosome, as well as creating a worldwide group of scientists who discuss matters on chromatin and gene regulation in a journal club type format.

Fragile Nucleosome is an international community of scientists interested in chromatin and gene regulation. Fragile Nucleosome is active in several spaces: one is the Discord server where several hundred scientists chat informally on scientific matters. You can join the Fragile Nucleosome Discord server. Another activity of the group is the organization of weekly virtual seminars on Zoom. Our webinars are usually conducted on Wednesdays 9am Pacific time (5pm UK, 6pm Central Europe). Most previous seminars have been recorded and can be viewed at our YouTube channel. The schedule of upcoming webinars is shown below. Our third activity is the organization of weekly journal clubs detailed at a separate page (Fragile Nucleosome Journal Club).

His lab site is at https://generegulation.org/ but had published a paper describing what he felt what the #science2_0 to #science3_0 transition would look like (see his blog page on this at https://generegulation.org/open-science/).

### This concept of science 3.0 he had coined back in 2009.  As Dr Teif had mentioned

So essentially I first introduced this word Science 3.0 in 2009, and since then we did a lot to implement this in practice. The Twitter account @generegulation is also one of examples

### This is curious as we still have an ill defined concept of what #science3_0 would look like but it is a good read nonetheless.

His paper,  entitled “Science 3.0: Corrections to the Science 2.0 paradigm” is on the Cornell preprint server at https://arxiv.org/abs/1301.2522

Abstract

### Science 3.0: Corrections to the Science 2.0 paradigm

The concept of Science 2.0 was introduced almost a decade ago to describe the new generation of online-based tools for researchers allowing easier data sharing, collaboration and publishing. Although technically sound, the concept still does not work as expected. Here we provide a systematic line of arguments to modify the concept of Science 2.0, making it more consistent with the spirit and traditions of science and Internet. Our first correction to the Science 2.0 paradigm concerns the open-access publication models charging fees to the authors. As discussed elsewhere, we show that the monopoly of such publishing models increases biases and inequalities in the representation of scientific ideas based on the author’s income. Our second correction concerns post-publication comments online, which are all essentially non-anonymous in the current Science 2.0 paradigm. We conclude that scientific post-publication discussions require special anonymization systems. We further analyze the reasons of the failure of the current post-publication peer-review models and suggest what needs to be changed in Science 3.0 to convert Internet into a large journal club. [bold face added]
In this paper it is important to note the transition of a science 1.0, which involved hard copy journal publications usually only accessible in libraries to a more digital 2.0 format where data, papers, and ideas could be easily shared among networks of scientists.
As Dr. Teif states, the term “Science 2.0” had been coined back in 2009, and several influential journals including Science, Nature and Scientific American endorsed this term and suggested scientists to move online and their discussions online.  However, even at present there are thousands on this science 2.0 platform, Dr Teif notes the number of scientists subscribed to many Science 2.0 networking groups such as on LinkedIn and ResearchGate have seemingly saturated over the years, with little new members in recent times.
The consensus is that science 2.0 networking is:
1. good because it multiplies the efforts of many scientists, including experts and adds to the scientific discourse unavailable on a 1.0 format
2. that online data sharing is good because it assists in the process of discovery (can see this evident with preprint servers, bio-curated databases, Github projects)
3. open-access publishing is beneficial because free access to professional articles and open-access will be the only publishing format in the future (although this is highly debatable as many journals are holding on to a type of “hybrid open access format” which is not truly open access
4. only sharing of unfinished works and critiques or opinions is good because it creates visibility for scientists where they can receive credit for their expert commentary

### A.  Science 3.0 Still Needs Peer Review

Peer review of scientific findings will always be an imperative in the dissemination of well-done, properly controlled scientific discovery.  As Science 2.0 relies on an army of scientific volunteers, the peer review process also involves an army of scientific experts who give their time to safeguard the credibility of science, by ensuring that findings are reliable and data is presented fairly and properly.  It has been very evident, in this time of pandemic and the rapid increase of volumes of preprint server papers on Sars-COV2, that peer review is critical.  Many of these papers on such preprint servers were later either retracted or failed a stringent peer review process.

Now many journals of the 1.0 format do not generally reward their peer reviewers other than the self credit that researchers use on their curriculum vitaes.  Some journals, like the MDPI journal family, do issues peer reviewer credits which can be used to defray the high publication costs of open access (one area that many scientists lament about the open access movement; where the burden of publication cost lies on the individual researcher).

An issue which is highlighted is the potential for INFORMATION NOISE regarding the ability to self publish on Science 2.0 platforms.

### The NEW BREED was born in 4/2012

An ongoing effort on this platform, https://pharmaceuticalintelligence.com/, is to establish a scientific methodology for curating scientific findings where one the goals is to assist to quell the information noise that can result from the massive amounts of new informatics and data occurring in the biomedical literature.

### Greylock Partners Announces Unique $500 Million Venture to act as Seed Capital Funding for Earliest Stage Startups Reporter: Stephen J. Williams, Ph.D. Greylock Partners CEO Reid Hoffman announces a$500 million fund to help the earliest stage startups find capital.

See video below:

https://www.bloomberg.com/news/videos/2021-09-24/intv-sara-guoh-greylock-partners-video

See transcript from Bloomberg.com

00:00This is a lot of money for seed stage deals which is typicallysmaller. Why do you want to make seed such a priority.

00:09So see it has always been a priority for us. We’ve been activeat this stage for a long time and some of our biggest wins

00:15historically have been incubation and seed. So I think companieslike Workday and Palo Alto Networks and more recently abnormal

00:21and Snorkel. And then this year 70 percent of our investmentsyou must mints or seeds before we announce this fund. And so

00:29when we saw this level of opportunity we also want to make surewe had enough funding to really back entrepreneurs and to

00:36support them through their journey and make sure entrepreneursalso know they have different options at the seed for the type

00:41of partners they work with. Now at the seed stage you’re talkingabout companies in their infancy. How early are you investing. I

00:49mean is this ideas on a napkin stage with a couple ofentrepreneurs that you believe in or is it beyond that.

00:58So there definitely is a whole range. We don’t catch everysingle person. Like the day they left their job. Right. But you

01:04know abnormal was to see it in 2018 when it was a slide deck andtwo co-founders. We backed another company recently and self on

01:12first capital. That was a repeat founder we have history with.Similarly no product yet. Just an idea and an early team. And so

01:20the range of when we do see it really depends on when weencounter companies. We do like to get to know people as early

01:26as possible. And sometimes that’s the right time for us to writethe check. Obviously Greylock is a multi-stage venture venture

01:32capital firm and I think founders might have the question here.You know if you give me the seed funding we’ll follow on and

01:38reserves come out of that same bucket. And what could this meanin terms of a longer term relationship with Greylock. What’s the

01:46answer to that. So the first thing I’d start with is seeds forus our core investments. Right. So many firms look at them as

01:54options to then follow on. We look at seeds as investments we’retrying to make money on. We’re building a relationship for the

02:01long term to begin with. Right. So. So I’d start with that thenI’d say it is a third of our fund. So it is a big piece of our

02:09investing. And and you know there are many instances where wethen follow on and invest even more because our conviction

02:16continues or even grows. But the point of us doing seed is notjust a follow on it’s to make that investment. How big is each

02:24deal. I mean would you say that seed is the new series A.I think I think that.

02:33Well let’s see the market data would tell us that round sizesoverall have increased for the same level of progress. And I

02:41think that makes sense right. And the reason being the markethas become a lot smarter at the attractiveness of early stage

02:48technology opportunities. And so great returns in tech venturecapital over many years mean there’s more capital than ever and

02:57people are savvier about software and Internet companies. ButI’d say there is you know I think kind of the noble creature

03:04doesn’t matter so much. We think of it as being the firstinstitutional partner to go to a set of founders. The world is

03:12changing quickly. I mean we’re still in the middle of apandemic. And who would’ve known that you know working from home

03:16was going to be a thing 18 months ago. What are the trends thatyou are most excited about right now that you’re doubling down

03:22on at the seed stage.Yeah. So we invest across the technology spectrum business

03:30consumer. The one you just mentioned in terms of just the seachange of the pandemic in terms of how we do our work together

03:36as one. I’m really excited about but we’ve been we’ve beeninvesting in let’s say just this. There’s a shortage globally

03:44because the pandemic. But even before of human connection andand intimacy and people look for it online. And so we invest in

03:53companies like Dischord and Common ROOM and Promotion that helppeople connect more online. So that’s when we’ll continue to

04:00invest in. And then of course we’re investing across all of yourusual range of SAS social data A.I. etc. and then spending more

04:10and more time in fintech and crypto in particular. Now what arethe potential problems with seed stage. Is that at a certain

04:16point as the company develops maybe they pivot they change. Overtime they could potentially ultimately compete with another one

04:23of your core portfolio companies. How do you manage that.So it’s a good question but it is also something that doesn’t

04:30only happen at the scene and funnily enough Greylock has been aninvestor in several companies that were like great companies

04:37post pivot right. So like first semester and discord and nextdoor after they decided to be what they are today. And so that

04:46you know I’d start with the premise of our our philosophy isthat the company should do what’s best for the company. And we

04:53know our our philosophy is to be fully behind companies and notto go invest in a bunch of competitors in a sector just because

04:59we like this sector. But if that were to happen you know wewould we would just divide those interests within the firm and

05:06like make sure that there’s no information flow and just addressit in a reasonable way. I’ve talked with many of your partners

05:12over the years about investing in more women. And I’m curioushow you look at it as an opportunity to potentially you know

05:22spread the wealth a little bit across more women entrepreneurspeople of color people who historically haven’t gotten a chance

05:29in Silicon Valley and Silicon Valley hasn’t benefited from theirideas.

05:34OK. So I’d say this is an issue that’s near and dear to myheart. We are working on it. Two of the last three founders I

05:40backed are women. One is the seed stage founder. One of thefounders. I backed at the seed stage is Hispanic. But. But I

05:49would say you know one thing I want to make sure is clear. Likeyou want to back great founders from diverse backgrounds across

05:56the spectrum. And like we wouldn’t like do it more in seedbecause seed isn’t important. Because it is important to us.

06:02Right. It’s just across the portfolio. This is a priority.

From TechStartups

#### Greylock Partners raises $500 million to invest in seed-stage startups Nickie LouisePOSTED ON SEPTEMBER 22, 2021 Greylock Partners has raised$500 million to invest exclusively in seed-stage startups. The announcement comes a year after the firm raised $1 billion for its 16th flagship fund to invest in early- and growth-stage tech startups. Guo and general partner Saam Motamedi said in an interview the fund is part of an expansion of a$1.1 billion fund, which we reported last year, to $1.6 billion, The Information reported. The funding is among the industry’s largest devoted to seed investments, which often represent a startup’s first outside capital. The pool of funds will give the 56-year-old venture capital firm the ability to write large checks at “lean-in valuations” and emphasize its commitment to early-stage investing, said general partner Sarah Guo. In a thread post on Twitter, Greylock said, “We at @GreylockVC are excited to announce we’ve raised$500M dedicated to seed investing. This is the industry’s largest pool of venture capital dedicated to backing founders at day one.”

Press Release from Grelock

#### More articles on Venture Capital on this Online Open Access Journal Include:

youngStartup Ventures “Where Innovation Meets Capital” – First Round of VC Firms Announced, August 4th – 6th, 2020.

Real Time Coverage @BIOConvention #BIO2019: Dealmakers’ Intentions: 2019 Market Outlook June 5 Philadelphia PA

Podcast Episodes by THE EUROPEAN VC

Real Time Coverage @BIOConvention #BIO2019: June 4 Morning Sessions; Global Biotech Investment & Public-Private Partnerships

37th Annual J.P. Morgan HEALTHCARE CONFERENCE: News at #JPM2019 for Jan. 8, 2019: Deals and Announcements

Tweet Collection by @pharma_BI and @AVIVA1950 and Re-Tweets for e-Proceedings 14th Annual BioPharma & Healthcare Summit, Friday, September 4, 2020, 8 AM EST to 3-30 PM EST – Virtual Edition

## NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

### NCCN Shares Latest Expert Recommendations for Prostate Cancer in Spanish and Portuguese

Reporter: Stephen J. Williams, Ph.D.

Currently many biomedical texts and US government agency guidelines are only offered in English or only offered in different languages upon request. However Spanish is spoken in a majority of countries worldwide and medical text in that language would serve as an under-served need. In addition, Portuguese is the main language in the largest country in South America, Brazil.

The LPBI Group and others have noticed this need for medical translation to other languages. Currently LPBI Group is translating their medical e-book offerings into Spanish (for more details see https://pharmaceuticalintelligence.com/vision/)

Below is an article on The National Comprehensive Cancer Network’s decision to offer their cancer treatment guidelines in Spanish and Portuguese.

PLYMOUTH MEETING, PA [8 September, 2021] — The National Comprehensive Cancer Network® (NCCN®)—a nonprofit alliance of leading cancer centers in the United States—announces recently-updated versions of evidence- and expert consensus-based guidelines for treating prostate cancer, translated into Spanish and Portuguese. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) feature frequently updated cancer treatment recommendations from multidisciplinary panels of experts across NCCN Member Institutions. Independent studies have repeatedly found that following these recommendations correlates with better outcomes and longer survival.

“Everyone with prostate cancer should have access to care that is based on current and reliable evidence,” said Robert W. Carlson, MD, Chief Executive Officer, NCCN. “These updated translations—along with all of our other translated and adapted resources—help us to define and advance high-quality, high-value, patient-centered cancer care globally, so patients everywhere can live better lives.”

Prostate cancer is the second most commonly occurring cancer in men, impacting more than a million people worldwide every year.[1] In 2020, the NCCN Guidelines® for Prostate Cancer were downloaded more than 200,000 times by people outside of the United States. Approximately 47 percent of registered users for NCCN.org are located outside the U.S., with Brazil, Spain, and Mexico among the top ten countries represented.

“NCCN Guidelines are incredibly helpful resources in the work we do to ensure cancer care across Latin America meets the highest standards,” said Diogo Bastos, MD, and Andrey Soares, MD, Chair and Scientific Director of the Genitourinary Group of The Latin American Cooperative Oncology Group (LACOG). The organization has worked with NCCN in the past to develop Latin American editions of the NCCN Guidelines for Breast Cancer, Colon Cancer, Non-Small Cell Lung Cancer, Prostate Cancer, Multiple Myeloma, and Rectal Cancer, and co-hosted a webinar on “Management of Prostate Cancer for Latin America” earlier this year. “We appreciate all of NCCN’s efforts to make sure these gold-standard recommendations are accessible to non-English speakers and applicable for varying circumstances.”

NCCN also publishes NCCN Guidelines for Patients®, containing the same treatment information in non-medical terms, intended for patients and caregivers. The NCCN Guidelines for Patients: Prostate Cancer were found to be among the most trustworthy sources of information online according to a recent international study. These patient guidelines have been divided into two books, covering early and advanced prostate cancer; both have been translated into Spanish and Portuguese as well.

NCCN collaborates with organizations across the globe on resources based on the NCCN Guidelines that account for local accessibility, consideration of metabolic differences in populations, and regional regulatory variation. They can be downloaded free-of-charge for non-commercial use at NCCN.org/global or via the Virtual Library of NCCN Guidelines App. Learn more and join the conversation with the hashtag #NCCNGlobal.

[1] Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, in press. The online GLOBOCAN 2018 database is accessible at http://gco.iarc.fr/, as part of IARC’s Global Cancer Observatory.

About the National Comprehensive Cancer Network

The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of leading cancer centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating quality, effective, efficient, and accessible cancer care so patients can live better lives. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) provide transparent, evidence-based, expert consensus recommendations for cancer treatment, prevention, and supportive services; they are the recognized standard for clinical direction and policy in cancer management and the most thorough and frequently-updated clinical practice guidelines available in any area of medicine. The NCCN Guidelines for Patients® provide expert cancer treatment information to inform and empower patients and caregivers, through support from the NCCN Foundation®. NCCN also advances continuing educationglobal initiativespolicy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

### Developing Machine Learning Models for Prediction of Onset of Type-2 Diabetes

Reporter: Amandeep Kaur, B.Sc., M.Sc.

A recent study reports the development of an advanced AI algorithm which predicts up to five years in advance the starting of type 2 diabetes by utilizing regularly collected medical data. Researchers described their AI model as notable and distinctive based on the specific design which perform assessments at the population level.

The first author Mathieu Ravaut, M.Sc. of the University of Toronto and other team members stated that “The main purpose of our model was to inform population health planning and management for the prevention of diabetes that incorporates health equity. It was not our goal for this model to be applied in the context of individual patient care.”

Research group collected data from 2006 to 2016 of approximately 2.1 million patients treated at the same healthcare system in Ontario, Canada. Even though the patients were belonged to the same area, the authors highlighted that Ontario encompasses a diverse and large population.

The newly developed algorithm was instructed with data of approximately 1.6 million patients, validated with data of about 243,000 patients and evaluated with more than 236,000 patient’s data. The data used to improve the algorithm included the medical history of each patient from previous two years- prescriptions, medications, lab tests and demographic information.

When predicting the onset of type 2 diabetes within five years, the algorithm model reached a test area under the ROC curve of 80.26.

The authors reported that “Our model showed consistent calibration across sex, immigration status, racial/ethnic and material deprivation, and a low to moderate number of events in the health care history of the patient. The cohort was representative of the whole population of Ontario, which is itself among the most diverse in the world. The model was well calibrated, and its discrimination, although with a slightly different end goal, was competitive with results reported in the literature for other machine learning–based studies that used more granular clinical data from electronic medical records without any modifications to the original test set distribution.”

This model could potentially improve the healthcare system of countries equipped with thorough administrative databases and aim towards specific cohorts that may encounter the faulty outcomes.

Research group stated that “Because our machine learning model included social determinants of health that are known to contribute to diabetes risk, our population-wide approach to risk assessment may represent a tool for addressing health disparities.”

Sources:

Reference:

Ravaut M, Harish V, Sadeghi H, et al. Development and Validation of a Machine Learning Model Using Administrative Health Data to Predict Onset of Type 2 Diabetes. JAMA Netw Open. 2021;4(5):e2111315. doi:10.1001/jamanetworkopen.2021.11315 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2780137

### AI in Drug Discovery: Data Science and Core Biology @Merck &Co, Inc., @GNS Healthcare, @QuartzBio, @Benevolent AI and Nuritas

Reporters: Aviva Lev-Ari, PhD, RN and Irina Robu, PhD

https://pharmaceuticalintelligence.com/2020/08/27/ai-in-drug-discovery-data-science-and-core-biology-merck-co-inc-gns-healthcare-quartzbio-benevolent-ai-and-nuritas/

### Can Blockchain Technology and Artificial Intelligence Cure What Ails Biomedical Research and Healthcare

Curator: Stephen J. Williams, Ph.D.

https://pharmaceuticalintelligence.com/2018/12/10/can-blockchain-technology-and-artificial-intelligence-cure-what-ails-biomedical-research-and-healthcare/

### HealthCare focused AI Startups from the 100 Companies Leading the Way in A.I. Globally

Reporter: Aviva Lev-Ari, PhD, RN

### AI in Psychiatric Treatment – Using Machine Learning to Increase Treatment Efficacy in Mental Health

Reporter: Aviva Lev- Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/06/04/ai-in-psychiatric-treatment-using-machine-learning-to-increase-treatment-efficacy-in-mental-health/

### Vyasa Analytics Demos Deep Learning Software for Life Sciences at Bio-IT World 2018 – Vyasa’s booth (#632)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/05/10/vyasa-analytics-demos-deep-learning-software-for-life-sciences-at-bio-it-world-2018-vyasas-booth-632/

### New Diabetes Treatment Using Smart Artificial Beta Cells

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2017/11/08/new-diabetes-treatment-using-smart-artificial-beta-cells/

## Multiple Major Scientific Journals Will Fully Adopt Open Access Under Plan S

### Multiple Major Scientific Journals Will Fully Adopt Open Access Under Plan S

Curator: Stephen J. Williams, PhD

More university library systems have been pressuring major scientific publishing houses to adopt an open access strategy in order to reduce the library system’s budgetary burdens.  In fact some major universities like the California system of universities (University of California and other publicly funded universities in the state as well as Oxford University in the UK, even MIT have decided to become their own publishing houses in a concerted effort to fight back against soaring journal subscription costs as well as the costs burdening individual scientists and laboratories (some of the charges to publish one paper can run as high as 8000.00 USD while the journal still retains all the rights of distribution of the information). Therefore more and more universities, as well as concerted efforts by the European Union and the US government are mandating that scientific literature be published in an open access format. The results of this pressure are evident now as major journals like Nature, JBC, and others have plans to go fully open access in 2021. Below is a listing and news reports of some of these journals plans to undertake a full Open Access Format. #### Nature to join open-access Plan S, publisher says 09 APRIL 2020 UPDATE 14 APRIL 2020 Springer Nature says it commits to offering researchers a route to publishing open access in Nature and most Nature-branded journals from 2021. ### Richard Van Noorden After a change in the rules of the bold open-access (OA) initiative known as Plan S, publisher Springer Nature said on 8 April that many of its non-OA journals — including Nature — were now committed to joining the plan, pending discussion of further technical details. This means that Nature and other Nature-branded journals that publish original research will now look to offer an immediate OA route after January 2021 to scientists who want it, or whose funders require it, a spokesperson says. (Nature is editorially independent of its publisher, Springer Nature.) “We are delighted that Springer Nature is committed to transitioning its journals to full OA,” said Robert Kiley, head of open research at the London-based biomedical funder Wellcome, and the interim coordinator for Coalition S, a group of research funders that launched Plan S in 2018. But Lisa Hinchliffe, a librarian at the University of Illinois at Urbana–Champaign, says the changed rules show that publishers have successfully pushed back against Plan S, softening its guidelines and expectations — in particular in the case of hybrid journals, which publish some content openly and keep other papers behind paywalls. “The coalition continues to take actions that rehabilitate hybrid journals into compliance rather than taking the hard line of unacceptability originally promulgated,” she says. ## What is Plan S? The goal of Plan S is to make scientific and scholarly works free to read as soon as they are published. So far, 17 national funders, mostly in Europe, have joined the initiative, as have the World Health Organization and two of the world’s largest private biomedical funders — the Bill & Melinda Gates Foundation and Wellcome. The European Commission will also implement an OA policy that is aligned with Plan S. Together, this covers around 7% of scientific articles worldwide, according to one estimate. A 2019 report published by the publishing-services firm Clarivate Analytics suggested that 35% of the research content published in Nature in 2017 acknowledged a Plan S funder (see ‘Plan S papers’). ## PLAN S PAPERS  Journal Total papers in 2017 % acknowledging Plan S funder Nature 290 35% Science 235 31% Proc. Natl Acad. Sci. USA 639 20% Source: The Plan S footprint: Implications for the scholarly publishing landscape (Institute for Scientific Information, 2019) #### Opening ASBMB publications freely to all Lila M. Gierasch, Editor-in-Chief, Journal of Biological Chemistry Kerry-Anne Rye, Editors-in-Chief, Journal of Lipid Research and Alma L. Burlingame, Editor-in-Chief, Molecular and Cellular Proteomics We are extremely excited to announce on behalf of the American Society for Biochemistry and Molecular Biology (ASBMB) that the Journal of Biological Chemistry (JBC), Molecular & Cellular Proteomics (MCP), and the Journal of Lipid Research (JLR) will be published as fully open-access journals beginning in January 2021. This is a landmark decision that will have huge impact for readers and authors. As many of you know, many researchers have called for journals to become open access to facilitate scientific progress, and many funding agencies across the globe are either already requiring or considering a requirement that all scientific publications based on research they support be published in open-access journals. The ASBMB journals have long supported open access, making the accepted author versions of manuscripts immediately and permanently available, allowing authors to opt in to the immediate open publication of the final version of their paper, and endorsing the goals of the larger open-access movement (1). However, we are no longer satisfied with these measures. To live up to our goals as a scientific society, we want to freely distribute the scientific advances published in JBC, MCP, and JLR as widely and quickly as possible to support the scientific community. How better can we facilitate the dissemination of new information than to make our scientific content freely open to all? For ASBMB journals and others who have contemplated or made the transition to publishing all content open access, achieving this milestone generally requires new financial mechanisms. In the case of the ASBMB journals, the transition to open access is being made possible by a new partnership with Elsevier, whose established capabilities and economies of scale make the costs associated with open-access publication manageable for the ASBMB (2). However, we want to be clear: The ethos of ASBMB journals will not change as a consequence of this new alliance. The journals remain society journals: The journals are owned by the society, and all scientific oversight for the journals will remain with ASBMB and its chosen editors. Peer review will continue to be done by scientists reviewing the work of scientists, carried out by editorial board members and external referees on behalf of the ASBMB journal leadership. There will be no intervention in this process by the publisher. Although we will be saying “goodbye” to many years of self-publishing (115 in the case of JBC), we are certain that we are taking this big step for all the right reasons. The goal for JBC, MCP, and JLR has always been and will remain to help scientists advance their work by rapidly and effectively disseminating their results to their colleagues and facilitating the discovery of new findings (13), and open access is only one of many innovations and improvements in science publishing that could help the ASBMB journals achieve this goal. We have been held back from fully exploring these options because of the challenges of “keeping the trains running” with self-publication. In addition to allowing ASBMB to offer all the content in its journals to all readers freely and without barriers, the new partnership with Elsevier opens many doors for ASBMB publications, from new technology for manuscript handling and production, to facilitating reader discovery of content, to deploying powerful analytics to link content within and across publications, to new opportunities to improve our peer review mechanisms. We have all dreamed of implementing these innovations and enhancements (45) but have not had the resources or infrastructure needed. A critical aspect of moving to open access is how this decision impacts the cost to authors. Like most publishers that have made this transition, we have been extremely worried that achieving open-access publishing would place too big a financial burden on our authors. We are pleased to report the article-processing charges (APCs) to publish in ASBMB journals will be on the low end within the range of open-access fees:2,000 for members and \$2,500 for nonmembers. While slightly higher than the cost an author incurs now if the open-access option is not chosen, these APCs are lower than the current charges for open access on our existing platform.

References

1.↵ Gierasch, L. M., Davidson, N. O., Rye, K.-A., and Burlingame, A. L. (2019) For the sake of science. J. Biol. Chem. 294, 2976 FREE Full Text

2.↵ Gierasch, L. M. (2017) On the costs of scientific publishing. J. Biol. Chem. 292, 16395–16396 FREE Full Text

3.↵ Gierasch, L. M. (2020) Faster publication advances your science: The three R’s. J. Biol. Chem. 295, 672 FREE Full Text

4.↵ Gierasch, L. M. (2017) JBC is on a mission to facilitate scientific discovery. J. Biol. Chem. 292, 6853–6854 FREE Full Text

5.↵ Gierasch, L. M. (2017) JBC’s New Year’s resolutions: Check them off! J. Biol. Chem. 292, 21705–21706 FREE Full Text

#### Open access publishing under Plan S to start in 2021

BMJ

2019; 365 doi: https://doi.org/10.1136/bmj.l2382 (Published 31 May 2019)Cite this as: BMJ 2019;365:l2382

From 2021, all research funded by public or private grants should be published in open access journals, according to a group of funding agencies called coALition S.1

The plan is the final version of a draft that was put to public consultation last year and attracted 344 responses from institutions, almost half of them from the UK.2 The responses have been considered and some changes made to the new system called Plan S, a briefing at the Science Media Centre in London was told on 29 May.

The main change has been to delay implementation for a year, to 1 January 2021, to allow more time for those involved—researchers, funders, institutions, publishers, and repositories—to make the necessary changes, said John-Arne Røttingen, chief executive of the Research Council of Norway.

“All research contracts signed after that date should include the obligation to publish in an open access journal,” he said. T……

#### Plan S

Not to be confused with S-Plan.

Plan S is an initiative for open-access science publishing launched in 2018[1][2] by “cOAlition S”,[3] a consortium of national research agencies and funders from twelve European countries. The plan requires scientists and researchers who benefit from state-funded research organisations and institutions to publish their work in open repositories or in journals that are available to all by 2021.[4] The “S” stands for “shock”.[5]

## Principles of the plan

The plan is structured around ten principles.[3] The key principle states that by 2021, research funded by public or private grants must be published in open-access journals or platforms, or made immediately available in open access repositories without an embargo. The ten principles are:

1. authors should retain copyrighton their publications, which must be published under an open license such as Creative Commons;
2. the members of the coalition should establish robust criteria and requirements for compliant open access journals and platforms;
3. they should also provide incentives for the creation of compliant open access journals and platforms if they do not yet exist;
4. publication fees should be covered by the funders or universities, not individual researchers;
5. such publication fees should be standardized and capped;
6. universities, research organizations, and libraries should align their policies and strategies;
7. for books and monographs, the timeline may be extended beyond 2021;
8. open archives and repositories are acknowledged for their importance;
9. hybrid open-access journalsare not compliant with the key principle;
10. members of the coalition should monitor and sanction non-compliance.

### Member organisations

Organisations in the coalition behind Plan S include:[14]

International organizations that are members:

Plan S is also supported by:

### Live Notes, Real Time Conference Coverage AACR 2020: Tuesday June 23, 2020 Noon-2:45 Educational Sessions

Reporter: Stephen J. Williams, PhD

Follow Live in Real Time using

#AACR20

@pharma_BI

@AACR

Elaine R Mardis, William N Hait

DETAILS

#### Improving diagnostic yield in pediatric cancer precision medicine

##### Elaine R Mardis
• Advent of genomics have revolutionized how we diagnose and treat lung cancer
• We are currently needing to understand the driver mutations and variants where we can personalize therapy
• PD-L1 and other checkpoint therapy have not really been used in pediatric cancers even though CAR-T have been successful
• The incidence rates and mortality rates of pediatric cancers are rising
• Large scale study of over 700 pediatric cancers show cancers driven by epigenetic drivers or fusion proteins. Need for transcriptomics.  Also study demonstrated that we have underestimated germ line mutations and hereditary factors.
• They put together a database to nominate patients on their IGM Cancer protocol. Involves genetic counseling and obtaining germ line samples to determine hereditary factors.  RNA and protein are evaluated as well as exome sequencing. RNASeq and Archer Dx test to identify driver fusions
• PECAN curated database from St. Jude used to determine driver mutations. They use multiple databases and overlap within these databases and knowledge base to determine or weed out false positives
• They have used these studies to understand the immune infiltrate into recurrent cancers (CytoCure)
• They found 40 germline cancer predisposition genes, 47 driver somatic fusion proteins, 81 potential actionable targets, 106 CNV, 196 meaningful somatic driver mutations

Tuesday, June 23

12:00 PM – 12:30 PM EDT

Awards and Lectures

Norman E Sharpless, Elaine R Mardis

DETAILS

##### NCI Director Address: Norman E Sharpless
• They are functioning well at NCI with respect to grant reviews, research, and general functions in spite of the COVID pandemic and the massive demonstrations on also focusing on the disparities which occur in cancer research field and cancer care
• There are ongoing efforts at NCI to make a positive difference in racial injustice, diversity in the cancer workforce, and for patients as well
• Need a diverse workforce across the cancer research and care spectrum
• Data show that areas where the clinicians are successful in putting African Americans on clinical trials are areas (geographic and site specific) where health disparities are narrowing
• Grants through NCI new SeroNet for COVID-19 serologic testing funded by two RFAs through NIAD (RFA-CA-30-038 and RFA-CA-20-039) and will close on July 22, 2020

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Immunology, Tumor Biology, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Tumor Immunology and Immunotherapy for Nonimmunologists: Innovation and Discovery in Immune-Oncology

This educational session will update cancer researchers and clinicians about the latest developments in the detailed understanding of the types and roles of immune cells in tumors. It will summarize current knowledge about the types of T cells, natural killer cells, B cells, and myeloid cells in tumors and discuss current knowledge about the roles these cells play in the antitumor immune response. The session will feature some of the most promising up-and-coming cancer immunologists who will inform about their latest strategies to harness the immune system to promote more effective therapies.

Judith A Varner, Yuliya Pylayeva-Gupta

#### Introduction

##### New techniques reveal critical roles of myeloid cells in tumor development and progression
• Different type of cells are becoming targets for immune checkpoint like myeloid cells
• In T cell excluded or desert tumors T cells are held at periphery so myeloid cells can infiltrate though so macrophages might be effective in these immune t cell naïve tumors, macrophages are most abundant types of immune cells in tumors
• CXCLs are potential targets
• PI3K delta inhibitors,
• Reduce the infiltrate of myeloid tumor suppressor cells like macrophages
• When should we give myeloid or T cell therapy is the issue
##### New approaches in cancer immunotherapy: Programming bacteria to induce systemic antitumor immunity

Tuesday, June 23

12:45 PM – 1:46 PM EDT

Virtual Educational Session

Cancer Chemistry

Chemistry to the Clinic: Part 2: Irreversible Inhibitors as Potential Anticancer Agents

There are numerous examples of highly successful covalent drugs such as aspirin and penicillin that have been in use for a long period of time. Despite historical success, there was a period of reluctance among many to purse covalent drugs based on concerns about toxicity. With advances in understanding features of a well-designed covalent drug, new techniques to discover and characterize covalent inhibitors, and clinical success of new covalent cancer drugs in recent years, there is renewed interest in covalent compounds. This session will provide a broad look at covalent probe compounds and drug development, including a historical perspective, examination of warheads and electrophilic amino acids, the role of chemoproteomics, and case studies.

Benjamin F Cravatt, Richard A. Ward, Sara J Buhrlage

#### Discovering and optimizing covalent small-molecule ligands by chemical proteomics

##### Benjamin F Cravatt
• Multiple approaches are being investigated to find new covalent inhibitors such as: 1) cysteine reactivity mapping, 2) mapping cysteine ligandability, 3) and functional screening in phenotypic assays for electrophilic compounds
• Using fluorescent activity probes in proteomic screens; have broad useability in the proteome but can be specific
• They screened quiescent versus stimulated T cells to determine reactive cysteines in a phenotypic screen and analyzed by MS proteomics (cysteine reactivity profiling); can quantitate 15000 to 20,000 reactive cysteines
• Isocitrate dehydrogenase 1 and adapter protein LCP-1 are two examples of changes in reactive cysteines they have seen using this method
• They use scout molecules to target ligands or proteins with reactive cysteines
• For phenotypic screens they first use a cytotoxic assay to screen out toxic compounds which just kill cells without causing T cell activation (like IL10 secretion)
• INTERESTINGLY coupling these MS reactive cysteine screens with phenotypic screens you can find NONCANONICAL mechanisms of many of these target proteins (many of the compounds found targets which were not predicted or known)

#### The covalent targeting of cysteine residues in drug discovery and its application to the discovery of Osimertinib

##### Richard A. Ward
• Cysteine activation: thiolate form of cysteine is a strong nucleophile
• Thiolate form preferred in polar environment
• Activation can be assisted by neighboring residues; pKA will have an effect on deprotonation
• pKas of cysteine vary in EGFR
• cysteine that are too reactive give toxicity while not reactive enough are ineffective

#### Accelerating drug discovery with lysine-targeted covalent probes

Tuesday, June 23

12:45 PM – 2:15 PM EDT

Virtual Educational Session

Molecular and Cellular Biology/Genetics

Virtual Educational Session

Tumor Biology, Immunology

Metabolism and Tumor Microenvironment

This Educational Session aims to guide discussion on the heterogeneous cells and metabolism in the tumor microenvironment. It is now clear that the diversity of cells in tumors each require distinct metabolic programs to survive and proliferate. Tumors, however, are genetically programmed for high rates of metabolism and can present a metabolically hostile environment in which nutrient competition and hypoxia can limit antitumor immunity.

Jeffrey C Rathmell, Lydia Lynch, Mara H Sherman, Greg M Delgoffe

#### Tumor microenvironment metabolism and its effects on antitumor immunity and immunotherapeutic response

##### Greg M Delgoffe
• Multiple metabolites, reactive oxygen species within the tumor microenvironment; is there heterogeneity within the TME metabolome which can predict their ability to be immunosensitive
• Took melanoma cells and looked at metabolism using Seahorse (glycolysis): and there was vast heterogeneity in melanoma tumor cells; some just do oxphos and no glycolytic metabolism (inverse Warburg)
• As they profiled whole tumors they could separate out the metabolism of each cell type within the tumor and could look at T cells versus stromal CAFs or tumor cells and characterized cells as indolent or metabolic
• T cells from hyerglycolytic tumors were fine but from high glycolysis the T cells were more indolent
• When knock down glucose transporter the cells become more glycolytic
• Showed this result in head and neck cancer as well
• Metformin a complex 1 inhibitor which is not as toxic as most mito oxphos inhibitors the T cells have less hypoxia and can remodel the TME and stimulate the immune response
• Metformin now in clinical trials
• T cells though seem metabolically restricted; T cells that infiltrate tumors are low mitochondrial phosph cells
• T cells from tumors have defective mitochondria or little respiratory capacity
• They have some preliminary findings that metabolic inhibitors may help with CAR-T therapy

#### Obesity, lipids and suppression of anti-tumor immunity

##### Lydia Lynch
• Hypothesis: obesity causes issues with anti tumor immunity
• Less NK cells in obese people; also produce less IFN gamma
• RNASeq on NOD mice; granzymes and perforins at top of list of obese downregulated
• Upregulated genes that were upregulated involved in lipid metabolism
• All were PPAR target genes
• NK cells from obese patients takes up palmitate and this reduces their glycolysis but OXPHOS also reduced; they think increased FFA basically overloads mitochondria
• PPAR alpha gamma activation mimics obesity

Tuesday, June 23

12:45 PM – 2:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials

The Evolving Role of the Pathologist in Cancer Research

Long recognized for their role in cancer diagnosis and prognostication, pathologists are beginning to leverage a variety of digital imaging technologies and computational tools to improve both clinical practice and cancer research. Remarkably, the emergence of artificial intelligence (AI) and machine learning algorithms for analyzing pathology specimens is poised to not only augment the resolution and accuracy of clinical diagnosis, but also fundamentally transform the role of the pathologist in cancer science and precision oncology. This session will discuss what pathologists are currently able to achieve with these new technologies, present their challenges and barriers, and overview their future possibilities in cancer diagnosis and research. The session will also include discussions of what is practical and doable in the clinic for diagnostic and clinical oncology in comparison to technologies and approaches primarily utilized to accelerate cancer research.

Jorge S Reis-Filho, Thomas J Fuchs, David L Rimm, Jayanta Debnath

DETAILS

Tuesday, June 23

12:45 PM – 2:45 PM EDT

High-dimensional imaging technologies in cancer research

David L Rimm

• Using old methods and new methods; so cell counting you use to find the cells then phenotype; with quantification like with Aqua use densitometry of positive signal to determine a threshold to determine presence of a cell for counting
• Hiplex versus multiplex imaging where you have ten channels to measure by cycling of flour on antibody (can get up to 20plex)
• Hiplex can be coupled with Mass spectrometry (Imaging Mass spectrometry, based on heavy metal tags on mAbs)
• However it will still take a trained pathologist to define regions of interest or field of desired view

#### Invited Speaker

##### Thomas J Fuchs
• Founder of spinout of Memorial Sloan Kettering
• Separates AI from computational algothimic
• Dealing with not just machines but integrating human intelligence
• Making decision for the patients must involve human decision making as well
• How do we get experts to do these decisions faster
• AI in pathology: what is difficult? =è sandbox scenarios where machines are great,; curated datasets; human decision support systems or maps; or try to predict nature
• 1) learn rules made by humans; human to human scenario 2)constrained nature 3)unconstrained nature like images and or behavior 4) predict nature response to nature response to itself
• In sandbox scenario the rules are set in stone and machines are great like chess playing
• In second scenario can train computer to predict what a human would predict
• So third scenario is like driving cars
• System on constrained nature or constrained dataset will take a long time for commuter to get to decision
• Fourth category is long term data collection project
• He is finding it is still finding it is still is difficult to predict nature so going from clinical finding to prognosis still does not have good predictability with AI alone; need for human involvement
• End to end partnering (EPL) is a new way where humans can get more involved with the algorithm and assist with the problem of constrained data
• An example of a workflow for pathology would be as follows from Campanella et al 2019 Nature Medicine: obtain digital images (they digitized a million slides), train a massive data set with highthroughput computing (needed a lot of time and big software developing effort), and then train it using input be the best expert pathologists (nature to human and unconstrained because no data curation done)
• Led to first clinically grade machine learning system (Camelyon16 was the challenge for detecting metastatic cells in lymph tissue; tested on 12,000 patients from 45 countries)
• The first big hurdle was moving from manually annotated slides (which was a big bottleneck) to automatically extracted data from path reports).
• Now problem is in prediction: How can we bridge the gap from predicting humans to predicting nature?
• With an AI system pathologist drastically improved the ability to detect very small lesions

Virtual Educational Session

Epidemiology

Cancer Increases in Younger Populations: Where Are They Coming from?

Incidence rates of several cancers (e.g., colorectal, pancreatic, and breast cancers) are rising in younger populations, which contrasts with either declining or more slowly rising incidence in older populations. Early-onset cancers are also more aggressive and have different tumor characteristics than those in older populations. Evidence on risk factors and contributors to early-onset cancers is emerging. In this Educational Session, the trends and burden, potential causes, risk factors, and tumor characteristics of early-onset cancers will be covered. Presenters will focus on colorectal and breast cancer, which are among the most common causes of cancer deaths in younger people. Potential mechanisms of early-onset cancers and racial/ethnic differences will also be discussed.

Stacey A. Fedewa, Xavier Llor, Pepper Jo Schedin, Yin Cao

#### Cancers that are and are not increasing in younger populations

##### Stacey A. Fedewa

• Early onset cancers, pediatric cancers and colon cancers are increasing in younger adults
• Younger people are more likely to be uninsured and these are there most productive years so it is a horrible life event for a young adult to be diagnosed with cancer. They will have more financial hardship and most (70%) of the young adults with cancer have had financial difficulties.  It is very hard for women as they are on their childbearing years so additional stress
• Types of early onset cancer varies by age as well as geographic locations. For example in 20s thyroid cancer is more common but in 30s it is breast cancer.  Colorectal and testicular most common in US.
• SCC is decreasing by adenocarcinoma of the cervix is increasing in women’s 40s, potentially due to changing sexual behaviors
• Breast cancer is increasing in younger women: maybe etiologic distinct like triple negative and larger racial disparities in younger African American women
• Increased obesity among younger people is becoming a factor in this increasing incidence of early onset cancers

## Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic

### Crowdsourcing Difficult-to-Collect Epidemiological Data in Pandemics: Lessons from Ebola to the current COVID-19 Pandemic

Curator: Stephen J. Williams, Ph.D.

At the onset of the COVID-19 pandemic, epidemiological data from the origin of the Sars-Cov2 outbreak, notably from the Wuhan region in China, was sparse.  In fact, official individual patient data rarely become available early on in an outbreak, when that data is needed most. Epidemiological data was just emerging from China as countries like Italy, Spain, and the United States started to experience a rapid emergence of the outbreak in their respective countries.  China, made of 31 geographical provinces, is a vast and complex country, with both large urban and rural areas.

As a result of this geographical diversity and differences in healthcare coverage across the country, epidemiological data can be challenging.  For instance, cancer incidence data for regions and whole country is difficult to calculate as there are not many regional cancer data collection efforts, contrasted with the cancer statistics collected in the United States, which is meticulously collected by cancer registries in each region, state and municipality.  Therefore, countries like China must depend on hospital record data and autopsy reports in order to back-extrapolate cancer incidence data.  This is the case in some developed countries like Italy where cancer registry is administered by a local government and may not be as extensive (for example in the Napoli region of Italy).

Population density China by province. Source https://www.unicef.cn/en/figure-13-population-density-province-2017

Epidemiologists, in areas in which data collection may be challenging, are relying on alternate means of data collection such as using devices connected to the internet-of-things such as mobile devices, or in some cases, social media is becoming useful to obtain health related data.  Such as effort to acquire pharmacovigilance data, patient engagement, and oral chemotherapeutic adherence using the social media site Twitter has been discussed in earlier posts: (see below)

Twitter is Becoming a Powerful Tool in Science and Medicine at https://pharmaceuticalintelligence.com/2014/11/06/twitter-is-becoming-a-powerful-tool-in-science-and-medicine/

Now epidemiologists are finding crowd-sourced data from social media and social networks becoming useful in collecting COVID-19 related data in those countries where health data collection efforts may be sub-optimal.  In a recent paper in The Lancet Digital Health [1], authors Kaiyuan Sun, Jenny Chen, and Cecile Viboud present data from the COVID-19 outbreak in China using information collected over social network sites as well as public news outlets and find strong correlations with later-released government statistics, showing the usefulness in such social and crowd-sourcing strategies to collect pertinent time-sensitive data.  In particular, the authors aim was to investigate this strategy of data collection to reduce the time delays between infection and detection, isolation and reporting of cases.

The paper is summarized below:

Kaiyuan Sun, PhD Jenny Chen, BScn Cécile Viboud, PhD . (2020).  Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study.  The Lancet: Digital Health; Volume 2, Issue 4, E201-E208.

## Summary

### Background

As the outbreak of coronavirus disease 2019 (COVID-19) progresses, epidemiological data are needed to guide situational awareness and intervention strategies. Here we describe efforts to compile and disseminate epidemiological information on COVID-19 from news media and social networks.

### Methods

In this population-level observational study, we searched DXY.cn, a health-care-oriented social network that is currently streaming news reports on COVID-19 from local and national Chinese health agencies. We compiled a list of individual patients with COVID-19 and daily province-level case counts between Jan 13 and Jan 31, 2020, in China. We also compiled a list of internationally exported cases of COVID-19 from global news media sources (Kyodo News, The Straits Times, and CNN), national governments, and health authorities. We assessed trends in the epidemiology of COVID-19 and studied the outbreak progression across China, assessing delays between symptom onset, seeking care at a hospital or clinic, and reporting, before and after Jan 18, 2020, as awareness of the outbreak increased. All data were made publicly available in real time.

### Findings

We collected data for 507 patients with COVID-19 reported between Jan 13 and Jan 31, 2020, including 364 from mainland China and 143 from outside of China. 281 (55%) patients were male and the median age was 46 years (IQR 35–60). Few patients (13 [3%]) were younger than 15 years and the age profile of Chinese patients adjusted for baseline demographics confirmed a deficit of infections among children. Across the analysed period, delays between symptom onset and seeking care at a hospital or clinic were longer in Hubei province than in other provinces in mainland China and internationally. In mainland China, these delays decreased from 5 days before Jan 18, 2020, to 2 days thereafter until Jan 31, 2020 (p=0·0009). Although our sample captures only 507 (5·2%) of 9826 patients with COVID-19 reported by official sources during the analysed period, our data align with an official report published by Chinese authorities on Jan 28, 2020.

### Interpretation

News reports and social media can help reconstruct the progression of an outbreak and provide detailed patient-level data in the context of a health emergency. The availability of a central physician-oriented social network facilitated the compilation of publicly available COVID-19 data in China. As the outbreak progresses, social media and news reports will probably capture a diminishing fraction of COVID-19 cases globally due to reporting fatigue and overwhelmed health-care systems. In the early stages of an outbreak, availability of public datasets is important to encourage analytical efforts by independent teams and provide robust evidence to guide interventions.

A Few notes on Methodology:

• The authors used crowd-sourced reports from DXY.cn, a social network for Chinese physicians, health-care professionals, pharmacies and health-care facilities. This online platform provides real time coverage of the COVID-19 outbreak in China
• More data was curated from news media, television and includes time-stamped information on COVID-19 cases
• These reports are publicly available, de-identified patient data
• No patient consent was needed and no ethics approval was required
• Data was collected between January 20, 2020 and January 31,2020
• Sex, age, province of identification, travel history, dates of symptom development was collected
• Additional data was collected for other international sites of the pandemic including Cambodia, Canada, France, Germany, Hong Kong, India, Italy, Japan, Malaysia, Nepal, Russia, Singapore, UK, and USA
• All patients in database had laboratory confirmation of infection

Results

• 507 patient data was collected with 153 visited and 152 resident of Wuhan
• Reported cases were skewed toward males however the overall population curve is skewed toward males in China
• Most cases (26%) were from Beijing (urban area) while an equal amount were from rural areas combined (Shaanzi and Yunnan)
• Age distribution of COVID cases were skewed toward older age groups with median age of 45 HOWEVER there were surprisingly a statistically high amount of cases less than 5 years of age
• Outbreak progression based on the crowd-sourced patient line was consistent with the data published by the China Center for Disease Control
• Median reporting delay in the authors crowd-sourcing data was 5 days
• Crowd-sourced data was able to detect apparent rapid growth of newly reported cases during the collection period in several provinces outside of Hubei province, which is consistent with local government data

The following graphs show age distribution for China in 2017 and predicted for 2050.

projected age distribution China 2050. Source https://chinapower.csis.org/aging-problem/

The authors have previously used this curation of news methodology to analyze the Ebola outbreak[2].

A further use of the crowd-sourced database was availability of travel histories for patients returning from Wuhan and onset of symptoms, allowing for estimation of incubation periods.

The following published literature has also used these datasets:

Backer JA, Klinkenberg D, Wallinga J: Incubation period of 2019 novel coronavirus (2019-nCoV) infections among travellers from Wuhan, China, 20-28 January 2020. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin 2020, 25(5).

Lauer SA, Grantz KH, Bi Q, Jones FK, Zheng Q, Meredith HR, Azman AS, Reich NG, Lessler J: The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application. Annals of internal medicine 2020, 172(9):577-582.

Li Q, Guan X, Wu P, Wang X, Zhou L, Tong Y, Ren R, Leung KSM, Lau EHY, Wong JY et al: Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia. The New England journal of medicine 2020, 382(13):1199-1207.

Dataset is available on the Laboratory for the Modeling of Biological and Socio-technical systems website of Northeastern University at https://www.mobs-lab.org/.

References

1. Sun K, Chen J, Viboud C: Early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study. The Lancet Digital health 2020, 2(4):e201-e208.
2. Cleaton JM, Viboud C, Simonsen L, Hurtado AM, Chowell G: Characterizing Ebola Transmission Patterns Based on Internet News Reports. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2016, 62(1):24-31.

## Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

### Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Minisymposium on Signaling in Cancer 11:45am-1:30 pm

Reporter: Stephen J. Williams, PhD.

#### SESSION VMS.MCB01.01 – Emerging Signaling Vulnerabilities in Cancer April 27, 2020, 11:45 AM – 1:30 PM Virtual Meeting: All Session Times Are U.S. EDT DESCRIPTION

All session times are U.S. Eastern Daylight Time (EDT). Access to AACR Virtual Annual Meeting I sessions are free with registration. Register now at http://www.aacr.org/virtualam2020

Session Type

Virtual Minisymposium

Track(s)

Molecular and Cellular Biology/Genetics

16 Presentations
11:45 AM – 1:30 PM
– Chairperson

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:45 AM – 1:30 PM
– Chairperson

• in 80’s and 90’s signaling focused on defects and also oncogene addiction.  Now the field is switching to finding vulnerabilities in signaling cascades in cancer

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

11:45 AM – 11:55 AM
– Introduction

J. Silvio Gutkind. UCSD Moores Cancer Center, La Jolla, CA

11:55 AM – 12:05 PM
1085 – Interrogating the RAS interactome identifies EFR3A as a novel enhancer of RAS oncogenesis

Hema Adhikari, Walaa Kattan, John F. Hancock, Christopher M. Counter. Duke University, Durham, NC, University of Texas MD Anderson Cancer Center, Houston, TX

Abstract: Activating mutations in one of the three RAS genes (HRAS, NRAS, and KRAS) are detected in as much as a third of all human cancers. As oncogenic RAS mediates it tumorigenic signaling through protein-protein interactions primarily at the plasma membrane, we sought to document the protein networks engaged by each RAS isoform to identify new vulnerabilities for future therapeutic development. To this end, we determined interactomes of oncogenic HRAS, NRAS, and KRAS by BirA-mediated proximity labeling. This analysis identified roughly ** proteins shared among multiple interactomes, as well as a smaller subset unique to a single RAS oncoprotein. To identify those interactome components promoting RAS oncogenesis, we created and screened sgRNA library targeting the interactomes for genes modifying oncogenic HRAS-, NRAS-, or KRAS-mediated transformation. This analysis identified the protein EFR3A as not only a common component of all three RAS interactomes, but when inactivated, uniformly reduced the growth of cells transformed by any of the three RAS isoforms. EFR3A recruits a complex containing the druggable phosphatidylinositol (Ptdlns) 4 kinase alpha (PI4KA) to the plasma membrane to generate the Ptdlns species PI4P. We show that EFR3A sgRNA reduced multiple RAS effector signaling pathways, suggesting that EFR3A acts at the level of the oncoprotein itself. As lipids play a critical role in the membrane localization of RAS, we tested and found that EFR3A sgRNA reduced not only the occupancy of RAS at the plasma membrane, but also the nanoclustering necessary for signaling. Furthermore, the loss of oncogenic RAS signaling induced by EFR3A sgRNA was rescued by targeting PI4K to the plasma membrane. Taken together, these data support a model whereby EFR3A recruits PI4K to oncogenic RAS to promote plasma membrane localization and nonclustering, and in turn, signaling and transformation. To investigate the therapeutic potential of this new RAS enhancer, we show that EFR3A sgRNA reduced oncogenic KRAS signaling and transformed growth in a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines. Encouraged by these results we are exploring whether genetically inactivating the kinase activity of PI4KA inhibits oncogenic signaling and transformation in PDAC cell lines. If true, pharmacologically targeting PI4K may hold promise as a way to enhance the anti-neoplastic activity of drugs targeting oncogenic RAS or its effectors.

@DukeU

@DukeMedSchool

@MDAndersonNews

• different isoforms of ras mutations exist differentially in various tumor types e.g. nras vs kras
• the C terminal end serve as hotspots of mutations and probably isoform specific functions
• they determined the interactomes of nras and kras and determined how many candidates are ras specific
• they overlayed results from proteomic and CRSPR screen; EFR3a was a potential target that stuck out
• using TCGA patients with higher EFR3a had poorer prognosis
• EFR3a promotes Ras signaling; and required for RAS driven tumor growth (in RAS addicted tumors?)
• EGFR3a promotes clustering of oncogenic RAS at plasma membrane

12:05 PM – 12:10 PM
– Discussion

12:10 PM – 12:20 PM
1086 – Downstream kinase signaling is dictated by specific KRAS mutations; Konstantin Budagyan, Jonathan Chernoff. Drexel University College of Medicine, Philadelphia, PA, Fox Chase Cancer Center, Philadelphia, PA @FoxChaseCancer

Abstract: Oncogenic KRAS mutations are common in colorectal cancer (CRC), found in ~50% of tumors, and are associated with poor prognosis and resistance to therapy. There is substantial diversity of KRAS alleles observed in CRC. Importantly, emerging clinical and experimental analysis of relatively common KRAS mutations at amino acids G12, G13, A146, and Q61 suggest that each mutation differently influences the clinical properties of a disease and response to therapy. For example, KRAS G12 mutations confer resistance to EGFR-targeted therapy, while G13D mutations do not. Although there is clinical evidence to suggest biological differences between mutant KRAS alleles, it is not yet known what drives these differences and whether they can be exploited for allele-specific therapy. We hypothesized that different KRAS mutants elicit variable alterations in downstream signaling pathways. To investigate this hypothesis, we created a novel system by which we can model KRAS mutants in isogenic mouse colon epithelial cell lines. To generate the cell lines, we developed an assay using fluorescent co-selection for CRISPR-driven genome editing. This assay involves simultaneous introduction of single-guide RNAs (sgRNAs) to two different endogenous loci resulting in double-editing events. We first introduced Cas9 and blue fluorescent protein (BFP) into mouse colon epithelial cell line containing heterozygous KRAS G12D mutation. We then used sgRNAs targeting BFP and the mutant G12D KRAS allele along with homology-directed repair (HDR) templates for a GFP gene and a KRAS mutant allele of our choice. Cells that successfully undergo HDR are GFP-positive and contain the desired KRAS mutation. Therefore, selection for GFP-positive cells allows us to identify those with phenotypically silent KRAS edits. Ultimately, this method allows us to toggle between different mutant alleles while preserving the wild-type allele, all in an isogenic background. Using this method, we have generated cell lines with endogenous heterozygous KRAS mutations commonly seen in CRC (G12D, G12V, G12C, G12R, G13D). In order to elucidate cellular signaling pathway differences between the KRAS mutants, we screened the mutated cell lines using a small-molecule library of ~160 protein kinase inhibitors. We found that there are mutation-specific differences in drug sensitivity profiles. These observations suggest that KRAS mutants drive specific cellular signaling pathways, and that further exploration of these pathways may prove to be valuable for identification of novel therapeutic opportunities in CRC.

• Flourescent coselection of KRAS edits by CRSPR screen in a colorectal cancer line; a cell that is competent to undergo HR can undergo combination multiple KRAS
• target only mutant allele while leaving wild type intact;
• it was KRAS editing event in APC  +/- mouse cell line
• this enabled a screen for kinase inhibitors that decreased tumor growth in isogenic cell lines; PKC alpha and beta 1 inhibitors, also CDK4 inhibitors inhibited cell growth
• questions about heterogeneity in KRAS clones; they looked at off target guides and looked at effects in screens; then they used top two clones that did not have off target;  questions about 3D culture- they have not done that; Question ? dependency on AKT activity? perhaps the G12E has different downstream effectors

12:20 PM – 12:25 PM
– Discussion

12:25 PM – 12:35 PM
1087 – NF1 regulates the RAS-related GTPases, RRAS and RRAS2, independent of RAS activity; Jillian M. Silva, Lizzeth Canche, Frank McCormick. University of California, San Francisco, San Francisco, CA @UCSFMedicine

Abstract: Neurofibromin, which is encoded by the neurofibromatosis type 1 (NF1) gene, is a tumor suppressor that acts as a RAS-GTPase activating protein (RAS-GAP) to stimulate the intrinsic GTPase activity of RAS as well as the closely related RAS subfamily members, RRAS, RRAS2, and MRAS. This results in the conversion of the active GTP-bound form of RAS into the inactive GDP-bound state leading to the downregulation of several RAS downstream effector pathways, most notably MAPK signaling. While the region of NF1 that regulates RAS activity represents only a small fraction of the entire protein, a large extent of the NF1 structural domains and their corresponding mechanistic functions remain uncharacterized despite the fact there is a high frequency of NF1 mutations in several different types of cancer. Thus, we wanted to elucidate the underlying biochemical and signaling functions of NF1 that are unrelated to the regulation of RAS and how loss of these functions contributes to the pathogenesis of cancer. To accomplish this objective, we used CRISPR-Cas9 methods to knockout NF1 in an isogenic “RASless” MEF model system, which is devoid of the major oncogenic RAS isoforms (HRAS, KRAS, and NRAS) and reconstituted with the KRAS4b wild-type or mutant KRASG12C or KRASG12D isoform. Loss of NF1 led to elevated RAS-GTP levels, however, this increase was not as profound as the levels in KRAS-mutated cells or provided a proliferative advantage. Although ablation of NF1 resulted in sustained activation of MAPK signaling, it also unexpectedly, resulted in a robust increase in AKT phosphorylation compared to KRAS-mutated cells. Surprisingly, loss of NF1 in KRAS4b wild-type and KRAS-mutated cells potently suppressed the RAS-related GTPases, RRAS and RRAS2, with modest effects on MRAS, at both the transcript and protein levels. A Clariom™D transcriptome microarray analysis revealed a significant downregulation in the NF-κB target genes, insulin-like growth factor binding protein 2 (IGFBP2), argininosuccinate synthetase 1 (ASS1), and DUSP1, in both the NF1 knockout KRAS4b wild-type and KRAS-mutated cells. Moreover, NF1Null melanoma cells also displayed a potent suppression of RRAS and RRAS2 as well as these NF-κB transcription factors. Since RRAS and RRAS2 both contain the same NF-κB transcription factor binding sites, we hypothesize that IGFBP2, ASS1, and/or DUSP1 may contribute to the NF1-mediated regulation of these RAS-related GTPases. More importantly, this study provides the first evidence of at least one novel RAS-independent function of NF1 to regulate the RAS-related subfamily members, RRAS and RRAS2, in a manner exclusive of its RAS-GTPase activity and this may provide insight into new potential biomarkers and molecular targets for treating patients with mutations in NF1.
• NF1 and SPRED work together to signal from RTK cKIT through RAS
• NF1 knockout cells had higher KRAS and had increased cell proliferation
• NF1 -/-  or SPRED loss had increased ERK phosphorylation and some increase in AKT activity compared to parental cells
• they used isogenic cell lines devoid of all RAS isoforms and then reconstituted with specific RAS WT or mutants
• NF1 and SPRED KO both reduce RRAS expression; in an AKT independent mannner
• NF1 SPRED KO cells have almost no IGFBP2 protein expression and SNAIL so maybe affecting EMT?
• this effect is independent of its RAS GTPAse activity (noncanonical)

12:35 PM – 12:40 PM
– Discussion

12:40 PM – 12:50 PM
1088 – Elucidating the regulation of delayed-early gene targets of sustained MAPK signaling; Kali J. Dale, Martin McMahon. University of Utah, Salt Lake City, UT, Huntsman Cancer Institute, Salt Lake City, UT

Abstract: RAS and its downstream effector, BRAF, are commonly mutated proto-oncogenes in many types of human cancer. Mutationally activated RAS or BRAF signal through the MEK→ERK MAP kinase (MAPK) pathway to regulate key cancer cell hallmarks such as cell division cycle progression, reduced programmed cell death, and enhanced cell motility. Amongst the list of RAS/RAF-regulated genes are those encoding integrins, alpha-beta heterodimeric transmembrane proteins that regulate cell adhesion to the extracellular matrix. Altered integrin expression has been linked to the acquisition of more aggressive behavior by melanoma, lung, and breast cancer cells leading to diminished survival of cancer patients. We have previously documented the ability of the RAS-activated MAPK pathway to induce the expression of ITGB3 encoding integrin β3 in several different cell types. RAS/RAF-mediated induction of ITGB3 mRNA requires sustained, high-level activation of RAF→MEK→ERK signaling mediated by oncogene activation and is classified as “delayed-early”, in that it is sensitive to the protein synthesis inhibitor cycloheximide. However, to date, the regulatory mechanisms that allow for induced ITGB3 downstream of sustained, high-level activation of MAPK signaling remains obscure. We have identified over 300 DEGs, including those expressing additional cell surface proteins, that display similar regulatory characteristics as ITGB3. We use integrin β3 as a model to test our hypothesis that there is a different mechanism of regulation for delayed-early genes (DEG) compared to the canonical regulation of Immediate-Early genes. There are three regions in the chromatin upstream of the ITGB3 that become more accessible during RAF activation. We are relating the chromatin changes seen during RAF activation to active enhancer histone marks. To elucidate the essential genes of this regulation process, we are employing the use of a genome-wide CRISPR knockout screen. The work presented from this abstract will help elucidate the regulatory properties of oncogenic progression in BRAF mutated cancers that could lead to the identification of biomarkers.

12:50 PM – 12:55 PM
– Discussion

12:55 PM – 1:05 PM
1090 – Regulation of PTEN translation by PI3K signaling maintains pathway homeostasis

Radha Mukherjee, Kiran Gireesan Vanaja, Jacob A. Boyer, Juan Qiu, Xiaoping Chen, Elisa De Stanchina, Sarat Chandarlapaty, Andre Levchenko, Neal Rosen. Memorial Sloan Kettering Cancer Center, New York, NY, Yale University, West Haven, CT, Memorial Sloan Kettering Cancer Center, New York, NY, Memorial Sloan Kettering Cancer Center, New York, NY @sloan_kettering

Abstract: The PI3K pathway is a key regulator of metabolism, cell proliferation and migration and some of its components (e.g. PIK3CA and PTEN) are frequently altered in cancer by genetic events that deregulate its output. However, PI3K signaling is not usually the primary driver of these tumors and inhibitors of components of the pathway have only modest antitumor effects. We now show that both physiologic and oncogenic activation of the PI3K signaling by growth factors and an activating hotspot PIK3CA mutation respectively, cause an increase in the expression of the lipid phosphatase PTEN, thus limiting the duration of the signal and the output of the pathway in tumors. Pharmacologic and physiologic inhibition of the pathway by HER2/PI3K/AKT/mTOR inhibitors and nutrient starvation respectively reduce PTEN, thus buffering the effects of inhibition and contributing to the rebound in pathway activity that occurs in tumors. This regulation is found to be a feature of multiple types of cancer, non-cancer cell line and PDX models thereby highlighting its role as a key conserved feedback loop within the PI3K signaling network, both in vitro and in vivo. Regulation of expression is due to mTOR/4EBP1 dependent control of PTEN translation and is lost when 4EBP1 is knocked out. Translational regulation of PTEN is therefore a major homeostatic regulator of physiologic PI3K signaling and plays a role in reducing the output of oncogenic mutants that deregulate the pathway and the antitumor activity of PI3K pathway inhibitors.

• mTOR can be a potent regulator of PTEN and therefore a major issue when developing PI3K inhibitors

1:05 PM – 1:10 PM
– Discussion

1:10 PM – 1:20 PM
1091 – BI-3406 and BI 1701963: Potent and selective SOS1::KRAS inhibitors induce regressions in combination with MEK inhibitors or irinotecan

Daniel Gerlach, Michael Gmachl, Juergen Ramharter, Jessica Teh, Szu-Chin Fu, Francesca Trapani, Dirk Kessler, Klaus Rumpel, Dana-Adriana Botesteanu, Peter Ettmayer, Heribert Arnhof, Thomas Gerstberger, Christiane Kofink, Tobias Wunberg, Christopher P. Vellano, Timothy P. Heffernan, Joseph R. Marszalek, Mark Pearson, Darryl B. McConnell, Norbert Kraut, Marco H. Hofmann. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria, The University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria

• there is rational for developing an SOS1 inhibitor (GEF); BI3406 shows better PK and PD as a candidate
• most sensitive cell lines to inhibitor carry KRAS mutation; NRAS or BRAF mutations are not sensititve
• KRAS mutation defines sensitivity so they created KRAS mut isogenic cell lines
• found best to co inhibit SOS and MEK as observed plasticity with only SOS
• dual combination in lung NSCLC pancreatic showed enhanced efficacy compared to monotherapy
• SOS1 inhibition plus irinotecan enhances DNA double strand breaks; no increased DNA damage in normal stroma but preferentially in tumor cells
• phase 1 started in 2019;

@Boehringer

1:20 PM – 1:25 PM
– Discussion

1:25 PM – 1:30 PM
– Closing Remarks

Adrienne D. Cox. University of North Carolina at Chapel Hill, Chapel Hill, NC

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews

## Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

### Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 11:45am-1:15pm Advances in Cancer Drug Discovery

SESSION VMS.CH01.01 – Advances in Cancer Drug Design and Discovery

April 27, 2020, 11:45 AM – 1:15 PM
Virtual Meeting: All Session Times Are U.S. EDT
DESCRIPTIONAll session times are U.S. Eastern Daylight Time (EDT).

Session Type
Virtual Minisymposium
Track(s)
Cancer Chemistry
14 Presentations
11:45 AM – 11:45 AM
– ChairpersonZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:45 AM – 11:45 AM
– ChairpersonChristopher G. Nasveschuk. C4 Therapeutics, Watertown, MA

11:45 AM – 11:50 AM
– IntroductionZoran Rankovic. St. Jude Children’s Research Hospital, Memphis, TN

11:50 AM – 12:00 PM
1036 – Discovery of a highly potent, efficacious and orally active small-molecule inhibitor of embryonic ectoderm development (EED)Changwei Wang, Rohan Kalyan Rej, Jianfeng Lu, Mi Wang, Kaitlin P. Harvey, Chao-Yie Yang, Ester Fernandez-Salas, Jeanne Stuckey, Elyse Petrunak, Caroline Foster, Yunlong Zhou, Rubin Zhou, Guozhi Tang, Jianyong Chen, Shaomeng Wang. Rogel Cancer Center and Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, Life Sciences Institute, University of Michigan, Ann Arbor, MI, Ascentage Pharma Group, Taizhou, Jiangsu, China

12:00 PM – 12:05 PM
– Discussion

12:05 PM – 12:15 PM
1037 – Orally available small molecule CD73 inhibitor reverses immunosuppression through blocking of adenosine productionXiaohui Du, Brian Blank, Brenda Chan, Xi Chen, Yuping Chen, Frank Duong, Lori Friedman, Tom Huang, Melissa R. Junttila, Wayne Kong, Todd Metzger, Jared Moore, Daqing Sun, Jessica Sun, Dena Sutimantanapi, Natalie Yuen, Tatiana Zavorotinskaya. ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA, ORIC Pharmaceuticals, South San Francisco, CA

12:15 PM – 12:20 PM
– Discussion

12:20 PM – 12:30 PM
1038 – A potent and selective PARP14 inhibitor decreases pro-tumor macrophage function and elicits inflammatory responses in tumor explantsLaurie Schenkel, Jennifer Molina, Kerren Swinger, Ryan Abo, Danielle Blackwell, Anne Cheung, William Church, Kristy Kuplast-Barr, Alvin Lu, Elena Minissale, Mario Niepel, Melissa Vasbinder, Tim Wigle, Victoria Richon, Heike Keilhack, Kevin Kuntz. Ribon Therapeutics, Cambridge, MA

12:30 PM – 12:35 PM
– Discussion

12:35 PM – 12:45 PM
1039 – Fragment-based drug discovery to identify small molecule allosteric inhibitors of SHP2. Philip J. Day, Valerio Berdini, Juan Castro, Gianni Chessari, Thomas G. Davies, James E. H. Day, Satoshi Fukaya, Chris Hamlett, Keisha Hearn, Steve Hiscock, Rhian Holvey, Satoru Ito, Yasuo Kodama, Kenichi Matsuo, Yoko Nakatsuru, Nick Palmer, Amanda Price, Tadashi Shimamura, Jeffrey D. St. Denis, Nicola G. Wallis, Glyn Williams, Christopher N. Johnson. Astex Pharmaceuticals, Inc., Cambridge, United Kingdom, Taiho Pharmaceutical Co., Ltd, Tsukuba, Japan

Abstract: The ubiquitously expressed protein tyrosine phosphatase SHP2 is required for signalling downstream of receptor tyrosine kinases (RTKs) and plays a role in regulating many cellular processes. Recent advances have shown that genetic knockdown and pharmacological inhibition of SHP2 suppresses RAS/MAPK signalling and inhibits proliferation of RTK-driven cancer cell lines. SHP2 is now understood to act upstream of RAS and plays a role in KRAS-driven cancers, an area of research which is rapidly growing. Considering that RTK deregulation often leads to a wide range of cancers and the newly appreciated role of SHP2 in KRAS-driven cancers, SHP2 inhibitors are therefore a promising therapeutic approach.
SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase domain and a C-terminal tail. SHP2 switches between “open” active and “closed” inactive forms due to autoinhibitory interactions between the N-SH2 domain and the phosphatase domain. Historically, phosphatases were deemed undruggable as there had been no advancements with active site inhibitors. We hypothesised that fragment screening would be highly applicable and amenable to this target to enable alternative means of inhibition through identification of allosteric binding sites. Here we describe the first reported fragment screen against SHP2.
Using our fragment-based PyramidTM approach, screening was carried out on two constructs of SHP2; a closed autoinhibited C-terminal truncated form (phosphatase and both SH2 domains), as well as the phosphatase-only domain. A combination of screening methods such as X-ray crystallography and NMR were employed to identify fragment hits at multiple sites on SHP2, including the tunnel-like allosteric site reported by Chen et al, 2016. Initial fragment hits had affinities for SHP2 in the range of 1mM as measured by ITC. Binding of these hits was improved using structure-guided design to generate compounds which inhibit SHP2 phosphatase activity and are promising starting points for further optimization.

• anti estrogen receptor therapy: ER degraders is one class
• AZ9833 enhances degradation of ER alpha
• worked in preclinical mouse model (however very specific)
• PK parameters were good for orally available in rodents;  also in vitro and in vivo correlation correlated in rats but not in dogs so they were not sure if good to go in humans
• they were below Km in rats but already at saturated in dogs, dogs were high clearance
• predicted human bioavailability at 40%

12:45 PM – 12:50 PM
– Discussion

12:50 PM – 1:00 PM
1042 – Preclinical pharmacokinetic and metabolic characterization of the next generation oral SERD AZD9833Eric T. Gangl, Roshini Markandu, Pradeep Sharma, Andy Sykes, Petar Pop-Damkov, Pablo Morentin Gutierrez, James S. Scott, Dermot F. McGinnity, Adrian J. Fretland, Teresa Klinowska. AstraZeneca, Waltham, MA

1:00 PM – 1:05 PM
– Discussion

1:05 PM – 1:15 PM
– Closing RemarksChristopher G. Nasveschuk. MA

@pharma_BI

@AACR

@GenomeInstitute

@CureCancerNow

@UCLAJCCC

#AACR20

#AACR2020

#curecancernow

#pharmanews