Posts Tagged ‘Cancer’

Mission 4: Use of Systems Biology for Design of inhibitor of Galectins as Cancer Therapeutic – Strategy and Software

Posted in Artificial Intelligence in CANCER, Artificial Intelligence in Medicine - Applications in Therapeutics, BioIT: BioInformatics, BioSimilars, BioTechnology - Venture Creation, Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Informatics, cancer metabolism, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Genetics & Pharmaceutical, Genome Biology, Genomic Expression, Glycobiology: Biopharmaceutical Production, Glycobiology: Biopharmaceutical Production, Pharmacodynamics and Pharmacokinetics, Innovations, LPBI Group, e-Scientific Media, DFP, R&D-M3DP, R&D-Drug Discovery, US Patents: SOPs and Team Management, MicroEngineering Cell-Tissue & Systems, Natural Language Processing (NLP), Phosphorylation, S-nitrosylation, Signaling, Signaling & Cell Circuits, Small Molecules in Development of Therapeutic Drugs, Ubiquitin, Ubiquitinylation, tagged angiogenesis, Cancer, carbohydrate, galectin-3, LPBI, metastasis, PROTAC, Synthetic biology, systems biology on December 13, 2022| Leave a Comment »

Use of Systems Biology for Design of inhibitor of Galectins as Cancer Therapeutic – Strategy and Software

Curator: Stephen J. Williams, Ph.D.

Below is a slide representation of the overall mission 4 to produce a PROTAC to inhibit Galectins 1, 3, and 9.

Using A Priori Knowledge of Galectin Receptor Interaction to Create a BioModel of Galectin 3 Binding

Now after collecting literature from PubMed on “galectin-3” AND “binding” to determine literature containing kinetic data we generate a WordCloud on the articles.

This following file contains the articles needed for BioModels generation.

https://pharmaceuticalintelligence.com/wp-content/uploads/2022/12/Curating-Galectin-articles-for-Biomodels.docx

From the WordCloud we can see that these corpus of articles describe galectin binding to the CRD (carbohydrate recognition domain). Interestingly there are many articles which describe van Der Waals interactions as well as electrostatic interactions. Certain carbohydrate modifictions like Lac NAc and Gal 1,4 may be important. Many articles describe the bonding as well as surface interactions. Many studies have been performed with galectin inhibitors like TDGs (thio-digalactosides) like TAZ TDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside). This led to an interesting article

Dual thio-digalactoside-binding modes of human galectins as the structural basis for the design of potent and selective inhibitors

Tung-Ju Hsieh¹, Hsien-Ya Lin^1 2, Zhijay Tu¹, Ting-Chien Lin^1 2, Shang-Chuen Wu^1 3, Yu-Yao Tseng¹, Fu-Tong Liu⁴, Shang-Te Danny Hsu^1 3, Chun-Hung Lin^1 2 3 5

Affiliations 2016 Jul 15;6:29457.

doi: 10.1038/srep29457.

PMID: 27416897
PMCID: PMC4945863
DOI: 10.1038/srep29457

Free PMC article

Abstract

Human galectins are promising targets for cancer immunotherapeutic and fibrotic disease-related drugs. We report herein the binding interactions of three thio-digalactosides (TDGs) including TDG itself, TD139 (3,3′-deoxy-3,3′-bis-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside, recently approved for the treatment of idiopathic pulmonary fibrosis), and TAZTDG (3-deoxy-3-(4-[m-fluorophenyl]-1H-1,2,3-triazol-1-yl)-thio-digalactoside) with human galectins-1, -3 and -7 as assessed by X-ray crystallography, isothermal titration calorimetry and NMR spectroscopy. Five binding subsites (A-E) make up the carbohydrate-recognition domains of these galectins. We identified novel interactions between an arginine within subsite E of the galectins and an arene group in the ligands. In addition to the interactions contributed by the galactosyl sugar residues bound at subsites C and D, the fluorophenyl group of TAZTDG preferentially bound to subsite B in galectin-3, whereas the same group favored binding at subsite E in galectins-1 and -7. The characterised dual binding modes demonstrate how binding potency, reported as decreased Kd values of the TDG inhibitors from μM to nM, is improved and also offer insights to development of selective inhibitors for individual galectins.

Figures

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

Posted in Cancer - General, Cancer and Current Therapeutics, Cancer Informatics, Childhood cancer, Clinical & Translational, Curation, Global Medical Publishers by Country, Health Care System by Country, LPBI Management, Personal Health Applications: Tech Innovations serves HealhCare, Pharmaceutical Industry Competitive Intelligence, Pharmacovigilance, Population Health Management, Prostate Cancer: Monitoring vs Treatment, Scientific Publishing, tagged Brazil, breast cancer, Cancer, cancer treatment, Clinical decision support system, clinical trial guidelines, colon cancer, FDA, FDA guidance, Latin America, LPBI, Medical guideline, medical text, national cancer institute, National Comprehensive Cancer Network, NCCN, Regulatory, Spanish, translation, treatment decisions, treatment guidance on September 14, 2021| Leave a Comment »

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.

Source: https://www.nccn.org/home/news/newsdetails?NewsId=2871

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 education, global initiatives, policy, and research collaboration and publication in oncology. Visit NCCN.org for more information and follow NCCN on Facebook @NCCNorg, Instagram @NCCNorg, and Twitter @NCCN.

Please see LPBI Group’s efforts in medical text translation and Natural Language Processing of Medical Text at

2021-2022 VISION – 2.0 LPBI

2021-2022 Medical Text Analysis (NLP)

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Innovation massively expands view into workings of single cells summary

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, cancer-general, Cell Biology, Cell Biology, Signaling & Cell Circuits, Diagnostics and Lab Tests, single cell sequencing, tagged Cancer, cell fragments, DNA, DNA Sequencing, health, research, Single-cell sequencing on July 8, 2021| Leave a Comment »

Reporter: Danielle Smolyar, Research Assistant 3 – Text Analysis for 2.0 LPBI Group’s TNS #1 – 2020/2021 Academic Internship in Medical Test Analysis (MTA)

Reporting on a Study published on July 6, 2021 by Oregon Health & Science University

Recently, researchers have found many ways to manipulate and alter gene activity in specific cells. As a result of seeing this alteration, it has caused much development and progress in understanding cancer, brain function, and immunity.

IMAGE SOURCE: 3D-model of DNA. Credit: Michael Ströck/Wikimedia/ GNU Free Documentation Lic

Tissues and Organs are composed of cells that look the same but have different roles. For example, single-cell analysis allows us to research and test the cells within an organ or cancerous tumor. However, the single-cell study has its boundaries and limits in trying a more significant number of cells. This result is not an accurate data and analysis of the cells.

Andrew Adey, Ph.D., the senior author of a paper in Nature Biotechnology, https://www.nature.com/articles/s41587-021-00962-z

Mulqueen, R. M., Pokholok, D., O’Connell, B. L., Thornton, C. A., Zhang, F., O’Roak, B. J., Link, J., Yardımcı, G. G., Sears, R. C., Steemers, F. J., & Adey, A. C. (2021, July 5). High-content single-cell combinatorial indexing. Nature News. https://www.nature.com/articles/s41587-021-00962-z

states that the new method gives us the ability to have a ten-fold improvement in the amount of DNA produced from a single DNA sequence. A DNA sequence is composed of units which are called bases. The sequence puts the bases in chronological order for it to code correctly.

To understand cancer better, single-cell studies are a crucial factor in doing so. Different cells catch on to other mutations in the DNA sequence in a cancerous tumor, which ultimately alters the DNA sequence. This results in tumor cells with new alterations, which could eventually spread to the rest of the body.

Adey and his team provided evidence that the method they had created can show DNA alterations that have come from cells present in tumor samples from patients with pancreatic cancer. Adey stated,

quote “For example, you can potentially identify rare cell subtypes within a tumor that are resistant to therapy.”

Abey and his team have been working with OHSU Knight Cancer Institute, and with them, they are testing a single-cell method to see if patients’ tumors have changed by doing chemo or drug therapy.

This new method allows itself to create DNA libraries and fragments of DNA that helps analyze the different genes and mutations within the sequence. This method uses something called an enzymatic reaction that attaches primers to the end of each DNA fragment. For the cells to be analyzed, each primer must be present on both ends of the fragment.

As a result of this new method, all library fragments present must-have primers on both ends of the fragments. At the same time, it improves efficiency by reducing its sequencing price overall, that these adapters can be used instead of the regular custom workflows.

SOURCE

Original article:

Mulqueen, R.M., Pokholok, D., O’Connell, B.L. et al. High-content single-cell combinatorial indexing. Nat Biotechnol (2021). https://doi.org/10.1038/s41587-021-00962-z

Research categories – Cell biology, cancer-general, research, DNA Fragment TAGS- DNA, sequencing, cell fragments, single-cell

Other related articles published on this Open Access Online Scientific Journal include the following:

Series B: Frontiers in Genomics Research

Series Content Consultant:

Larry H. Bernstein, MD, FCAP, Emeritus CSO, LPBI Group

Volume Content Consultant:

Prof. Marcus W. Feldman

BURNET C. AND MILDRED FINLEY WOHLFORD PROFESSOR IN THE SCHOOL OF HUMANITIES AND SCIENCES

Stanford University, Co-Director, Center for Computational, Evolutionary and Human Genetics (2012 – Present)

Latest in Genomics Methodologies for Therapeutics:

Gene Editing, NGS & BioInformatics,

Simulations and the Genome Ontology

2019

Volume Two

https://www.amazon.com/dp/B08385KF87

Part 4: Single Cell Genomics

Introduction to Part 4: Single Cell Genomics – Voice of Aviva Lev-Ari & Stephen Williams

4.1 The Science

4.1.1 Single-cell biology

Special | 05 July 2017

https://www.nature.com/collections/gbljnzchgg

4.1.2 The race to map the human body — one cell at a time, A host of detailed cell atlases could revolutionize understanding of cancer and other diseases

by Heidi Ledford 20 February 2017

https://www.nature.com/news/the-race-to-map-the-human-body-one-cell-at-a-time-1.21508

4.1.3 Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

Curator: Aviva Lev-Ari, PhD, RN

Single-cell Genomics: Directions in Computational and Systems Biology – Contributions of Prof. Aviv Regev @Broad Institute of MIT and Harvard, Cochair, the Human Cell Atlas Organizing Committee with Sarah Teichmann of the Wellcome Trust Sanger Institute

4.1.4 Cellular Genetics

https://www.sanger.ac.uk/science/programmes/cellular-genetics

4.1.5 Cellular Genomics

https://www.garvan.org.au/research/cellular-genomics

4.1.6 SINGLE CELL GENOMICS 2019 – sometimes the sum of the parts is greater than the whole, September 24-26, 2019, Djurönäset, Stockholm, Sweden http://www.weizmann.ac.il/conferences/SCG2019/single-cell-genomics-2019

Reporter: Aviva Lev-Ari, PhD, RN

SINGLE CELL GENOMICS 2019, September 24-26, 2019, Djurönäset, Stockholm, Sweden

4.1.7 Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

Reporter: Aviva Lev-Ari, PhD, RN

Norwich Single-Cell Symposium 2019, Earlham Institute, single-cell genomics technologies and their application in microbial, plant, animal and human health and disease, October 16-17, 2019, 10AM-5PM

4.1.8 Newly Found Functions of B Cell

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Newly Found Functions of B Cell

4.1.9 RESEARCH HIGHLIGHTS: HUMAN CELL ATLAS

https://www.broadinstitute.org/research-highlights-human-cell-atlas

4.2 Technologies and Methodologies

4.2.1 How to build a human cell atlas – Aviv Regev is a maven of hard-core biological analyses. Now she is part of an effort to map every cell in the human body.

Anna Nowogrodzki, 05 July 2017, Article tools

https://www.nature.com/news/how-to-build-a-human-cell-atlas-1.22239

4.2.2 Featuring Computational and Systems Biology Program at Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute (SKI), The Dana Pe’er Lab

Reporter: Aviva Lev-Ari, PhD, RN

Featuring Computational and Systems Biology Program at Memorial Sloan Kettering Cancer Center, Sloan Kettering Institute (SKI), The Dana Pe’er Lab

4.2.3 Genomic Diagnostics: Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single Molecule DNA Sequencing

Curator: Aviva Lev-Ari, PhD, RN

Genomic Diagnostics: Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single Molecule DNA Sequencing

4.2.4 Three Technology Leaders in Single Cell Sequencing: 10X Genomics, Illumina and MissionBio

Reporter: Aviva Lev-Ari, PhD, RN

Three Technology Leaders in Single Cell Sequencing: 10X Genomics, Illumina and MissionBio

4.2.5 scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

scPopCorn: A New Computational Method for Subpopulation Detection and their Comparative Analysis Across Single-Cell Experiments

4.2.6 Nano-guided cell networks: new methods to detect intracellular signaling and implications

Curator: Stephen J. Williams, PhD

Nano-guided cell networks: new methods to detect intracellular signaling and implications

4.3 Clinical Aspects

4.3.1 Using single cell sequencing data to model the evolutionary history of a tumor.

Kim KI, Simon R.

BMC Bioinformatics. 2014 Jan 24;15:27. doi: 10.1186/1471-2105-15-27.

PMID:

4.3.2 eProceedings 2019 Koch Institute Symposium – 18th Annual Cancer Research Symposium – Machine Learning and Cancer, June 14, 2019, 8:00 AM-5:00 PM ET MIT Kresge Auditorium, 48 Massachusetts Ave, Cambridge, MA

Real Time Press Coverage: Aviva Lev-Ari, PhD, RN

eProceeding 2019 Koch Institute Symposium – 18th Annual Cancer Research Symposium – Machine Learning and Cancer, June 14, 2019, 8:00 AM-5:00 PMET MIT Kresge Auditorium, 48 Massachusetts Ave, Cambridge, MA

4.3.3 The Impact of Heterogeneity on Single-Cell Sequencing

Samantha L. Goldman1,2, Matthew MacKay1,2, Ebrahim Afshinnekoo1,2,3, Ari M. Melnick4, Shuxiu Wu5,6 and Christopher E. Mason1,2,3,7*

https://www.frontiersin.org/articles/10.3389/fgene.2019.00008/full

4.3.4 Single-cell approaches to immune profiling

https://www.nature.com/articles/d41586-018-05214-w

4.3.5 Single-cell sequencing made simple. Data from thousands of single cells can be tricky to analyse, but software advances are making it easier.

by Jeffrey M. Perkel

https://www.nature.com/news/single-cell-sequencing-made-simple-1.22233

4.3.6 Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

Single-cell RNA-seq helps in finding intra-tumoral heterogeneity in pancreatic cancer

4.3.7 Cancer Genomics: Multiomic Analysis of Single Cells and Tumor Heterogeneity

Curator: Stephen J. Williams, PhD

Cancer Genomics: Multiomic Analysis of Single Cells and Tumor Heterogeneity

4.4 Business and Legal

4.4.1 iBioChips integrate diagnostic assays and cellular engineering into miniaturized chips that achieve cutting-edge sensitivity and high-throughput. We have resolved traditional biotech challenges with innovative biochip approaches

https://ibiochips.com/?gclid=Cj0KCQjwuLPnBRDjARIsACDzGL0wb6u79VHHkftodfApMYs-oxI-5cOZIBUaELdmd2wDOIk3W0OQg2caAqMyEALw_wcB

4.4.2 Targeted Single-Cell Solutions for High Impact Applications – Mission Bio’s Tapestri® Platform is the only technology that provides single-cell targeted DNA sequencing at single-base resolution.

Homepage

Part 4: Summary – Single Cell Genomics – Voice of Stephen Williams

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Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

Posted in Artificial Intelligence in CANCER, Cancer - General, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Screening, Clinical Genomics, CRISPR/Cas9 & Gene Editing, Genetics & Innovations in Treatment, Machine Learning, Mutant Gene Expression, Personalized and Precision Medicine & Genomic Research, Precision Cancer Medicine, tagged Artificial intelligence, Cancer, Cancer prognosis prediction, cancer progression, computational algorithm, driver gene, Machine Learning on May 4, 2021| Leave a Comment »

Machine Learning (ML) in cancer prognosis prediction helps the researcher to identify multiple known as well as candidate cancer diver genes

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

This image has an empty alt attribute; its file name is morethanthes.jpg — **Seeing “through” the cancer with the power of data analysis — possible with the help of artificial intelligence. Credit: MPI f. Molecular Genetics/ Ella Maru Studio**
**Image Source: https://medicalxpress.com/news/2021-04-sum-mutations-cancer-genes-machine.html**

Cancer has been characterized as a heterogeneous disease consisting of many different subtypes. The early diagnosis and prognosis of a cancer type have become a necessity in cancer research, as it can facilitate the subsequent clinical management of patients. The importance of classifying cancer patients into high or low-risk groups has led many research teams, from the biomedical and the bioinformatics field, to study the application of machine learning (ML) and Artificial Intelligence (AI) methods. Therefore, these techniques have been utilized as an aim to model the progression and treatment of cancerous conditions by predicting new algorithms.

In the majority of human cancers, heritable loss of gene function through cell division may be mediated as often by epigenetic as by genetic abnormalities. Epigenetic modification occurs through a process of interrelated changes in CpG island methylation and histone modifications. Candidate gene approaches of cell cycle, growth regulatory and apoptotic genes have shown epigenetic modification associated with loss of cognate proteins in sporadic pituitary tumors.

On 11th November 2020, researchers from the University of California, Irvine, has established the understanding of epigenetic mechanisms in tumorigenesis and publicized a previously undetected repertoire of cancer driver genes. The study was published in “Science Advances”

Researchers were able to identify novel tumor suppressor genes (TSGs) and oncogenes (OGs), particularly those with rare mutations by using a new prediction algorithm, called DORGE (Discovery of Oncogenes and tumor suppressor genes using Genetic and Epigenetic features) by integrating the most comprehensive collection of genetic and epigenetic data.

The senior author Wei Li, Ph.D., the Grace B. Bell chair and professor of bioinformatics in the Department of Biological Chemistry at the UCI School of Medicine said

Existing bioinformatics algorithms do not sufficiently leverage epigenetic features to predict cancer driver genes, even though epigenetic alterations are known to be associated with cancer driver genes.

The Study

This study demonstrated how cancer driver genes, predicted by DORGE, included both known cancer driver genes and novel driver genes not reported in current literature. In addition, researchers found that the novel dual-functional genes, which DORGE predicted as both TSGs and OGs, are highly enriched at hubs in protein-protein interaction (PPI) and drug/compound-gene networks.

**Flowchart for the illustration of the DORGE method**
**Image Source**: https://advances.sciencemag.org/content/suppl/2020/11/09/6.46.eaba6784.DC1/aba6784_SM.pdf

Prof. Li explained that the DORGE algorithm, successfully leveraged public data to discover the genetic and epigenetic alterations that play significant roles in cancer driver gene dysregulation and could be instrumental in improving cancer prevention, diagnosis and treatment efforts in the future.

Another new algorithmic prediction for the identification of cancer genes by Machine Learning has been carried out by a team of researchers at the Max Planck Institute for Molecular Genetics (MPIMG) in Berlin and the Institute of Computational Biology of Helmholtz Zentrum München combining a wide variety of data analyzed it with “Artificial Intelligence” and identified numerous cancer genes. They termed the algorithm as EMOGI (Explainable Multi-Omics Graph Integration). EMOGI can predict which genes cause cancer, even if their DNA sequence is not changed. This opens up new perspectives for targeted cancer therapy in personalized medicine and the development of biomarkers. The research was published in Nature Machine Intelligence on 12th April 2021.

In cancer, cells get out of control. They proliferate and push their way into tissues, destroying organs and thereby impairing essential vital functions. This unrestricted growth is usually induced by an accumulation of DNA changes in cancer genes—i.e. mutations in these genes that govern the development of the cell. But some cancers have only very few mutated genes, which means that other causes lead to the disease in these cases.

The Study

**Overlap of EMOGI’s positive predictions with known cancer genes (KCGs) and candidate cancer genes**
**Image Source**: https://static-content.springer.com/esm/art%3A10.1038%2Fs42256-021-00325-y/MediaObjects/42256_2021_325_MOESM1_ESM.pdf

The aim of the study has been represented in 4 main headings

Additional targets for personalized medicine
Better results by combination
In search of hints for further studies
Suitable for other types of diseases as well

The team was headed by Annalisa Marsico. The team used the algorithm to identify 165 previously unknown cancer genes. The sequences of these genes are not necessarily altered-apparently, already a dysregulation of these genes can lead to cancer. All of the newly identified genes interact closely with well-known cancer genes and be essential for the survival of tumor cells in cell culture experiments. The EMOGI can also explain the relationships in the cell’s machinery that make a gene a cancer gene. The software integrates tens of thousands of data sets generated from patient samples. These contain information about DNA methylations, the activity of individual genes and the interactions of proteins within cellular pathways in addition to sequence data with mutations. In these data, a deep-learning algorithm detects the patterns and molecular principles that lead to the development of cancer.

Marsico says

Ideally, we obtain a complete picture of all cancer genes at some point, which can have a different impact on cancer progression for different patients

Unlike traditional cancer treatments such as chemotherapy, personalized treatments are tailored to the exact type of tumor. “The goal is to choose the best treatment for each patient, the most effective treatment with the fewest side effects. In addition, molecular properties can be used to identify cancers that are already in the early stages.

Roman Schulte-Sasse, a doctoral student on Marsico’s team and the first author of the publication says

To date, most studies have focused on pathogenic changes in sequence, or cell blueprints, at the same time, it has recently become clear that epigenetic perturbation or dysregulation gene activity can also lead to cancer.

This is the reason, researchers merged sequence data that reflects blueprint failures with information that represents events in cells. Initially, scientists confirmed that mutations, or proliferation of genomic segments, were the leading cause of cancer. Then, in the second step, they identified gene candidates that are not very directly related to the genes that cause cancer.

Clues for future directions

The researcher’s new program adds a considerable number of new entries to the list of suspected cancer genes, which has grown to between 700 and 1,000 in recent years. It was only through a combination of bioinformatics analysis and the newest Artificial Intelligence (AI) methods that the researchers were able to track down the hidden genes.

Schulte-Sasse says “The interactions of proteins and genes can be mapped as a mathematical network, known as a graph.” He explained by giving an example of a railroad network; each station corresponds to a protein or gene, and each interaction among them is the train connection. With the help of deep learning—the very algorithms that have helped artificial intelligence make a breakthrough in recent years – the researchers were able to discover even those train connections that had previously gone unnoticed. Schulte-Sasse had the computer analyze tens of thousands of different network maps from 16 different cancer types, each containing between 12,000 and 19,000 data points.

Many more interesting details are hidden in the data. Patterns that are dependent on particular cancer and tissue were seen. The researchers were also observed this as evidence that tumors are triggered by different molecular mechanisms in different organs.

Marsico explains

The EMOGI program is not limited to cancer, the researchers emphasize. In theory, it can be used to integrate diverse sets of biological data and find patterns there. It could be useful to apply our algorithm for similarly complex diseases for which multifaceted data are collected and where genes play an important role. An example might be complex metabolic diseases such as diabetes.

Main Source

New prediction algorithm identifies previously undetected cancer driver genes

https://advances.sciencemag.org/content/6/46/eaba6784

Integration of multiomics data with graph convolutional networks to identify new cancer genes and their associated molecular mechanisms

https://www.nature.com/articles/s42256-021-00325-y#citeas

Other Related Articles published in this Open Access Online Scientific Journal include the following:

AI System Used to Detect Lung Cancer

Reporter: Irina Robu, PhD

https://pharmaceuticalintelligence.com/2019/06/28/ai-system-used-to-detect-lung-cancer/

Deep Learning extracts Histopathological Patterns and accurately discriminates 28 Cancer and 14 Normal Tissue Types: Pan-cancer Computational Histopathology Analysis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/10/28/deep-learning-extracts-histopathological-patterns-and-accurately-discriminates-28-cancer-and-14-normal-tissue-types-pan-cancer-computational-histopathology-analysis/

Evolution of the Human Cell Genome Biology Field of Gene Expression, Gene Regulation, Gene Regulatory Networks and Application of Machine Learning Algorithms in Large-Scale Biological Data Analysis

Curator & Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2019/12/08/evolution-of-the-human-cell-genome-biology-field-of-gene-expression-gene-regulation-gene-regulatory-networks-and-application-of-machine-learning-algorithms-in-large-scale-biological-data-analysis/

Cancer detection and therapeutics

Curator: Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/05/02/cancer-detection-and-therapeutics/

Free Bio-IT World Webinar: Machine Learning to Detect Cancer Variants

Reporter: Stephen J. Williams, PhD

https://pharmaceuticalintelligence.com/2016/05/04/free-bio-it-world-webinar-machine-learning-to-detect-cancer-variants/

Artificial Intelligence: Genomics & Cancer

https://pharmaceuticalintelligence.com/ai-in-genomics-cancer/

Premalata Pati, PhD, PostDoc in Biological Sciences, Medical Text Analysis with Machine Learning

https://pharmaceuticalintelligence.com/2021-medical-text-analysis-nlp/premalata-pati-phd-postdoc-in-pharmaceutical-sciences-medical-text-analysis-with-machine-learning/

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Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

Posted in Apoptosis, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Cell Biology, Signaling & Cell Circuits, Cell death pathways, Cell Processing System in Cell Therapy Process Development, Drug Carrier Design, Drug Delivery Platform Technology, Funding Opportunities for Cancer Research, Proteolysis, Proteosome, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Small Molecules in Development of Therapeutic Drugs, Ubiquitin, tagged Cancer, E3 Ligase, PROTAC, protein degradation on June 22, 2020| Leave a Comment »

Live Conference Coverage AACR 2020 in Real Time: Monday June 22, 2020 Late Day Sessions

Reporter: Stephen J. Williams, PhD

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Register for FREE at https://www.aacr.org/

AACR VIRTUAL ANNUAL MEETING II

June 22-24: Free Registration for AACR Members, the Cancer Community, and the Public
This virtual meeting will feature more than 120 sessions and 4,000 e-posters, including sessions on cancer health disparities and the impact of COVID-19 on clinical trials

This Virtual Meeting is Part II of the AACR Annual Meeting. Part I was held online in April and was centered only on clinical findings. This Part II of the virtual meeting will contain all the Sessions and Abstracts pertaining to basic and translational cancer research as well as clinical trial findings.

REGISTER NOW

Virtual Educational Session

Prevention Research, Science Policy, Epidemiology, Survivorship

Carcinogens at Home: Science and Pathways to Prevention

Chemicals known to cause cancer are used and released to the environment in large volumes, exposing people where they live, work, play, and go to school. The science establishing an important role for such exposures in the development of cancers continues to strengthen, yet cancer prevention researchers are largely unfamiliar with the data drawn upon in identifying carcinogens and making decisions about their use. Characterizing and reducing harmful exposures and accelerating the devel

Julia Brody, Kathryn Z. Guyton, Polly J. Hoppin, Bill Walsh, Mary H. Ward

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Educational Session

Tumor Biology, Molecular and Cellular Biology/Genetics, Clinical Research Excluding Trials

EMT Still Matters: Let’s Explore! – Dedicated to the Memory of Isaiah J. Fidler

During carcinoma progression, initially benign epithelial cells acquire the ability to invade locally and disseminate to distant tissues by activating epithelial-mesenchymal transition (EMT). EMT is a cellular process during which epithelial cells lose their epithelial features and acquire mesenchymal phenotypes and behavior. Growing evidence supports the notion that EMT programs during tumor progression are usually activated to various extents and often partial and reversible, thus pr

Jean-Paul Thiery, Heide L Ford, Jing Yang, Geert Berx

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

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

One of These Things Is Not Like the Other: The Many Faces of Senescence in Cancer

Cellular senescence is a stable cell growth arrest that is broadly recognized to act as a barrier against tumorigenesis. Senescent cells acquire a senescence-associated secretory phenotype (SASP), a transcriptional response involving the secretion of inflammatory cytokines, immune modulators, and proteases that can shape the tumor microenvironment. The SASP can initially stimulate tumor immune surveillance and reinforce growth arrest. However, if senescent cells are not removed by the

Clemens A Schmitt, Andrea Alimonti, René Bernards

DETAILS

Monday, June 22

1:30 PM – 3:00 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Molecular and Cellular Biology/Genetics

Recent Advances in Applications of Cell-Free DNA

The focus of this educational session will be on recent developments in cell-free DNA (cfDNA) analysis that have the potential to impact the care of cancer patients. Tumors continually shed DNA into the circulation, where it can be detected as circulating tumor DNA (ctDNA). Analysis of ctDNA has become a routine part of care for a subset of patients with advanced malignancies. However, there are a number of exciting potential applications that have promising preliminary data but that h

Michael R Speicher, Maximilian Diehn, Aparna Parikh

DETAILS

Monday, June 22

1:30 PM – 3:30 PM EDT

Virtual Methods Workshop

Clinical Research Excluding Trials, Clinical Trials, Experimental and Molecular Therapeutics, Molecular and Cellular Biology/Genetics

Translating Genetics and Genomics to the Clinic and Population

This session will describe how advances in understanding cancer genomes and in genetic testing technologies are being translated to the clinic. The speakers will illustrate the clinical impact of genomic discoveries for diagnostics and treatment of common tumor types in adults and in children. Cutting-edge technologies for characterization of patient and tumor genomes will be described. New insights into the importance of patient factors for cancer risk and outcome, including predispos

Heather L. Hampel, Gordana Raca, Jaclyn Biegel, Jeffrey M Trent

DETAILS

Monday, June 22

1:30 PM – 3:22 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Drug Development, Epidemiology

Under-representation in Clinical Trials and the Implications for Drug Development

The U.S. Food and Drug Administration relies on data from clinical trials to determine whether medical products are safe and effective. Ideally, patients enrolled in those trials are representative of the population in which the product will be used if approved, including people of different ages, races, ethnic groups, and genders. Unfortunately, with few patients enrolling in clinical trials, many groups are not well-represented in clinical trials. This session will explore challenges

Ajay K. Nooka, Nicole J. Gormley, Kenneth C Anderson, Ruben A. Mesa, Daniel J. George, Yelak Biru, RADM Richardae Araojo, Lola A. Fashoyin-Aje

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Cancer Chemistry

Targeted Protein Degradation: Target Validation Tools and Therapeutic Opportunity

This educational session will cover the exciting emerging field of targeted protein degradation. Key learning topics will include: 1. an introduction to the technology and its relevance to oncology; 2. PROTACS, degraders, and CELMoDs; 3. enzymology and protein-protein interactions in targeted protein degraders; 4. examples of differentiated biology due to degradation vs. inhibition; 5. how to address questions of specificity; and 6. how the field is approaching challenges in optimizing therapies

George Burslem, Mary Matyskiela, Lyn H. Jones, Stewart L Fisher, Andrew J Phillips

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Bioinformatics and Systems Biology, Experimental and Molecular Therapeutics, Drug Development, Molecular and Cellular Biology/Genetics

Obstacles and opportunities for protein degradation drug discovery

Lyn H. Jones

PROTACs ubiquitin mediated by E3 ligases; first discovered by DeShaies and targeted to specific proteins
PROTACs used in drug discovery against a host of types of targets including kinases and membrane receptors
PROTACs can be modular but lack molecular structural activity relationships
can use chemical probes for target validation
four requirements: candidate exposure at site of action (for example lipophilicity for candidates needed to cross membranes and accumulate in lysosomes), target engagement (ternary occupancy as measured by FRET), functional pharmacology, relevant phenotype
PROTACs hijack the proteosomal degradation system

Proteolysis-targeting chimeras as therapeutics and tools for biological discovery

George Burslem

first PROTAC developed to coopt the VHL ubiquitin ligase system which degrades HIF1alpha but now modified for EREalpha
in screen for potential PROTACS there were compounds which bound high affinity but no degradation so phenotypic screening very important
when look at molecular dynamics can see where PROTAC can add additional protein protein interaction, verifed by site directed mutagenesis
able to target bcr-Abl
he says this is a rapidly expanding field because of all the new E3 ligase targets being discovered

Expanding the horizons of cereblon modulators

Mary Matyskiela

Translating cellular targeted protein degradation to in vivo models using an enzymology framework

Stewart L Fisher

new targeting compounds have an E3 ligase binding domain, a target binding domain and a linker domain
in vivo these compounds are very effective; BRD4 degraders good invitro and in vivo with little effect on body weight
degraders are essential activators of E3 ligases as these degraders bring targets in close proximity so activates a catalytic cycle of a multistep process (has now high turnover number)
in enzymatic pathway the degraders make a productive complex so instead of a kcat think of measuring a kprod or productivity of degraders linked up an E3 ligase
the degraders are also affecting the rebound protein synthesis; so Emax never to zero and see a small rebound of protein synthesis

Data-Driven Approaches for Choosing Combinatorial Therapies

Drug combinations remain the gold standard for treating cancer, as they significantly outperform single agents. However, due to the enormous size of drug combination space, it is virtually impossible to interrogate all possible combinations. This session will discuss approaches to identify novel combinations using both experimental and computational approaches. Speakers will discuss i) approaches to drug screening in cell lines, the impact of the microenvironment, and attempts to more

Bence Szalai, James E Korkola, Lisa Tucker-Kellogg, Jeffrey W Tyner

DETAILS

Monday, June 22

3:45 PM – 5:21 PM EDT

Virtual Educational Session

Tumor Biology

Cancer Stem Cells and Therapeutic Resistance

Cancer stem cells are a subpopulation of cells with a high capacity for self-renewal, differentiation and resistance to therapy. In this session, we will define cancer stem cells, discuss cellular plasticity, interactions between cancer stem cells and the tumor microenvironment, and mechanisms that contribute to therapeutic resistance.

Robert S Kerbel, Dolores Hambardzumyan, Jennifer S. Yu

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Drug Development, Experimental and Molecular Therapeutics

Molecular Imaging in Cancer Research

This session will cover the fundamentals as well as the major advances made in the field of molecular imaging. Topics covered will include the basics for optical, nuclear, and ultrasound imaging; the pros and cons of each modality; and the recent translational advancements. Learning objectives include the fundamentals of each imaging modality, recent advances in the technology, the processes involved to translate an imaging agent from bench to bedside, and how molecular imaging can gui

Julie Sutcliffe, Summer L Gibbs, Mark D Pagel, Katherine W Ferrara

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Immunology, Experimental and Molecular Therapeutics, Drug Development

Tumor Endothelium: The Gatekeepers of Tumor Immune Surveillance

Tumor-associated endothelium is a gatekeeper that coordinates the entry and egress of innate and adaptive immune cells within the tumor microenvironment. This is achieved, in part, via the coordinated expression of chemokines and cell adhesion molecules on the endothelial cell surface that attract and retain circulating leukocytes. Crosstalk between adaptive immune cells and the tumor endothelium is therefore essential for tumor immune surveillance and the success of immune-based thera

Dai Fukumura, Maria M Steele, Wen Jiang, Andrew C Dudley

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Immunology, Experimental and Molecular Therapeutics

Novel Strategies in Cancer Immunotherapy: The Next Generation of Targets for Anticancer Immunotherapy

T-cell immunotherapy in the form of immune checkpoint blockade or cellular T-cell therapies has been tremendously successful in some types of cancer. This success has opened the door to consider what other modalities or types of immune cells can be harnessed for exert antitumor functions. In this session, experts in their respective fields will discuss topics including novel approaches in immunotherapy, including NK cells, macrophage, and viral oncotherapies.

Evanthia Galanis, Kerry S Campbell, Milan G Chheda, Jennifer L Guerriero

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Tumor Biology, Drug Development, Immunology, Clinical Research Excluding Trials

Benign Cells as Drivers of Cancer Progression: Fat and Beyond

Carcinomas develop metastases and resistance to therapy as a result of interaction with tumor microenvironment, composed of various nonmalignant cell types. Understanding the complexity and origins of tumor stromal cells is a prerequisite for development of effective treatments. The link between obesity and cancer progression has revealed the engagement of adipose stromal cells (ASC) and adipocytes from adjacent fat tissue. However, the molecular mechanisms through which they stimulate

Guojun Wu, Matteo Ligorio, Mikhail Kolonin, Maria T Diaz-Meco

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Educational Session

Clinical Research Excluding Trials, Experimental and Molecular Therapeutics, Tumor Biology

Dharma Master Jiantai Symposium on Lung Cancer: Know Thy Organ – Lessons Learned from Lung and Pancreatic Cancer Research

The term “cancer” encompasses hundreds of distinct disease entities involving almost every possible site in the human body. Effectively interrogating cancer, either in animals models or human specimens, requires a deep understanding of the involved organ. This includes both the normal cellular constituents of the affected tissue as well as unique aspects of tissue-specific tumorigenesis. It is critical to “Know Thy Organ” when studying cancer. This session will focus on two of the most

Trudy G Oliver, Hossein Borghaei, Laura Delong Wood, Howard C Crawford

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Clinical Trials

Clinical Trial Design: Part 1: Novel Approaches and Methods in Clinical Trial Design

Good clinical trial design has always had to balance the competing interests of effectively and convincingly answering the question with the limitations imposed by scarce resources, complex logistics, and risks and potential benefits to participants. New targeted therapies, immuno-oncology, and novel combination treatments add new challenges on top of the old ones. This session will introduce these concerns and 1) suggest ways to consider what outcomes are relevant, 2) how we can best

Mary W. Redman, Nolan A. Wages, Susan G Hilsenbeck, Karyn A. Goodman

DETAILS

Monday, June 22

3:45 PM – 5:45 PM EDT

Virtual Methods Workshop

Tumor Biology, Drug Development

High-Throughput Screens for Drivers of Progression and Resistance

The sequencing of human cancers now provides a landscape of the genetic alterations that occur in human cancer, and increasingly knowledge of somatic genetic alterations is becoming part of the evaluation of cancer patients. In some cases, this information leads directly to the selection of particular therapeutic approaches; however, we still lack the ability to decipher the significance of genetic alterations in many cancers. This session will focus on recent developments that permit the identification of molecular targets in specific cancers. This information, coupled with genomic characterization of cancer, will facilitate the development of new therapeutic agents and provide a path to implement precision cancer medicine to all patients.

William C Hahn, Mark A Dawson, Mariella Filbin, Michael Bassik

DETAILS

Monday, June 22

3:45 PM – 5:15 PM EDT

Defining a cancer dependency map

William C Hahn

Introduction

William C Hahn

Genome-scale CRISPR screens in 3D spheroids identify cancer vulnerabilities

Michael Bassik

Utilizing single-cell RNAseq and CRISPR screens to target cancer stem cells in pediatric brain tumors

Mariella Filbin

many gliomas are defined by discreet mutational spectra that also discriminates based on age and site as well (for example many cortical tumors have mainly V600E Braf mutations while thalamus will be FGFR1
they did single cell RNAseq on needle biopsy from 7 gliomas which gave about 3500 high quality single cells; obtained full length RNA
tumors clustered mainly where the patient it came from but had stromal cell contamination probably so did a deconvolution? Copy number variation showed which were tumor cells and did principle component analysis
it seems they used a human glioma model as training set
identified a stem cell like glioma cell so concentrated on the genes altered in these for translational studies
developed multiple PDX models from patients
PDX transcriptome closest to patient transcriptome but organoid grown in serum free very close while organoids grown in serum very distinct transcriptome
developed a CRISPR barcoded library to determine genes for survival genes
pulled out BMI1 and EZH2 (polycomb complex proteins) as good targets

Virtual Methods Workshop

Prevention Research, Survivorship, Clinical Research Excluding Trials, Epidemiology

Implementation Science Methods for Cancer Prevention and Control in Diverse Populations: Integration of Implementation Science Methods in Care Settings

Through this Education Session we will use examples from ongoing research to provide an overview of implementation science approaches to cancer prevention and control research. We draw on examples to highlight study design approaches, research methods, and real-world solutions when applying implementation science to achieve health equity. Approaches to defining change in the care setting and measuring sustained changes are also emphasized. Using real examples of patient navigation prog

Graham A Colditz, Sanja Percac-Lima, Nathalie Huguet

DETAILS

Monday, June 22

3:45 PM – 5:30 PM EDT

Virtual Educational Session

Regulatory Science and Policy, Epidemiology

COVID-19 and Cancer: Guidance for Clinical Trial Conduct and Considerations for RWE

This session will consider the use of real-world evidence in the context of oncology clinical trials affected by the COVID-19 pandemic. Key aspects of the FDA’s recent “Guidance on Conduct of Clinical Trials of Medical Products of Medical Products during COVID-19 Public Health Emergency” will be discussed, including telemedicine, accounting for missing data, obtaining laboratory tests and images locally, using remote informed consent procedures, and additional considerations for contin

Wendy Rubinstein, Paul G. Kluetz, Amy P. Abernethy, Jonathan Hirsch, C.K. Wang

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Symposium: New Drugs on the Horizon Part 3 12:30-1:25 PM

Reporter: Stephen J. Williams, PhD

New Drugs on the Horizon: Part 3
Introduction

Andrew J. Phillips, C4 Therapeutics

symposium brought by AACR CICR and had about 30 proposals for talks and chose three talks
unfortunately the networking event is not possible but hope to see you soon in good health

ABBV-184: A novel survivin specific T cell receptor/CD3 bispecific therapeutic that targets both solid tumor and hematological malignancies

Edward B Reilly
AbbVie Inc. @abbvie

T-cell receptors (TCR) can recognize the intracellular targets whereas antibodies only recognize the 25% of potential extracellular targets
survivin is expressed in multiple cancers and correlates with poor survival and prognosis
CD3 bispecific TCR to survivn (Ab to CD3 on T- cells and TCR to survivin on cancer cells presented in MHC Class A3)
ABBV184 effective in vivo in lung cancer models as single agent;
in humanized mouse tumor models CD3/survivin bispecific can recruit T cells into solid tumors; multiple immune cells CD4 and CD8 positive T cells were found to infiltrate into tumor
therapeutic window as measured by cytokine release assays in tumor vs. normal cells very wide (>25 fold)
ABBV184 does not bind platelets and has good in vivo safety profile
First- in human dose determination trial: used in vitro cancer cell assays to determine 1st human dose
looking at AML and lung cancer indications
phase 1 trial is underway for safety and efficacy and determine phase 2 dose
survivin has very few mutations so they are not worried about a changing epitope of their target TCR peptide of choice

The discovery of TNO155: A first in class SHP2 inhibitor

Matthew J. LaMarche
Novartis @Novartis

SHP2 is an intracellular phosphatase that is upstream of MEK ERK pathway; has an SH2 domain and PTP domain
knockdown of SHP2 inhibits tumor growth and colony formation in soft agar
55 TKIs there are very little phosphatase inhibitors; difficult to target the active catalytic site; inhibitors can be oxidized at the active site; so they tried to target the two domains and developed an allosteric inhibitor at binding site where three domains come together and stabilize it
they produced a number of chemical scaffolds that would bind and stabilize this allosteric site
block the redox reaction by blocking the cysteine in the binding site
lead compound had phototoxicity; used SAR analysis to improve affinity and reduce phototox effects
was very difficult to balance efficacy, binding properties, and tox by adjusting stuctures
TNO155 is their lead into trials
SHP2 expressed in T cells and they find good combo with I/O with uptick of CD8 cells
TNO155 is very selective no SHP1 inhibition; SHP2 can autoinhibit itself when three domains come together and stabilize; no cross reactivity with other phosphatases
they screened 1.5 million compounds and got low hit rate so that is why they needed to chemically engineer and improve on the classes they found as near hits

Closing Remarks

Xiaojing Wang
Genentech, Inc. @genentech

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

Posted in Biomarkers: Inflammation, Cancer - General, Cancer and Current Therapeutics, Cancer Researchers Fighting COVID-19, Coronavirus Gene Expression, COVID-19, COVID-19: Pandemic Surgery Guidance, Economic Impact of Coronavirus Pandemic, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, SAR-Cov-2 a vasculotropic (blood vessels) RNA Virus, SARS-CoV-2, Seasonality & Environmental Factors in Resurgence, Serology tests for coronavirus antibodies, Vaccinology, Viral diseases, Virus Infective Acute Respiratory Syndrome: SARS-CoV, tagged #COVID-19, #COVID19andcancer, AACR, American Association for Cancer Research, Cancer, COVID-19, patient safety, SARS-CoV-2 on April 28, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 28, 2020 Session on COVID-19 and Cancer 9:00 AM

Reporter: Stephen J. Williams, PhD

COVID-19 and Cancer

Introduction

Antoni Ribas
UCLA Medical Center

Almost 60,000 viewed the AACR 2020 Virtual meeting for the April 27 session
The following speakers were the first cancer researchers treating patients at the epicenters of the pandemic even though nothing was known about the virus

The experience of treating patients with cancer during the COVID-19 pandemic in China
Li Zhang, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

reporting a retrospective study from three hospitals from Wuhan
2.2% of Wuhan cancer patients were COVID positive; most were lung cancers and most male; 35% were stage four
most have hospital transmission of secondary infection; had severe events when admitted
74% were prescribed antivirals like ganciclovir and others; iv IgG was given to some
mortailtiy rate of 26%; by April 4 54% were cured and discharged; median time of infection to severe event was 7 days; clinical presentation SARS sepsis, and shock
by day 10 in lung cancer patients, see lung path but after supportive therapy improved
cancer patients at stage four who did not receive therapy were at higher risk
cancer patients who had received chemo in last 14 days had higher risk of infection
they followed up with cancer patients on I/O inhibitors; it seemed there was only one patient that contracted COVID19 so there may not be as much risk with immune checkpoint inhibitors

TERAVOLT (Thoracic cancERs international coVid 19 cOLlaboraTion): First results of a global collaboration to address the impact of COVID-19 in patients with thoracic malignancies

Marina Chiara Garassino

@marinagarassino
Fondazione IRCCS Istituto Nazionale dei Tumori

Dr Marina Chiara Garassino is the Chief of the Thoracic Oncology Unit at Istituto Nazionale dei Tumori, Milan, Italy. She leads the strategy for clinical and translational research in advanced and locally advanced NSCLC, SCLC, mesothelioma and thymic malignancies. Istituto Nazionale dei Tumori in Milan is the most important comprehensive cancer in Italy and one of the most important in Europe. As a medical oncologist, she has done research in precision medicine and in immuno-oncology. Her main research interests have been mainly development of new drugs and therapeutical strategies and biomarkers. She has contributed to over 150 peer-reviewed publications, including publications as first or last author in the New England Journal of Medicine, Lancet Oncology, Journal of Clinical Oncology, Annals of Oncology. She has delivered many presentations at international congresses, including AACR, ASCO, ECCO, ESMO, WCLC. Her education includes a degree and further specialization in Medical Oncology at Università degli Studi in Milan. She achieved a Master Degree in Oncology management at University of Economics “Luigi Bocconi”. She completed her training with an ESMO Clinical fellowship in 2009 at Christie’s Hospital in Manchester (UK). She was a member of the EMA SAG (Scientific Advisory Group). She is serving as ESMO Council member as the Chair of the National Societies Committee. She was the ESMO National Representative for Italy for 5 years (2011-2017). She is serving on several ESMO Committees (Public Policy extended Committee, Press Committee, Women for Oncology Committee, Lung Cancer faculty, Membership Committee).She used to be an active member of the Young Oncologist Committee. She’s serving on both ESMO, WCLC and ASCO annual congress Lung Cancer Track (2019, and 2020), Chair of ESMO National Societies, from 2019. She is the founder and president of Women for Oncology Italy.

2 million confirmed cases but half of patients are asymptomatic and not tested; pooled prevalance of COVID in cancer patients in Italy was 2%; must take them as high risk patients
they were not prepared for pandemic lasting for months instead of days; March 15 in middle of outbreak they started TERAVOLT registry; by March 26 had IRB approval; they are accruing 17 new patients per week; Ontario also joined in and has become worldwide (21 countries involved); in registry they also included radiologic exams and COVID testing result
most patients were males and many smokers; 75% had SCLC; 83% of cases had one comorbility like hypertension and one third had at least one comorbility; 73.9% of patients were on treatment (they see this in their clinic: 30% on chemo or TKI alone; other patients were just on folowup
most of symptoms overlap with symptoms of lung cancer like pneumonia and pneumonitits and multi organ failure; most were hospitalized
unexpected high mortality among lung cancer patients with COVID19; this mortality seems due to COVID and not to cancer;
study had some limitations like short followup and some surgical cases so some bias may be present
she stresses don’t go it alone and make your own registry JOIN A REGISTRY

Outcome of cancer patients infected with COVID-19, including toxicity of cancer treatments
Fabrice Barlesi @barlesi
Gustave Roussy Cancer Campus

Professor Fabrice Barlesi

As a specialist in lung cancer, precision medicine and cancer immunology, Prof. Fabrice Barlesi is a major contributor to research in the field of novel oncological therapies. He was apppointed General Director of Gustave Roussy in January 2020.

Fabrice Barlesi is Professor of Medicine at the University of Aix-Marseille. He has been head of the Multidisciplinary Oncology and Innovative Therapies Department of the Nord Hospital in Marseille (Marseille Public Hospitals) and the Marseille Centre for Early Trials in Oncology (CLIP2) which were established by him. He holds a doctorate in Sciences and Management with methods of analysis of health care systems, together with an ESSEC (international business school) master’s degree in general hospital management.

Professor Barlesi was also a co-founder of the Marseille Immunopôle French Immunology network, which aims to coordinate immunological expertise in the Aix-Marseille metropolitan area. In this context, he has organised PIONeeR (Investment in the future RHU 2017), the major international Hospital-University research project whose objective is to improve understanding of resistance to immunotherapy – anti-PD1(L1) – in lung cancer and help to prevent and overcome it. He was also vice-chair of the PACA (Provence, Alps and Côte d’Azur) Region Cancer Research Directorate.

Professor Barlesi is the author and co-author of some 300 articles in international journals and specialist publications. In 2018, the European Society of Medical Oncology (ESMO) and the International Association for the Study of Lung Cancer (IASLC) awarded him the prestigious Heine H. Hansen prize. He appears in the 2019 world list of most influential researchers (Highly cited researchers, Web of Science Group).

March 14 started protective measures and at peak had increased commited beds at highest rate
12% of cancer patients tested positive for COVID; (by RTPCR); they curated data across different chemo regimens used
they retrospectively collected data; primary endpoint was clinical worsening; median of disease 13 days;
they actually had more breast cancer patients and other solid malignancies; 23% of covid cases no symptoms; 83% finally did have the symptoms after followup; diarhea actually in 10% of cases so clinics are seeing this as a symptom
CT scan showed 66% cases had pneumonitits like display; 25% patients were managed as outpatient
24% patients worsened during treatment but 75% were able to go home (treated at home or well)
I/O did not have negative outcome and you can use these drugs without increasing risk to COVID
although many clinical trials have been hindered they are actively recruiting for COVID-cancer studies
outcomes with respect to death and symptoms are comparable to worldwide stats

Adapting oncologic practice to COVID19 outbreak: From outpatient triage to risk assessment for specific treatment in Madrid, Spain
Carlos Gomez-Martin
Octubre University Hospital

MOST slides were DO NOT POST so as requested data will not be shown; this study will be published soon
Summary is that Spain is seeing statistics like other European countries and similar results
Tocilizumab, the IL6 antagonists had been suggested as a treatment for cytokine storm and they are involved in a trial with this agent; results will be published

Experience in using oncology drugs in patients with COVID-19

Paolo A. Ascierto
Istituto Nazionale Tumori IRCCS Fondazione Pascale

giving surgery only for patients at highest risk of cancer mortality so using neoadjuvant therapy more often
telemedicine is a viable strategy for patient consult
for metastatic melanoma they are given highest priority for treatment
they are conducting a tocilizumab clinical trial and have accrued over 300 patients
results are in press so please look for publication soon
also can use TNF inhibitor, JAK inhibitor, IL1 inhibitor to treat cytokine storm

COVID-19 and cancer: Flattening the curve but widening disparities
Louis P. Voigt
Memorial Sloan Kettering Cancer Center

Sloan has performed about 5000 COVID tests; 78 patients needed hospitilization; 15 died; 40% still in ICU
they do see many African American patients
mortality rates in US (published) have been around 50-60 % for cancer patients with COVID; Sloan prelim results are lower but still accruing data

Patients with cancer appear more vulnerable to SARS-COV-2: A multi-center study during the COVID-19 outbreak
Hongbing Cai
Zhongnan Hospital of Wuhan University

metastatic cancer showed much higher risk than non cancer but non metastatic showed increased risk too
main criteria of outcome was ICU admission
patients need to be isolated and personalized treatment plans need to be made
many comparisons were between non cancer and cancer which was clearest significance; had not looked at cancer types or stage grade or treatment
it appears that there are more questions right now than answers so data collection is a priority

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For other Articles on the Online Open Access Journal on COVID19 and Cancer please see

https://pharmaceuticalintelligence.com/coronavirus-portal/

Opinion Articles from the Lancet: COVID-19 and Cancer Care in China and Africa

Actemra, immunosuppressive which was designed to treat rheumatoid arthritis but also approved in 2017 to treat cytokine storms in cancer patients SAVED the sickest of all COVID-19 patients

The Second in a Series of Virtual Town Halls with Leading Oncologist on Cancer Patient Care during COVID-19 Pandemic: What you need to know

Responses to the COVID-19 outbreak from Oncologists, Cancer Societies and the NCI: Important information for cancer patients

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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

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Conference Coverage with Social Media, Curation, Drug Delivery Platform Technology, Drug Development Process, Drug Discovery Chemistry, Pharmaceutical Drug Discovery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacodynamics and Pharmacokinetics, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, Scientific & Biotech Conferences: Press Coverage, Small Molecules in Development of Therapeutic Drugs, tagged #pharmanews, @Biotech News, AACR, American Association for Cancer Research, Cancer, Estrogen receptor alpha, pharmacokinetic, Pharmacokinetics, real time conference coverage, SHP2, small drug development on April 27, 2020| Leave a Comment »

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 Pyramid^TM 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

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Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks 9 am

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cancer Screening, Conference Coverage with Social Media, interventional oncology, Personalized and Precision Medicine & Genomic Research, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tagged #endcancer, #pharmanews, @pharma_BI, AACR, American Association for Cancer Research, Cancer, cancer conference, Conference Coverage with Social Media, real time conference coverage on April 27, 2020| Leave a Comment »

Live Notes, Real Time Conference Coverage 2020 AACR Virtual Meeting April 27, 2020 Opening Remarks and Clinical Session 9 am

Reporter: Stephen J. Williams, PhD.

9:00 AM Opening Session

9:00 AM – 9:05 AM
– Opening Video

9:05 AM – 9:15 AM
– AACR President: Opening Remarks Elaine R. Mardis. Nationwide Children’s Hospital, Columbus, OH

Dr. Elaine R. Mardis, Has Been Named American Association for Cancer Research President-Elect 2018-2019. She will officially become President-Elect at #AACR18: https://t.co/jdum36WIc5 pic.twitter.com/FuKHRfPHCZ

— AACR (@AACR) March 20, 2018

Dr. Mardis is the Robert E. and Louise F. Dunn Distinguished Professor of Medicine @GenomeInstitute at Washington University of St. Louis School of Medicine.

Opening remarks: Dr. Mardis gave her welcome from her office. She expressed many thanks to healthcare workers and the hard work of scientists and researchers. She also expressed some regret for the many scientists who had wonderful research to present and how hard it was to make the decision to go virtual however she feels there now more than ever still needs a venue to discuss scientific and clinical findings. Some of the initiatives that she has had the opportunity to engage in the areas of groundbreaking discoveries and clinical trials. 606,000 lives will be lost in US this year from cancer. AACR is being vigilant as also an advocacy platform and public policy platform in Congress and Washington. The AACR has been at the front of public policy on electronic cigarettes. Blood Cancer Discovery is their newest journal. They are going to host joint conferences with engineers, mathematicians and physicists to discuss how they can help to transform oncology. Cancer Health Disparity Annual Conference is one of the fastest growing conferences. They will release a report later this year about the scope of the problem and policy steps needed to alleviate these disparities. Lack of racial and ethnic minorities in cancer research had been identified an issue and the AACR is actively working to reduce the disparities within the ranks of cancer researchers. Special thanks to Dr. Margaret Foti for making the AACR the amazing organization it is.

9:15 AM – 9:30 AM- AACR Annual Meeting Program Chair: Review of Program for AACR Virtual Annual Meeting Antoni Ribas. UCLA Medical Center, Los Angeles, CA

Dr. Antoni Ribas, @UCLAJCCC, Elected American Association for Cancer Research President-Elect 2019–2020. https://t.co/4MbTy1jEDN pic.twitter.com/zq40gHjfAb

— AACR (@AACR) March 28, 2019

Antoni Ribas, MD PhD is Professor, Medicine, Surgery, Molecular and Medical Pharmacology; Director, Parker Institute for Cancer Immunotherapy Center at UCLA; Director, UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program aribas@mednet.ucla.edu

The AACR felt it was important to keep the discourse in the cancer research field as the Annual AACR meeting is the major way scientists and clinicians discuss the latest and most pertinent results. A three day virtual meeting June 22-24 will focus more on the translational and basic research while this meeting is more focused on clinical trials. There will be educational programs during the June virtual meeting. The COVID in Cancer part of this virtual meeting was put in specially for this meeting and there will be a special meeting on this in July. They have created an AACR COVID task force. The AACR has just asked Congress and NIH to extend the grants due to the COVID induced shutdown of many labs.

9:30 Open Clinical Plenary Session (there are 17 sessions today but will only cover a few of these)

9:30 AM – 9:31 AM
– Chairperson Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD @noza512

9:30 AM – 9:31 AM
– Chairperson Manuel Hidalgo. Weill Cornell Medicine, New York, NY

9:30 AM – 9:35 AM
– Introduction Nilofer S. Azad. Johns Hopkins Sidney Kimmel Comp. Cancer Center, Baltimore, MD

9:35 AM – 9:45 AM
CT011 – Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL Lajos Pusztai, et al

see https://www.abstractsonline.com/pp8/#!/9045/presentation/10593

AbstractBackground: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2.
Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches > 85%.
Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 – June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with > 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis).
Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets.

This combination of durvalumab and olaparib is safe in triple negative breast cancer
expected synergy between PARP inhibitors and PDL1 inhibitors as olaparib inhibits DNA repair and would increase the mutational burden, which is in lung cancer shown to be a biomarker for efficacy of immune checkpoint inhibitors such as Opdivio
three subsets of breast cancers were studied: her2 negative, triple negative and ER+ tumors
MRI imaging tumor size was used as response
olaparib arm had elevation of liver enzymes and there was a pancreatitis
however paclitaxel was used within the combination as well as a chemo arm but the immuno arm alone may not be better than chemo alone but experimental arm with all combo definitely better than chemo alone
they did not look at BRCA1/2 status, followup talk showed that this is a select group that may see enhanced benefit; PARP inhibitors were seen to be effective only in BRCA1/2 mutant ovarian cancer previously

10:10 AM – 10:20 AM
CT012 – Evaluation of atezolizumab (A), cobimetinib (C), and vemurafenib (V) in previously untreated patients with BRAFV600 mutation-positive advanced melanoma: Primary results from the phase 3 IMspire150 trial Grant A. McArthur,

for abstract please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10594

AbstractBackground: Approved systemic treatments for advanced melanoma include immune checkpoint inhibitor therapy (CIT) and targeted therapy with BRAF plus MEK inhibitors for BRAFV600E/K mutant melanoma. Response rates with CITs are typically lower than those observed with targeted therapy, but CIT responses are more durable. Preclinical and clinical data suggest a potential for synergy between CIT and BRAF plus MEK inhibitors. We therefore evaluated whether combining CIT with targeted therapy could improve efficacy vs targeted therapy alone. Methods: Treatment-naive patients with unresectable stage IIIc/IV melanoma (AJCC 7th ed), measurable disease by RECIST 1.1, and BRAFV600 mutations in their tumors were randomized to the anti-programmed death-ligand 1 antibody A + C + V or placebo (Pbo) + C + V. A or Pbo were given on days 1 and 15 of each 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival (PFS). Results: 514 patients were enrolled (A + C + V = 256; Pbo + C + V = 258) and followed for a median of 18.9 months. Investigator-assessed PFS was significantly prolonged with A + C + V vs Pbo + C + V (15.1 vs 10.6 months, respectively; hazard ratio: 0.78; 95% confidence interval: 0.63-0.97; P=0.025), an effect seen in all prognostic subgroups. While objective response rates were similar in the A + C + V and Pbo + C + V groups, median duration of response was prolonged with A + C + V (21.0 months) vs Pbo + C + V (12.6 months). Overall survival data were not mature at the time of analysis. Common treatment-related adverse events (AEs; >30%) in the A + C + V and Pbo + C + V groups were blood creatinine phosphokinase (CPK) increase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both arms), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), alanine aminotransferase (ALT) increase (33.9% vs 22.8%), and lipase increase (32.2% vs 27.4%). Common treatment-related grade 3/4 AEs (>10%) that occurred in the A + C + V and Pbo + C + V groups were lipase increase (20.4% vs 20.6%), blood CPK increase (20.0% vs 14.9%), ALT increase (13.0% vs 8.9%), and maculopapular rash (12.6% vs 9.6%). The incidence of treatment-related serious AEs was similar between the A + C + V (33.5%) and Pbo + C + V (28.8%) groups. 12.6% of patients in the A + C + V group and 15.7% in the Pbo + C + V group stopped all treatment because of AEs. The safety profile of the A + C + V regimen was generally consistent with the known profiles of the individual components. Conclusion: Combination therapy with A + C + V was tolerable and manageable, produced durable responses, and significantly increased PFS vs Pbo + C + V. Thus, A + C + V represents a viable treatment option for BRAFV600 mutation-positive advanced melanoma. ClinicalTrials.gov ID: NCT02908672

10:25 AM – 10:35 AM
CT013 – SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma Alain Algazi,

for abstract and more author information please see https://www.abstractsonline.com/pp8/#!/9045/presentation/10595

AbstractBackground: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma.
Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors.
Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34).
Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing.

combo of MEK and BRAF inhibitors can attract immune cells like TREGs so PDL1 inhibitor might help improve outcome
PFS was outcome endpoint
LDH was elevated in three patients (why are they seeing liver tox? curious like previous study); are seeing these tox with the PDL1 inhibitors
there was marked survival over placebo group and PFS was statistically with continuous dosing however intermittent dosing shows no improvement

Dr. Wafik el Diery gave a nice insight as follows

On-off dosing of cancer drugs does not help melanoma patients #AACR20 https://t.co/qwwlc8vSdJ

— Wafik S. El-Deiry, MD, PhD, FACP (@weldeiry) April 27, 2020

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Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

Posted in Cancer - General, Cancer and Current Therapeutics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Genomics, Cancer Prevention: Research & Programs, Cancer Vaccines: Targeting Cancer Genes for Immunotherapy, Childhood cancer, Conference Coverage with Social Media, REAL TIME Conference Coverage Twitter's Hashtags and Handles per Presentation/session, tagged #endcancer, AACR, American Association for Cancer Research, Cancer, cancer conference, Cancer research, Conference Coverage with Social Media, https://twitter.com/#!/pharma_BI, real time conference coverage, Twitter on April 26, 2020| Leave a Comment »

Live Conference Coverage of AACR 2020 Annual Virtual Meeting; April 27-28, 2020

Reporter: Stephen J. Williams, Ph.D.

The American Association for Cancer Research (AACR) will hold its Annual Meeting as a Virtual Online Format. Registration is free and open to all, including non members. Please go to

https://www.aacr.org/meeting/aacr-annual-meeting-2020/aacr-virtual-annual-meeting-i/?utm_source=Salesforce%20Marketing%20Cloud&utm_medium=Email&utm_campaign=&sfmc_s=0031I00000WsBJxQAN

to register for this two day meeting. Another two day session will be held in June 2020 and will focus more on basic cancer research.

Please follow @pharma_BI who will be live Tweeting Real Time Notes from this meeting using the hashtag

#AACR20

And @StephenJWillia2

The following is a brief summary of the schedule. Please register and go to AACR for detailed information on individual sessions.

AACR VIRTUAL ANNUAL MEETING I: SCHEDULE AT A GLANCE

AACR Virtual Annual Meeting I is available free Register Now

VIRTUAL MEETING I: BROWSER REQUIREMENTS AND ACCESSVIRTUAL MEETING I: FAQVIRTUAL MEETING I: MEETING PLANNER (ABSTRACT TITLES)

Presentation titles are available through the online meeting planner. The program also includes six virtual poster sessions consisting of brief slide videos. Poster sessions will not be presented live but will be available for viewing on demand. Poster session topics are as follows:

Phase I Clinical Trials
Phase II Clinical Trials
Phase III Clinical Trials
Phase I Trials in Progress
Phase II Trials in Progress
Phase III Trials in Progress

Schedule updated April 24, 2020

MONDAY, APRIL 27

Channel 1		Channel 2		Channel 3
9:00 a.m.-9:30 a.m. Opening Session _______________________
9:30 a.m.-11:40 a.m. Opening Clinical Plenary _______________________
11:40 a.m.-2:00 p.m. Clinical Plenary: Immunotherapy Clinical Trials 1 _______________________	___	11:45 a.m.-1:30 p.m. Minisymposium: Emerging Signaling Vulnerabilities in Cancer _______________________	___	11:45 a.m.-1:15 p.m. Minisymposium: Advances in Cancer Drug Design and Discovery __________________________
2:00 p.m.-4:50 p.m. Clinical Plenary: Lung Cancer Targeted Therapy _______________________	___	1:55 p.m.-4:15 p.m. Clinical Plenary: Breast Cancer Therapy _______________________	___	1:30 p.m.-3:30 p.m. Minisymposium: Drugging Undrugged Cancer Targets __________________________
4:50 p.m.-6:05 p.m. Symposium: New Drugs on the Horizon 1_______________________	___	4:50 p.m.-5:50 p.m. Minisymposium: Therapeutic Modification of the Tumor Microenvironment or Microbiome _______________________	___	4:00 p.m.-6:00 p.m. Minisymposium: Advancing Cancer Research Through An International Cancer Registry: AACR Project GENIE Use Cases__________________________

All session times are EDT.

TUESDAY, APRIL 28

Channel 1		Channel 2		Channel 3
9:00 a.m.-101:00 a.m. Clinical Plenary: COVID-19 and Cancer __________________________
11:00 a.m.-1:35 p.m. Clinical Plenary: Adoptive Cell Transfer Therapy__________________________	___	10:45 a.m.-12:30 p.m. Symposium: New Drugs on the Horizon 2_________________________	___	10:45 a.m.-12:30 p.m. Minisymposium: Translational Prevention Studies ______________________
	___	12:30 p.m.-1:25 p.m. Symposium: New Drugs on the Horizon 3 _________________________	___	12:30 p.m.-2:15 p.m. Minisymposium: Non-coding RNAs in Cancer ______________________
1:35 p.m.-3:35 p.m. Clinical Plenary: Early Detection and ctDNA__________________________	___	1:30 p.m.-3:50 p.m. Clinical Plenary: Immunotherapy Clinical Trials 2 _________________________	___	2:15 p.m.-3:45 p.m. Minisymposium: Novel Targets and Therapies______________________
3:35 p.m.-5:50 p.m. Minisymposium: Predictive Biomarkers for Immunotherapeutics__________________________	___	3:50 p.m.-5:35 p.m. Minisymposium: Evaluating Cancer Genomics from Normal Tissues through Evolution to Metastatic Disease _________________________	___	4:00 p.m.-4:55 p.m. Clinical Plenary: Targeted Therapy______________________
				5:00 p.m.-5:45 p.m. Symposium: NCI Activities– COVID-19 and Cancer Research Dinah Singer, NCI ______________________
				5:45 p.m.-6:00 p.m. Closing Session ______________________