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Archive for the ‘Cancer Prevention: Research & Programs’ Category


The Sylvester Comprehensive Cancer Center of the University of Miami named 71st NCI designated Cancer Center

 

Reporter: Stephen J. Williams, PhD

As seen in the Cancer Letter at https://cancerletter.com/articles/20190729_1/

Conversation with The Cancer Letter

Sylvester becomes 71st NCI-designated cancer center

Stephen Nimer

Director,

Sylvester Comprehensive Cancer Center

 

After six years of  aggressively recruiting and spending more than $250 million to build up its programs, Sylvester Comprehensive Cancer Center has become the 71st NCI-designated cancer center in the US and the only such institution in South Florida.

The designation was announced July 29.

Sylvester, which is a part of the University of Miami Leonard M. Miller School of Medicine, is one of 64 cancer centers with the NCI Cancer Center designation in the nation. Fifty of these centers hold the Comprehensive Cancer Center designation. Seven more are designated as Basic Laboratory Cancer Centers.

“There are over 21 million people who live in the state of Florida. In 2014, Florida became the third largest state in the United States, surpassing New York—yet New York has seven NCI designated cancer centers and Florida had had only one,” Stephen D. Nimer, director of Sylvester, said to The Cancer Letter.

“There are over six million people in our catchment area, South Florida, and if they wanted to go to an NCI-designated cancer center they’d have to either get on a plane or drive nearly 300 miles—to Tampa.”

Public health programs that helped Sylvester secure the NCI designation include the Game Changer vehicle, which brings evidence-based interventions to underserved communities in the cancer center’s catchment area (The Cancer Letter, April 27, 2018). The center’s cancer control program also includes the Firefighter Cancer Initiative, a long-term study of exposures to carcinogens and ways to reduce and prevent cancer risks for Florida firefighters.

 

 

The cancer center is working on deploying another Game Changer vehicle. Recently, Peter Tunney, a New York and Miami-based artist and gallerist who donated a painting for the first Game Changer van, donated another painting that Sylvester can sell to raise money for its programs (The Cancer Letter, April 27, 2018).

 

“When they got that designation, they were walking on sunshine,” Tunney said to The Cancer Letter. “I think it’s a universal idea. I think that’s the goal for all of us—for all of mankind, for sick and healthy—to have that feeling that is so rare today: I am walking on sunshine. It’s almost like a thing of the past. Who can walk on sunshine today, in this crazy world filled with suffering and illness? And I just feel like we can, we can, it’s possible to be grateful for the things we have.

The intense yellow wallpaper motif reminds Tunney of the wallpaper in his grandmother’s house in the 1960s and 1970s, the time when American astronauts walked on the moon. “It’s somebody’s grandmother’s wallpaper from the sixties. We look back at that time, we look back at landing on the moon, and everyone is aflutter, ‘Oh, those were the good old days.’ No, these are the good old days.”

The word “comprehensive” in Sylvester’s name doesn’t refer to its level of NCI designation. When it was founded in 1973, the institution was known as the Comprehensive Cancer Center for the State of Florida. In 1992, after receiving a $27.5 million gift from the philanthropist Harcourt Sylvester Jr., it was renamed Sylvester Comprehensive Cancer Center.

 

Sylvester director Nimer spoke with Paul Goldberg, editor and publisher of The Cancer Letter.

 

Paul Goldberg:

First of all, congratulations.

Stephen Nimer: 

Thank you; it’s a big deal.

 

PG:

How long did it take to get this done?

SN:

I’d say, six years. I arrived in 2012, seven years ago, and the first year started by assessing what’s going on at Sylvester. We then developed our first five-year strategic plan, which ran from 2014 to 2018, and we submitted our [Cancer Center Support Grant] application in September 2018. We’re now in the midst of our second five-year plan.

 

PG:

And how much money did it require?

SN:

I’d have to add it all up. One of the most important things for us was that the state, in 2014, started giving us a bit over $16 million a year so that we could become NCI-designated. The health system, over a five-to-six-year period, probably gave us somewhere between $90 and $100 million. And then we’ve raised philanthropy. The philanthropy over five to six years, is maybe close to $100 million. So, it’s probably $250 -$270 million.

 

PG:

How many people did you have to recruit?

SN:

We went in [to NCI] with 124 members on our CCSG application, but over the last seven years we’ve recruited nearly 150 people. In addition to recruiting researchers I’ve been given the opportunity to build the clinical programs also.

Many of the clinical people are not included on the grant, because the grant has very specific requirements to be a member. For example, we’ve hired a couple of breast cancer surgeons, and they are not listed on the grant, because they are not yet doing significant research.

The NCI doesn’t want to know about people who don’t have grants or aren’t running clinical trials. So, out of the 124, which is what we went in with, I believe nearly 50 of our members were new.

 

PG:

How is your cancer center different from all others?

SN:

One of the things that we got the highest marks on is our community outreach and engagement efforts and how relevant the research we’re doing is to our catchment area.

A couple of examples:

We have a West Indies population, so we have an endemic HTLV-1-infected population, and thus a significant number of HTLV-1-related adult T-cell leukemia patients. So, one of our physician scientists has an R01 studying ATL. And we have a number of clinical trials for people with adult T-cell leukemia.

We also have a large burden of advanced cervical cancer patients in our region, especially in Little Haiti. And so, we have a lot of efforts on early detection of high-risk HPV, prevention and clinical treatment trials for women with cervical cancer.

Another thing that distinguishes us from many centers is the diversity of our faculty, our students, and the patients we put on clinical trials. In our CCSG application, roughly 30% of the patients on interventional trials were black and 40% were Hispanic—so both racial and ethnic diversity. We also have incredible socio-economic diversity.

What’s unique among the black population in our catchment area is that it is Afro-Caribbean more than African American—different genetics, different cultures.

The Hispanic population is unique as well. MD Anderson is probably largely Mexican Americans. New York is probably mostly Dominican and Puerto Rican. We have significant populations of Cuban Americans, Venezuelans, Brazilians, Argentinians, Colombians—an incredibly diverse group.

One example of how this plays out is in our prostate cancer research. The watch-and-wait approach is an appropriate strategy for many people. We found that our black population has more anterior prostate cancer lesions, so when you do blind biopsies, you’re more likely to miss lesions.

And then we’ve looked among the Hispanic populations as to who has a better or worse prognosis and we’ve identified subgroups within the Hispanic population that have different genetics and a different biology. So, we are tailoring our approach. Based on genetic ancestry as well as other factors.

The other thing is, we have a very strong cancer epigenetics programs, a very strong program on infections and cancer, including H. Pylori, HPV, and hepatitis viruses B and C.

We are very focused on developing programs that meet the needs of the people in this six-million-plus community.

Our catchment area is four counties, somewhat famous, because of the election news nearly every cycle: Broward, Palm Beach County, Miami Dade and Monroe County.

 

PG:

New York, where you come from, has an NCI-designated cancer center on every street corner. And Miami—make that South Florida—has just one now. How is Florida different? You would have thought that there would be multiple NCI-designated cancer centers in South Florida.

SN:

Your point is very well taken. There are over 21 million people who live in the state of Florida. In 2014, Florida became the third largest state in the United States, surpassing New York—yet New York has seven NCI designated cancer centers and Florida had had only one.

Moffitt had gotten a huge investment from the state in the past, and that enabled them to become NCI-designated. And upon designation, they could recruit more researchers, attract more patients, and get more philanthropy, and get all the positives from that. And for the longest time, Florida has only had one.

There are over six million people in our catchment area, South Florida, and if they wanted to go to an NCI-designated cancer center they’d have to either get on a plane or drive nearly 300 miles—to Tampa.

Now, one problem that we face in our region, which is very splintered in terms of market share, etc. is that there’s a lot of community hospitals here that have cancer centers, but they are not necessarily conducting cancer research in any way.

I’ve been reading Joe Simone’s Journal of Clinical Oncology paper from 2002, where he talks about the fact that there are no criteria to call yourself a cancer center. And because people may feel like you can get great care anywhere, they may not seek out the experts.

Probably, in many markets throughout the US, there’s still an ongoing process of trying to educate people as to what’s the difference between an NCI-designated cancer center and one that’s not. And, obviously, the designation is given, because of the research that’s going on. And so, people wonder: “What is the connection between the research and me being a patient there?”

A big part of educating our community is to tell people that oftentimes the doctors who are doing research on a specific cancer have a deeper knowledge about its management. Also, experts more often make the correct diagnosis and come up with more exact multidisciplinary treatment approaches for many cancers.

NCI-designated cancer centers have more clinical trials and more investigator-initiated clinical trials. Now, with NCI designation, we’ll have access to the [NCI Cancer Therapy Evaluation Program] drugs and treatments. Already, we have a very robust phase I clinical trials program, having put 161 patients on phase I trials last year.

This means that we are doing more innovative things, not accepting the status quo, which is what you often get in community hospitals.

I get asked all the time: “Don’t only complicated cancers need to get seen in Sylvester?” and I usually say, “Any cancer that you have is complicated.”

There are other things we need to stress:  Sometimes patients spend more time figuring out which flat screen TV they’re going to buy than they do figuring out who should be taking care of them. And so, we tell patients to ask: “How sure are you that you have made the correct diagnosis?”

So many people are misdiagnosed in the US each year, and sometimes people are treated who don’t need to be treated and vice-versa.

For instance, we are working with Moffitt and the University of Florida on pancreas cancer. We’re hoping to look at how many patients in our state are told that with radiation, chemotherapy, and surgery there’s a potential for cure, as opposed to being told that pancreatic cancer is terrible, and you better get your affairs in order.

While the NCI designation, of course, relates to multidisciplinary and collaborative research efforts, we have—given the diversity of our catchment area and community—an important task to educate people in culturally appropriate ways.

 

PG:

Well, there’s a lot happening that actually very good. Having the University of Florida on the path to designation is also wonderful for the state. There’s so much room in there for growth.

SN:

Absolutely. Absolutely.

 

PG:

Since we are talking about Joe Simone’s paper, the word “comprehensive” is in the name of your cancer center. Yet, you don’t—yet—have the NCI-koshered comprehensive designation. Can you change the name? Do you need to?

SN:

The University of Miami’s cancer center started in 1973 shortly after Nixon signed the National Cancer Act. Later, with a naming gift from the Sylvester family, we opened our doors as the Sylvester Comprehensive Cancer Center in 1992. The comprehensive in our name does not refer to an NCI designation. It’s been our name because we have always delivered comprehensive cancer care.

 

PG:

Let’s talk about the Game Changer. That’s such a cool thing. That was one of your center’s great ideas.

SN:

The Game Changer vehicle has been really incredible, already in its impact on our cancer education and early detection programs (The Cancer Letter, April 27, 2018). We’re accruing people for research, and we’re already following some of their health habits.

We’re in the process of delivering HPV vaccines. We have been working with our AIDS group, so you can get PrEP. And we go into communities, like Little Havana, Liberty City, Little Haiti. We are also going into areas to provide education on HIV. As you know, the incidence of HIV in the Miami Dade area is the highest in the nation. So, the vehicle is already having an impact in so many ways.

We’ve just gotten the second Game Changer!

Peter Tunney, the artist, is going to wrap this one also. And this one’s going to focus primarily on Monroe County, which has been hit hard by hurricanes, and also has very poor medical infrastructure.

If you travel to Miami, for business or pleasure, you don’t realize that it’s not that far to get to an extraordinarily rural area. The density of population in Monroe county is very low and access to health care is limited.

The areas that we’re trying to reach have so much socioeconomic gap and disparities. And the Game Changer vehicles are going to help us reach people who otherwise do not access traditional medical systems.

You asked me about the Game Changer vehicle as an idea, and I wanted to shout out the leadership team that we’ve been able to put together at Sylvester. They have been incredible. Our people have worked together in amazing ways. And so, when you say, “That’s a great idea of yours,” yours is the whole team, of course.

 

PG:

Of course.

SN:

It’s remarkable how much work it takes to build the research programs that allow us to even have a competitive application. There were so, so many people who spent so much time for the benefit of the cancer center, and not for their own research.

 

PG:

Can we talk about hurricanes? They have an impact on your mission.

SN:

It’s interesting, because the Sylvester Comprehensive Cancer Center opened its doors in 1992, which is just when Hurricane Andrew hit. I’ve looked through our archives: There are some great articles in the Miami newspaper, because we remained open and provided care right after Hurricane Andrew, which has been the most devastating hurricane here in, I don’t know exactly how many years, maybe 30 or 50 or whatever.

But even following the more recent hurricanes, we’ve been able to provide care for our patients. After Hurricane Irma, in one of our satellites we were open the next day, and we treated 30 patients with chemotherapy who needed it, even though many folks were without electricity.

It’s a unique challenge. We have hurricane preparedness for our laboratories. We have drills for the hospital. And we have a command center.

During Irma, because I live on Miami Beach, in a mandatory evacuation zone, I had to leave my home for a few days. And so, my wife and I slept in the hospital for three nights. There’s food, water, and air conditioning in the hospital. It’s not a bad place to be!

 

PG:

You’re driving now to one of the clinics, even as we speak; right? One of the satellite clinics?

SN:

Yes.

 

PG:

Can you tell me about that?

SN:

We have seven sites where we deliver clinical care. The main site in downtown Miami, and then we have three quite large facilities, one in Coral Gables, one in Plantation, one in Deerfield Beach. And we have three other satellites that are smaller, in Coral Springs, Hollywood, and Kendall.

And this allows us to deliver regional care. We’re all on the same EPIC electronic medical record. And we have patients enrolled on clinical trials in the satellites. Not all the satellites at the moment can have a research pharmacy. But the plan is we’re going to continue our expansion of facilities and services and increase the number of accruals and the sophistication of the trials that are available here. Everybody working in these satellites is a University of Miami employee.

The doctors are all part of our site disease groups, and they teleconference in to meetings and lectures. And many of them spend a day in Miami at the main satellite for education and clinical and other purposes.

Many of the doctors in the satellites are principal investigators on the clinical trials. And it’s important because people don’t want to travel necessarily on the freeways here to get to downtown Miami. And so, we can deliver academic care out in the community, which is always important and a challenging thing to do.

 

PG:

Is there anything we’ve forgotten, anything we need to address?

SN:

Maybe I can talk briefly about the state money for a minute. When Sen. [Rick] Scott [(R-FL)] was the governor, he got us together in his office, the University of Florida, Moffitt, and the University of Miami, and asked us what we needed to become major cancer centers and attain NCI designation so we could have three such facilities in the state.

The next year, the state gave us $10. 5 million to split three ways. So, we each got $3.5 million to bring in somebody from outside the state of Florida, a world-class scientist, and provide them with $500,000 a year for seven years.

We brought Ramin Shiekhattar from the Wistar Institute. He’s one of the leaders of our Cancer Epigenetics Program and a year and a half ago, Ramin won one of the highly prestigious NIH Director’s Pioneer Awards. I believe they give 10 out a year.

Next, the state set up a pool of $60 million to be shared between the three institutions each year for five and now six years. These funds are being used so that all three institutions can attain NCI designation. The directors of these cancer centers get along extremely well, and, in a pretty unique model, we created something called the Florida Academic Cancer Center Alliance.

It exists to promote collaborations across our institutions to conduct important cancer research and bring more federal research dollars to the state.

There are one or two other points I’d like to make: Another person we brought in, Gilberto Lopes, is the head of our Global Oncology Program and the editor of the Journal of Global Oncology for ASCO.

He just gave a plenary talk at 2018 ASCO, showing that immunotherapy is better than chemotherapy for the upfront treatment of certain subsets of lung cancer. His talk was one of four plenary talks we’ve recently given at important national cancer meetings.

I think the other message is just the level at which we’re operating on now. We are demonstrating to our community that we have people who are national leaders, and programs that are among the very best in the country. For this, I must thank the incredible team of researchers who work at Sylvester.

I think that, as we recruit more and more people, this designation is going to help us. I’m very pleased that when we submit NIH grants, the reviewers comment upon the environment in Miami, we now get the high scores for the research environment.

 

PG:

This brings up a problem that held back Sylvester for years, which was the lack of independence of the cancer center, or at least it was perceived to be that. Do you have the independence you need now?

SN:

First of all, I would never have left Sloan Kettering without the authority I needed from the leadership of the University of Miami, the health system and the Miller School of Medicine…

 

PG:

Yeah, that’s a good point.

SN:

I should point out, that I am the head of the cancer center, but I’m also the head of the oncology service line for UHealth health system. This arrangement allows me to align the clinical and the research missions in a way that many cancer center directors cannot.

It’s a real privilege, and I have great leadership and great people working on the service line to make our patient care and patient-related activities superb.

 

PG:

Well, that’s hugely important.

Copyright (c) 2018 The Cancer Letter Inc.

More on NCI Designated Cancer Centers can be found here: https://www.cancer.gov/research/nci-role/cancer-centers

Other articles on NCI Cancer Centers on the Open Access Online Journal include:

Salivary Gland Cancer – Adenoid Cystic Carcinoma: Mutation Patterns: Exome- and Genome-Sequencing @ Memorial Sloan-Kettering Cancer Center

Engineered Bacteria used as Trojan Horse for Cancer Immunotherapy

First Cost-Effectiveness Study of Multi-Gene Panel Sequencing in Advanced Non-Small Cell Lung Cancer Shows Moderate Cost-Effectiveness, Exposes Crucial Practice Gap

 

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An Intelligent DNA Nanorobot to Fight Cancer by Targeting HER2 Expression

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

 

HER2 is an important prognostic biomarker for 20–30% of breast cancers, which is the most common cancer in women. Overexpression of the HER2 receptor stimulates breast cells to proliferate and differentiate uncontrollably, thereby enhancing the malignancy of breast cancer and resulting in a poor prognosis for affected individuals. Current therapies to suppress the overexpression of HER2 in breast cancer mainly involve treatment with HER2-specific monoclonal antibodies. However, these monoclonal anti-HER2 antibodies have severe side effects in clinical trials, such as diarrhea, abnormal liver function, and drug resistance. Removing HER2 from the plasma membrane or inhibiting the gene expression of HER2 is a promising alternative that could limit the malignancy of HER2-positive cancer cells.

 

DNA origami is an emerging field of DNA-based nanotechnology and intelligent DNA nanorobots show great promise in working as a drug delivery system in healthcare. Different DNA-based nanorobots have been developed as affordable and facile therapeutic drugs. In particular, many studies reported that a tetrahedral framework nucleic acid (tFNA) could serve as a promising DNA nanocarrier for many antitumor drugs, owing to its high biocompatibility and biosecurity. For example, tFNA was reported to effectively deliver paclitaxel or doxorubicin to cancer cells for reversing drug resistance, small interfering RNAs (siRNAs) have been modified into tFNA for targeted drug delivery. Moreover, the production and storage of tFNA are not complicated, and they can be quickly degraded in lysosomes by cells. Since both free HApt and tFNA can be diverted into lysosomes, so,  combining the HApt and tFNA as a novel DNA nanorobot (namely, HApt-tFNA) can be an effective strategy to improve its delivery and therapeutic efficacy in treating HER2-positive breast cancer.

 

Researchers reported that a DNA framework-based intelligent DNA nanorobot for selective lysosomal degradation of tumor-specific proteins on cancer cells. An anti-HER2 aptamer (HApt) was site-specifically anchored on a tetrahedral framework nucleic acid (tFNA). This DNA nanorobot (HApt-tFNA) could target HER2-positive breast cancer cells and specifically induce the lysosomal degradation of the membrane protein HER2. An injection of the DNA nanorobot into a mouse model revealed that the presence of tFNA enhanced the stability and prolonged the blood circulation time of HApt, and HApt-tFNA could therefore drive HER2 into lysosomal degradation with a higher efficiency. The formation of the HER2-HApt-tFNA complexes resulted in the HER2-mediated endocytosis and digestion in lysosomes, which effectively reduced the amount of HER2 on the cell surfaces. An increased HER2 digestion through HApt-tFNA further induced cell apoptosis and arrested cell growth. Hence, this novel DNA nanorobot sheds new light on targeted protein degradation for precision breast cancer therapy.

 

It was previously reported that tFNA was degraded by lysosomes and could enhance cell autophagy. Results indicated that free Cy5-HApt and Cy5-HApt-tFNA could enter the lysosomes; thus, tFNA can be regarded as an efficient nanocarrier to transmit HApt into the target organelle. The DNA nanorobot composed of HApt and tFNA showed a higher stability and a more effective performance than free HApt against HER2-positive breast cancer cells. The PI3K/AKT pathway was inhibited when membrane-bound HER2 decreased in SK-BR-3 cells under the action of HApt-tFNA. The research findings suggest that tFNA can enhance the anticancer effects of HApt on SK-BR-3 cells; while HApt-tFNA can bind to HER2 specifically, the compounded HER2-HApt-tFNA complexes can then be transferred and degraded in lysosomes. After these processes, the accumulation of HER2 in the plasma membrane would decrease, which could also influence the downstream PI3K/AKT signaling pathway that is associated with cell growth and death.

 

However, some limitations need to be noted when interpreting the findings: (i) the cytotoxicity of the nanorobot on HER2-positive cancer cells was weak, and the anticancer effects between conventional monoclonal antibodies and HApt-tFNA was not compared; (ii) the differences in delivery efficiency between tFNA and other nanocarriers need to be confirmed; and (iii) the confirmation of anticancer effects of HApt-tFNA on tumors within animals remains challenging. Despite these limitations, the present study provided novel evidence of the biological effects of tFNA when combined with HApt. Although the stability and the anticancer effects of HApt-tFNA may require further improvement before clinical application, this study initiates a promising step toward the development of nanomedicines with novel and intelligent DNA nanorobots for tumor treatment.

 

References:

 

https://pubs.acs.org/doi/10.1021/acs.nanolett.9b01320

 

https://www.ncbi.nlm.nih.gov/pubmed/27939064

 

https://www.ncbi.nlm.nih.gov/pubmed/11694782

 

https://www.ncbi.nlm.nih.gov/pubmed/27082923

 

https://www.ncbi.nlm.nih.gov/pubmed/25365825

 

https://www.ncbi.nlm.nih.gov/pubmed/26840503

 

https://www.ncbi.nlm.nih.gov/pubmed/29802035

 

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

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

 

Pancreatic cancer is a significant cause of cancer mortality; therefore, the development of early diagnostic strategies and effective treatment is essential. Improvements in imaging technology, as well as use of biomarkers are changing the way that pancreas cancer is diagnosed and staged. Although progress in treatment for pancreas cancer has been incremental, development of combination therapies involving both chemotherapeutic and biologic agents is ongoing.

 

Cancer is an evolutionary disease, containing the hallmarks of an asexually reproducing unicellular organism subject to evolutionary paradigms. Pancreatic ductal adenocarcinoma (PDAC) is a particularly robust example of this phenomenon. Genomic features indicate that pancreatic cancer cells are selected for fitness advantages when encountering the geographic and resource-depleted constraints of the microenvironment. Phenotypic adaptations to these pressures help disseminated cells to survive in secondary sites, a major clinical problem for patients with this disease.

 

The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology.

 

PDAC is the most common type of pancreatic cancer featured with high intra-tumoral heterogeneity and poor prognosis. In the present study to comprehensively delineate the PDAC intra-tumoral heterogeneity and the underlying mechanism for PDAC progression, single-cell RNA-seq (scRNA-seq) was employed to acquire the transcriptomic atlas of 57,530 individual pancreatic cells from primary PDAC tumors and control pancreases. The diverse malignant and stromal cell types, including two ductal subtypes with abnormal and malignant gene expression profiles respectively, were identified in PDAC.

 

The researchers found that the heterogenous malignant subtype was composed of several subpopulations with differential proliferative and migratory potentials. Cell trajectory analysis revealed that components of multiple tumor-related pathways and transcription factors (TFs) were differentially expressed along PDAC progression. Furthermore, it was found a subset of ductal cells with unique proliferative features were associated with an inactivation state in tumor-infiltrating T cells, providing novel markers for the prediction of antitumor immune response. Together, the findings provided a valuable resource for deciphering the intra-tumoral heterogeneity in PDAC and uncover a connection between tumor intrinsic transcriptional state and T cell activation, suggesting potential biomarkers for anticancer treatment such as targeted therapy and immunotherapy.

 

References:

 

https://www.ncbi.nlm.nih.gov/pubmed/31273297

 

https://www.ncbi.nlm.nih.gov/pubmed/21491194

 

https://www.ncbi.nlm.nih.gov/pubmed/27444064

 

https://www.ncbi.nlm.nih.gov/pubmed/28983043

 

https://www.ncbi.nlm.nih.gov/pubmed/24976721

 

https://www.ncbi.nlm.nih.gov/pubmed/27693023

 

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Lesson 10 on Cancer, Oncogenes, and Aberrant Cell Signal Termination in Disease for #TUBiol3373

Curator: Stephen J. Williams

Please click on the following file to get the Powerpoint Presentation for this lecture

cell signaling 10 lesson_SJW 2019

There is a good reference to read on The Hallmarks of Cancer published first in 2000 and then updated with 2 new hallmarks in 2011 (namely the ability of cancer cells to reprogram their metabolism and 2. the ability of cancer cells to evade the immune system)

a link to the PDF is given here:

hallmarks2000

hallmarks2011

Please also go to other articles on this site which are relevant to this lecture.  You can use the search box in the upper right hand corner of the Home Page or these are few links you might find interesting

Development of Chemoresistance to Targeted Therapies: Alterations of Cell Signaling & the Kinome

Proteomics, Metabolomics, Signaling Pathways, and Cell Regulation: a Compilation of Articles in the Journal http://pharmaceuticalintelligence.com

Feeling the Heat – the Link between Inflammation and Cancer

Lesson 4 Cell Signaling And Motility: G Proteins, Signal Transduction: Curations and Articles of reference as supplemental information: #TUBiol3373

Immunotherapy Resistance Rears Its Ugly Head: PD-1 Resistant Metastatic Melanoma and More

Novel Mechanisms of Resistance to Novel Agents

 

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

 

Gender of a person can affect the kinds of cancer-causing mutations they develop, according to a genomic analysis spanning nearly 2,000 tumours and 28 types of cancer. The results show striking differences in the cancer-causing mutations found in people who are biologically male versus those who are biologically female — not only in the number of mutations lurking in their tumours, but also in the kinds of mutations found there.

 

Liver tumours from women were more likely to carry mutations caused by a faulty system of DNA mending called mismatch repair, for instance. And men with any type of cancer were more likely to exhibit DNA changes thought to be linked to a process that the body uses to repair DNA with two broken strands. These biases could point researchers to key biological differences in how tumours develop and evolve across sexes.

 

The data add to a growing realization that sex is important in cancer, and not only because of lifestyle differences. Lung and liver cancer, for example, are more common in men than in women — even after researchers control for disparities in smoking or alcohol consumption. The source of that bias, however, has remained unclear.

In 2014, the US National Institutes of Health began encouraging researchers to consider sex differences in preclinical research by, for example, including female animals and cell lines from women in their studies. And some studies have since found sex-linked biases in the frequency of mutations in protein-coding genes in certain cancer types, including some brain cancers and advanced melanoma.

 

But the present study is the most comprehensive study of sex differences in tumour genomes so far. It looks at mutations not only in genes that code for proteins, but also in the vast expanses of DNA that have other functions, such as controlling when genes are turned on or off. The study also compares male and female genomes across many different cancers, which can allow researchers to pick up on additional patterns of DNA mutations, in part by increasing the sample sizes.

 

Researchers analysed full genome sequences gathered by the International Cancer Genome Consortium. They looked at differences in the frequency of 174 mutations known to drive cancer, and found that some of these mutations occurred more frequently in men than in women, and vice versa. When they looked more broadly at the loss or duplication of DNA segments in the genome, they found 4,285 sex-biased genes spread across 15 chromosomes.

 

There were also differences found when some mutations seemed to arise during tumour development, suggesting that some cancers follow different evolutionary paths in men and women. Researchers also looked at particular patterns of DNA changes. Such patterns can, in some cases, reflect the source of the mutation. Tobacco smoke, for example, leaves behind a particular signature in the DNA.

 

Taken together, the results highlight the importance of accounting for sex, not only in clinical trials but also in preclinical studies. This could eventually allow researchers to pin down the sources of many of the differences found in this study. Liver cancer is roughly three times as common in men as in women in some populations, and its incidence is increasing in some countries. A better understanding of its aetiology may turn out to be really important for prevention strategies and treatments.

 

References:

 

https://www.nature.com/articles/d41586-019-00562-7?utm_source=Nature+Briefing

 

https://www.nature.com/news/policy-nih-to-balance-sex-in-cell-and-animal-studies-1.15195

 

https://www.ncbi.nlm.nih.gov/pubmed/26296643

 

https://www.biorxiv.org/content/10.1101/507939v1

 

https://www.ncbi.nlm.nih.gov/pubmed/25985759

 

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

 

Protein kinase C (PKC) isozymes function as tumor suppressors in increasing contexts. These enzymes are crucial for a number of cellular activities, including cell survival, proliferation and migration — functions that must be carefully controlled if cells get out of control and form a tumor. In contrast to oncogenic kinases, whose function is acutely regulated by transient phosphorylation, PKC is constitutively phosphorylated following biosynthesis to yield a stable, autoinhibited enzyme that is reversibly activated by second messengers. Researchers at University of California San Diego School of Medicine found that another enzyme, called PHLPP1, acts as a “proofreader” to keep careful tabs on PKC.

 

The researchers discovered that in pancreatic cancer high PHLPP1 levels lead to low PKC levels, which is associated with poor patient survival. They reported that the phosphatase PHLPP1 opposes PKC phosphorylation during maturation, leading to the degradation of aberrantly active species that do not become autoinhibited. They discovered that any time an over-active PKC is inadvertently produced, the PHLPP1 “proofreader” tags it for destruction. That means the amount of PHLPP1 in patient’s cells determines his amount of PKC and it turns out those enzyme levels are especially important in pancreatic cancer.

 

This team of researchers reversed a 30-year paradigm when they reported evidence that PKC actually suppresses, rather than promotes, tumors. For decades before this revelation, many researchers had attempted to develop drugs that inhibit PKC as a means to treat cancer. Their study implied that anti-cancer drugs would actually need to do the opposite — boost PKC activity. This study sets the stage for clinicians to one day use a pancreatic cancer patient’s PHLPP1/PKC levels as a predictor for prognosis, and for researchers to develop new therapeutic drugs that inhibit PHLPP1 and boost PKC as a means to treat the disease.

 

The ratio — high PHLPP1/low PKC — correlated with poor prognoses: no pancreatic patient with low PKC in the database survived longer than five-and-a-half years. On the flip side, 50 percent of the patients with low PHLPP1/high PKC survived longer than that. While still in the earliest stages, the researchers hope that this information might one day aid pancreatic diagnostics and treatment. The researchers are next planning to screen chemical compounds to find those that inhibit PHLPP1 and restore PKC levels in low-PKC-pancreatic cancer cells in the lab. These might form the basis of a new therapeutic drug for pancreatic cancer.

 

References:

 

https://health.ucsd.edu/news/releases/Pages/2019-03-20-two-enzymes-linked-to-pancreatic-cancer-survival.aspx?elqTrackId=b6864b278958402787f61dd7b7624666

 

https://www.ncbi.nlm.nih.gov/pubmed/30904392

 

https://www.ncbi.nlm.nih.gov/pubmed/29513138

 

https://www.ncbi.nlm.nih.gov/pubmed/18511290

 

https://www.ncbi.nlm.nih.gov/pubmed/28476658

 

https://www.ncbi.nlm.nih.gov/pubmed/28283201

 

https://www.ncbi.nlm.nih.gov/pubmed/24231509

 

https://www.ncbi.nlm.nih.gov/pubmed/28112438

 

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Immunoediting can be a constant defense in the cancer landscape


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

 

There are many considerations in the cancer immunoediting landscape of defense and regulation in the cancer hallmark biology. The cancer hallmark biology in concert with key controls of the HLA compatibility affinity mechanisms are pivotal in architecting a unique patient-centric therapeutic application. Selection of random immune products including neoantigens, antigens, antibodies and other vital immune elements creates a high level of uncertainty and risk of undesirable immune reactions. Immunoediting is a constant process. The human innate and adaptive forces can either trigger favorable or unfavorable immunoediting features. Cancer is a multi-disease entity. There are multi-factorial initiators in a certain disease process. Namely, environmental exposures, viral and / or microbiome exposure disequilibrium, direct harm to DNA, poor immune adaptability, inherent risk and an individual’s own vibration rhythm in life.

 

When a human single cell is crippled (Deranged DNA) with mixed up molecular behavior that is the initiator of the problem. A once normal cell now transitioned into full threatening molecular time bomb. In the modeling and creation of a tumor it all begins with the singular molecular crisis and crippling of a normal human cell. At this point it is either chop suey (mixed bit responses) or a productive defensive and regulation response and posture of the immune system. Mixed bits of normal DNA, cancer-laden DNA, circulating tumor DNA, circulating normal cells, circulating tumor cells, circulating immune defense cells, circulating immune inflammatory cells forming a moiety of normal and a moiety of mess. The challenge is to scavenge the mess and amplify the normal.

 

Immunoediting is a primary push-button feature that is definitely required to be hit when it comes to initiating immune defenses against cancer and an adaptation in favor of regression. As mentioned before that the tumor microenvironment is a “mixed bit” moiety, which includes elements of the immune system that can defend against circulating cancer cells and tumor growth. Personalized (Precision-Based) cancer vaccines must become the primary form of treatment in this case. Current treatment regimens in conventional therapy destroy immune defenses and regulation and create more serious complications observed in tumor progression, metastasis and survival. Commonly resistance to chemotherapeutic agents is observed. These personalized treatments will be developed in concert with cancer hallmark analytics and immunocentrics affinity and selection mapping. This mapping will demonstrate molecular pathway interface and HLA compatibility and adaptation with patientcentricity.

References:

 

https://www.linkedin.com/pulse/immunoediting-cancer-landscape-john-catanzaro/

 

https://www.cell.com/cell/fulltext/S0092-8674(16)31609-9

 

https://www.researchgate.net/publication/309432057_Circulating_tumor_cell_clusters_What_we_know_and_what_we_expect_Review

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5840207/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00414/full

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593672/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4190561/

 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4388310/

 

https://www.linkedin.com/pulse/cancer-hallmark-analytics-omics-data-pathway-studio-review-catanzaro/

 

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