Lyda Hill Philanthropies backs CPI’s cancer prevention research with $750k challenge grant

DALLAS, TX — [December 3, 2025] —  Underscoring the growing momentum behind the prevention-first approach to cancer, the Cancer Prevention Initiative (CPI) today announced a  $1.5 million funding opportunity made possible by a commitment from Lyda Hill Philanthropies. The commitment fuels CPI’s mission to accelerate the discovery and development of new medicines—such as vaccines and preventive drugs—to stop cancer before it starts.

This latest investment will help launch a $750,000 matching challenge, designed to expand philanthropic support for cancer prevention research and attract new champions to the field. Every dollar contributed will be matched, doubling the impact of each gift and propelling CPI’s next wave of discovery.

“Lyda Hill Philanthropies shares our belief that high-quality science can replace the fear around cancer with understanding and hope,” said Dr. Theodora Ross, President of the Cancer Prevention Initiative (CPI). “Their visionary investment in CPI’s mission brings us closer to a future where cancer prevention leads to longer, healthier lives for many.”

Founded on the belief that prevention is the most powerful form of cure, CPI funds innovative research aimed at intercepting cancer before it begins. The organization focuses on inherited cancers—where genetic predisposition provides a clear target for early intervention—and uses this lens to unlock insights that can lead to the prevention of all cancers.

“For me, this work is deeply personal,” said Howard Janzen, Chair of CPI’s Board of Trustees. “Like so many families, mine has been touched by cancer. Supporting CPI means investing in a future where our children and grandchildren won’t face the same risks. Lyda Hill Philanthropies’ continued partnership is helping make that future possible.”

Since its founding, CPI has invested nearly $5 million in hereditary cancer prevention research, providing critical early support when other funders may not take the risk. These catalytic investments enable scientists to generate the early data needed to pursue larger funding opportunities—creating pathways for transforming bold ideas into life-saving prevention tools.

The commitment from Lyda Hill Philanthropies builds on years of support and shared vision. Lyda Hill Philanthropies is known for its belief in “science benefiting humanity” and its focus on advancing breakthrough solutions that improve human health.

To learn more about the Cancer Prevention Initiative or to contribute to the matching challenge, email info@cancerpreventioninitiative.org, or visit www.cancerpreventioninitiative.org.

About the Cancer Prevention Initiative (CPI)

The Cancer Prevention Initiative (CPI) is a nonprofit organization dedicated to accelerating the discovery and development of new medicines that prevent cancer. CPI invests in early-stage, high-impact research that brings bold prevention ideas to life—supporting the scientists and innovations capable of stopping cancer before it starts. By focusing on inherited cancers as a model for all cancers, CPI partners with leading researchers and philanthropists to build a future where prevention is the norm, not the exception. To learn more, visit www.cancerpreventioninitiative.org.

About Lyda Hill Philanthropies

Lyda Hill Philanthropies encompasses the charitable giving for founder Lyda Hill and includes her foundation and personal philanthropy. The organization is committed to funding transformational advances in science and nature, empowering nonprofit organizations, and improving the Texas and Colorado communities. Because Miss Hill believes that “science is the answer” to many of life’s most challenging issues, she has chosen to donate the entirety of her estate to philanthropy and scientific research. For more details, visit lydahillphilanthropies.org.

Media Contact:
Contact: Marion Stewart–Thomas
Cancer Prevention Initiative (CPI)
Email: info@cancerpreventioninitiative.org

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The Joy of Science: Interview with Nobel Laureate William G. Kaelin Jr., M.D.

CPI was fortunate to sit down for a conversation with Nobel Prize winner Dr. Bill Kaelin, from Harvard Medical School and the Howard Hughes Medical Institute (HHMI). We discussed topics ranging from training and motivation to discoveries, as well as the future of science and cancer prevention.

 

Biography

Dr. Kaelin received his BA and MD degrees from Duke University. He completed his residency in Internal Medicine at Johns Hopkins University School of Medicine where he was chief resident, and his clinical fellowship in Medical Oncology at the Dana-Farber Cancer Institute. His experience as a postdoctoral fellow in the laboratory of Dr. David Livingston at Dana-Farber was transformative in igniting and solidifying his interest in cancer research. He became an independent investigator at Dana-Farber in 1992. His work on the inherited cancer predisposition syndrome von Hippel–Lindau (VHL) disease established the VHL protein as critical for cellular oxygen sensing, and its dysregulation as a key step in the pathogenesis of kidney cancer.

Dr. Kaelin was elected to the National Academy of Sciences in 2010 and, together with Sir Peter Ratcliffe and Dr. Gregg Semenza, received the 2016 Albert Lasker Award for Basic Medical Research. The trio went on to share the 2019 Nobel Prize in Physiology or Medicine for their discoveries on how cells sense and adapt to oxygen availability.¹

Dr. Kaelin is currently the Sidney Farber Professor of Medicine at the Dana-Farber Cancer Institute and Harvard Medical School and has been an HHMI investigator for over 25 years.

 

You have received arguably the most prestigious prize in science and medicine, but your start in laboratory science wasn’t great.

Right, my first research experience was in a physical chemistry lab as an undergraduate/pre-med student at Duke. At the end of the semester, the professor gave me a C-, which for a premed is like having a wooden stake driven through your heart. I was around 20 years old at the time, and it wasn’t as if this grade crushed a dream I had of becoming a scientist because I aspired to be a clinical doctor. But I decided this was a sign that I lacked the creativity and originality to work in a laboratory. Of course, 25 years later I can appreciate that it was not proof I lacked scientific talent, but at that time it certainly solidified my view that I should be a clinical doctor and not a scientist. As a result, I redoubled my efforts to become a clinician – which in hindsight I’m happy about, because I think too many people with an eye toward becoming physician-scientists go through their clinical training as sort of dabblers, convinced they won’t eventually become clinicians. I’m glad I approached my clinical training thinking I was going to be a clinician. It served me well later when I made the hard pivot to science.

 

What was the catalyst that made you think, “Maybe I can be a scientist”?

As a third-year medical student at Duke, I worked for a year studying tumor blood flow in the radiation biology lab of Randy Jirtle. Here, I published a couple of papers and I didn’t get a C-, which suggested to me that I might not be so bad at research after all. And I learned about both angiogenesis and the obscure disease von Hippel-Lindau disease, which would become very important to my career.

I’ve been to maybe three lectures in my life where I was almost levitating out of my chair because I knew I was having the privilege of seeing the future. One of them was in 1982, when Mike Bishop came to Duke and gave a talk about oncogenes—genes which when mutated or overexpressed contribute to the development of cancer—including several kinases. I remember thinking that as soon as we discover kinase inhibitors there is going to be a change in therapeutics forever. For the next 20 years people told me why this couldn’t be done – but thankfully, they were proven wrong, and kinase inhibitors are now key players in cancer treatment. Mike Bishop’s talk planted a seed.

When I was a resident at Johns Hopkins, one of my bicycle buddies, Eric Fearon, told me that I should grab lunch and listen to a young faculty member he was working with named Bert Vogelstein. That was another of these experiences. The prevailing wisdom at that time was that solid tumors were too heterogeneous and complex to study with molecular biology tools, so their use was largely limited to the study of blood cancers. However, Bert’s colon cancer studies were shattering that view and I was primed to believe that we were about to have a revolution in the application of molecular biology to cancer.

Also, one of my chairmen at Hopkins – Jack Stobo – did weekly bench to bedside talks and described molecular biology techniques like Southern blots and how to apply them in human genetics.  In other words, there were several priming events that happened while I was in medical school and residency that kept me interested in cancer research.

When I came to Dana-Farber for my medical oncology fellowship I found my fellow fellows to be extremely accomplished from a scientific point of view. I think out of the eight people in my class, five or six were MD-PhDs. Several of them had published papers in the high-profile journals Cell, Science, and Nature. I remember Philip Kantoff was the star; he had published one of the early gene therapy papers. I was a lowly MD, voted “most likely to go into private practice”.

 

What were the early days of your independent career like?

As part of the fellowship training at Dana-Farber, there was an option to work in a lab for a couple of years. Although I didn’t think I was going to be a laboratory-based investigator, I thought I should at least work for a scientist who was good and famous. I tried desperately to get into Bob Weinberg’s lab, which had just cloned the RB tumor suppressor gene. He seemed interested but didn’t have space for a new person for another three years and I needed a spot in three months. While researching Bob Weinberg’s lab, I met a young guy named Shelly Bernstein who had trained with Bob Weinberg. Shelly was a pediatrician; he was very nice of course, all pediatricians are very nice, and he had just started his own lab which I joined. I had only been there for four months when he told me that he was shutting down his laboratory to go into clinical practice. Now I’m thinking that not only am I not destined to go into science but I’m causing other people to leave science!

My last clinical attending was David Livingston. While I was in Shelly’s lab, I picked up an article in Science magazine where a group had amplified part of the oncogene KRAS using PCR. PCR, or polymerase chain reaction, is a technique that can be used to make copies of specific regions of the genome. Just for fun, I tried doing the same following their protocol and it worked. I showed this to David. No one in David’s lab had ever done PCR so he immediately welcomed me into his lab and bought me a PCR machine. He told me that they’d just found that T antigen binds to the protein encoded by the RB gene that, when lost or altered, causes a childhood eye tumor called retinoblastoma. It seemed like everyone was working on RB. Bob Weinberg was working on RB, and now David’s working on RB. I think my expectations were so low it was easy for me to exceed them. In lab, I didn’t know enough to know the solutions to many problems, and I came up with my own solutions, some of which turned out to be better than the existing solutions. David was brilliant in every way a mentor could be brilliant. Both as a cheerleader and as a brilliant mind who had a great way of picking problems. One thing led to the next and I had some success in David’s lab.

 

When you started your own lab, you decided to focus on von Hippel-Lindau (VHL) disease. What spurred you into looking at VHL?

I was looking for something to work on that was different from what David was working on so I could establish my own scientific identity. I can still remember opening an issue of Science magazine and reading about the cloning of the VHL tumor suppressor gene (Latif et al., 1993)². Sadly, one of the three corresponding authors of that paper just died this week – Michael Lerman from the National Cancer Institute (NCI). I thought this paper was it; this is what I want to work on for sure. I had worked on the RB tumor suppressor gene and thought I knew something about tumor suppressor genes. I also thought some of the approaches we had used for studying RB would be helpful in studying VHL.

At the time, there was a lot of excitement in molecular oncology for cancers like Burkitt’s lymphoma and Hairy Cell leukemia. These cancers were very interesting but relatively uncommon. I thought, if we were going to make a dent in cancer mortality, we needed to start tackling the common cancers. I knew that one of the cancers VHL gene mutation carriers develop is kidney cancer and kidney cancer is one of the ten most common cancers. I thought that working on VHL will allow us to learn about kidney cancer. I also knew from my stint in the Jirtle laboratory that VHL tumors are highly angiogenic and I thought studying VHL would teach us about the molecular control of angiogenesis, a topic of great interest in cancer therapeutics at the time because of Judah Folkman. I knew from my stint as a chief resident at Johns Hopkins that VHL tumors also cause excessive red blood cell production. What angiogenesis and increased red blood cell production have in common is that they are normally induced by low oxygen. This led me to assume that VHL must play some role in oxygen sensing and that these VHL tumors, in which the VHL gene is mutant, have hijacked the oxygen sensing pathway.

It turned out the assumptions about kidney cancer, angiogenesis, and oxygen sensing were all correct. From that point forward we didn’t have to do anything that was genius. We didn’t have to create any new technologies. We did our experiments competently and carefully. I think more than anything else, it was really seeing the connection between VHL and oxygen sensing that was the most important thing. And being lucky.

 

When you decided to pursue VHL, were you more motivated by the desire to help patients by working on a cancer that affected many patients, or by the intellectual challenge of solving a complex medical puzzle? Or both?

I didn’t think I was choosing between the two. I thought that VHL was a great puzzle—any time a gene or a protein was linked to cancer, that was interesting. I thought VHL was particularly compelling because of all the reasons stated above. I wanted to know why the loss of this gene so reproducibly caused cancers with almost 90% penetrance in these families and why these cancers produced high levels of the molecular distress signals normally induced by oxygen starvation. I figured why not work on a potentially important problem but also one that seemed like a good puzzle.

 

Your work on VHL has led to the development of drugs like belzutifan, which reverses the impact of a faulty VHL in cancer. At that time did you have thoughts that therapeutic development was a possible outcome?

My assumption at that time was that if we understood the VHL pathway, opportunities might arise for pharmacological intervention. We all knew of genetically validated cancer targets that were undruggable; for instance, it was not clear what to do with RB loss although we knew how it worked. Most drugs act by inhibiting their targets and very few bring mutated proteins back to life.  From that point of view, VHL mutation, or worse, loss would normally be seen as “undruggable”. Nonetheless, it seemed possible that understanding the biochemical functions of the VHL protein would provide a path forward for pharmacologically mimicking its function or for exploiting vulnerabilities created when VHL function was lost. I hoped my research might lead to translational opportunities, but I knew it was not a given.

 

Except for your undergraduate research experience, you’ve had continuous research success– what do you attribute that to?

It is important to work on a good problem, pick a good project, find that question you’re so excited about that you can’t wait to go to work the next day. I always tell students that a nice fall back is to have genetics on your side, because at least you know you’re studying something that’s causal and not correlative. If you are doing clinical training, there are many clinical conundrums or medical paradoxes that are good places to start. Biological questions that map back to human diseases.

Usually, on the top on people’s list of questions I am now asked is “what’s the secret to winning the Nobel Prize?” Paradoxically, the secret to winning the Nobel Prize is not to think about winning the Nobel Prize. If you are picking good questions, doing your science well, having fun every day, and if you are very lucky, some recognitions like election to the National Academy or winning a Nobel might happen. But the real prize is the joy of doing science and the privilege of occasionally understanding things that have never been understood before, marveling at what nature is able to do. That’s the prize.  And even better if your work actually helps patients. It’s not a bigger discovery or a better piece of science because someone put a blue ribbon on it – that’s a beauty contest.

If you set out to win one of these prizes or one of these other accolades, statistically, you’re going to become an embittered, unhappy person. Whereas, if you are doing your work for the right reasons and you’re very, very lucky you might win a prize now and then.

One of my favorites of the many questions I’ve been asked about the Nobel Prize is when I was in China. A reporter asked me, “Does winning the Nobel Prize make the imposter syndrome better or worse?” and my answer was “yes”. Of course, on one level you could say I got the brass ring, so I couldn’t have been so bad. But the minute one stops feeling a little imposter syndrome, it’s probably over in terms of future success.  I think it’s important to have the right mixture of self-confidence and self-doubt.

 

If not the Nobel Prize, what gets you out of bed in the morning?

One of the many “David Livingstonisms” I like very much is that a good scientist should always think the most important thing they’re ever going to do lies ahead of them. I come to work every day with the idea that maybe one of the things we’re doing turns out to be important and useful. As a principal investigator, it is important for me to be fair to my postdocs who have entrusted their training to me. I have to believe any one of them could be doing the project that leads to that next really important thing. At any given time, I’m pretty pumped about the progress somebody is making in the lab. With our projects, I can easily imagine a trajectory that leads to something useful and impactful. I come to work with “I can’t wait to see what the next piece of data looks like.”

 

You are driven by this question you are passionate about, but how do you deal with downturns, times when it looks like nothing is working, and keep going?

I don’t take even the smallest successes for granted, like when the dye in the gel runs in the right direction. Celebrate even small achievements. It’s all magic.

I think one of the most important things for us mentors to do is to keep a close eye on the trainees who are doing all the right things, doing all the right experiments, but who are getting nowhere. Because it’s so important, especially for a young person, to have some taste of success within a reasonable timeline. I’ve seen that a little taste of success is enough to have people skyrocket. David was a big believer in putting talented young people into a fertile area and then watering them periodically. Sometimes, areas initially thought of as fertile turn out not to be and replanting will be necessary. As the mentor, I have the responsibility to find something else for them that will work. Sometimes it may look like things are going nowhere but you are very close, and you don’t know it yet. It can be really hard to know whether it’s a matter of persistence or whether it is just a dry well. You do get better with time at assigning probabilities of success in different projects. If a high-risk project has not yielded fruit within a reasonable length of time, it is sometimes important to switch to a “safer” project. It’s one of the things I think about a lot as a mentor; “how much failure can someone take?” But I’ve also been pleasantly surprised by how often “safe projects” have still led to really unexpected and exciting discoveries.

 

To be successful you need to pick a good project – a question that excites you and one that is meaningful— be positive, be persistent, and especially if you are a young researcher, choose the right mentor. Anything else?

You know how most jokes have an element of truth to them? There’s the old joke that one of the best predictors of winning a Nobel Prize is having trained with someone who has won the Nobel Prize. Turns out, it’s literally true, mostly for physics and chemistry but also somewhat for medicine. There is something in the training or the way of thinking that’s hard to capture in writing – I call it scientific intuition. David had a great nose for a good problem. On the flip side he also had a great nose for bullshit. He could go to a lecture and within 5 minutes turn to me and say that it’s complete bullshit. I have to be careful because this is all subjective, but I certainly meet scientists around the world who I’m sure are smarter than me and more technically capable than me, but they don’t have my scientific instincts and taste. And I find myself asking “why are you doing this, why are you working with this?”

 

The issue of pedigrees is interesting because by valuing pedigrees we can miss talented people who didn’t have opportunities for impressive pedigrees.

That is a great comment. I think to succeed you have to have the right balance of self-confidence and self-doubt as I have already said. They’re equally important, and it is not great to miss one or the other. I think if you’ve trained at a great place or if you’ve trained with a great person, you’re more willing to ask audacious questions. Because you think “who else is going to do it? of course, I’m going to do it.” Especially when I’m visiting people at places outside of Harvard, I provide encouragement that they are more capable than they think. They don’t have to go to Harvard to be talented and often just need a dose of confidence. It’s really getting the balance of confidence and self-doubt right. It’s sort of like the end of Wizard of Oz when they hand you the certificate that says you did this. Part of it is just having that extra gear that makes you a little bit more audacious. That’s why I say, to do significant work, it helps to be in a place that believes in you and supports you.

 

We want to ask you about the trend toward “team science.” Collaboration is important but on the other hand it can encourage group thinking and herd mentality. How do we maintain scientific integrity and original ideas in the midst of needing to have team science?

I’m always careful when answering a question about what to work on and whether to do it as part of a team not to be overly prescriptive, like you should do this type of science or that type of science. What is important is that you do the type of science that excites you; what is satisfying to one person may not be satisfying to another.

I have learned from sociologists that at one extreme are scientists they call the “lone hunter gatherer scientists.” They tend to dominate in the early stages of science – many lone hunter gatherer scientists going in different directions, following their noses, and the hope is that a couple of them will come back with something useful. As science matures and becomes more resource intensive and sometimes a little like engineering, the “communal harvesters” start to come in, and they start to displace some of the lone hunter gatherer scientists. They both have strengths and weaknesses. I am a lone hunter gatherer scientist— I want to work on my problem the way I want to work on it.

One of quotes in “Time, Love, and Memory”⁴ – a biography of Seymour Benzer– is that a good experiment should be pretty and witty. I see a lot of team science that is done because they have mega resources, such as access to precious samples and powerful technologies. When these things are put together, they can generate something publishable. I’m not saying it isn’t useful, but that’s a different kind of science than trying to see if you can solve a puzzle by tinkering in the laboratory and thinking about it deeply and in different ways. I like the science where I think “why, that person was really clever, I wish I had thought of that” as opposed to “if I had that machine and those samples, I could have done that”.

 

A lot of drug discovery, at least in the past, came from hunter gatherer-type science. It’ll be interesting to see with this new big science if we can come up with new drugs.

I think it is important to view cancer research activities as being scientific, engineering or both. I think it is especially important for funders and policy makers to identify that. Rick Klausner opened my eyes to this, that the reason President John Kennedy could say “we’re going to put a man on the moon in 10 years” is because it was fundamentally an engineering problem. When it’s an engineering problem, the timelines and the deliverables are predictable, and one can estimate the time and cost, as opposed to science where the timelines and deliverables are usually unpredictable.

Industry is really good at taking on certain engineering aspects – taking a paradigm that you know works and scaling it with resources, as opposed to the real out-of-the-box early science that I think we should be doing in academia. That’s why I’m a little sad that so many academic scientists are being coerced into doing things that feel better suited for industry.

 

The VHL story is great because it reflects what CPI aims to do – support basic biology in the hope that it will help develop medical interventions to prevent disease in the future. It sounds like you endorse CPI’s strategy.

Yes, I am a strong advocate for basic and fundamental work. Discoveries and opportunities come from unexpected places. When people come to me and say aunt Sadie died of cancer X so I want to give money to someone who works on cancer X, I say you can do that but if I’m a betting person I would bet that the next big breakthrough for cancer X will come from someone who is working on cancer Y or frankly from someone who doesn’t even know they are working on cancer. That someone could finally give us the last puzzle piece of basic knowledge that was missing. Now we can go back to cancer X and do something significant. You also have to be a little opportunistic and look for opportunities for prevention.

 

On the topic of prevention, do you think that belzutifan could be used to prevent cancers, particularly in VHL patients?

The challenge for prevention drugs is safety. The level of toxicity acceptable when treating a cancer patient is very different from what is acceptable in a prevention setting, where the drug is given to healthy individuals. In this regard, VHL patients were reluctant to be treated in a preventative setting with VEGF tyrosine kinase inhibitors because of their toxicity.  Belzutifan seems better tolerated in this population.

Actually, belzutifan is already being used preventatively in the VHL population although it’s not marketed as such. A study published this year³ (Srinivasan et al., 2025; Figure 1) shows the effectiveness of belzutifan for prevention in the VHL population. A truism in medical oncology is that most drugs work better in frontline setting. In this trial, they had 61 VHL patients with measurable kidney tumors, who were never treated with drugs or radiation. They were under surveillance for four years at the NCI before they were put on belzutifan. During these four years prior to belzutifan, the patients had to go to the operating room often to have tumors removed. But once they were put on belzutifan the surgeries effectively stopped. It’s not completely zero, but it’s pretty close. It is a very impressive result. (Please see Figure 1 in the attached pdf).

 What have you been involved in recently that you are particularly proud of?

Something I have been excited about recently are the GLP-1 drugs. I have been a member of the Eli Lilly and Company board since 2012. And I am proud to say that I was one of the people in 2015-2016 who convinced the board and management that there was more to obesity than simple lifestyle choice. I think we’re going to see a significant decrease in obesity in the next 10 to 20 years. Thank goodness for people like Joel Habener and others who had done the basic science around GLP1. This is another example of how basic science contributes to the development of new targeted interventions and how discoveries come from unexpected areas of research.

 

Thank you for an amazing conversation!

 

Disclaimer: Dr. Kaelin has a financial interest in belzutifan. He is not directly involved in the clinical trials of the drug.

 

References

1. https://www.nobelprize.org/prizes/medicine/2019/summary/
2. Latif et al., 1993. Science. Identification of the von Hippel-Lindau disease tumor suppressor gene.
3. Srinivasan et al., 2025. Lancet Oncology. Belzutifan for von Hippel-Lindau disease-associated renal cell carcinoma and other neoplasms (LITESPARK-004): 50 months follow-up from a single-arm, phase 2 study.
4. Time, Love, and Memory: A Great Biologist and His Quest for the Origins of Behavior is a biography of the great Seymour Benzer, Ph.D., a pioneer in molecular and behavioral genetics, by the Pulitzer Prize-winning author Janathan Weiner.

 

 

Von Hippel Lindau (VHL) disease is a hereditary disease that increases the risk in carriers of various cancers, including clear cell Renal Cell Carcinoma (ccRCCs). It is caused by inherited mutations in the eponymous tumor suppressor gene VHL. It is considered a rare disease affecting around 1:35,000 people globally. Since patients develop multiple tumors from a young age, and most show symptoms by age 30, they are typically enrolled in surveillance programs with MRI scans every 3–4 months to detect new tumors or changes in existing ones. Often, as a preventive measure, tumors are removed by surgery.

The name “VHL” was coined in 1936, based on the descriptions of the disease by Eugen von Hippel and Arvid Lindau. The VHL gene itself was identified in 1993. Until then, VHL disease was considered a rare curiosity with little clinical relevance and no clear connection to wider studies of cancer.

 

Belzutifan is a drug that blocks the protein HIF-2alpha. Under normal circumstances, HIF-2alpha helps cells adapt to low oxygen levels. However, in certain cancers HIF-2alpha builds up to abnormal levels due to VHL mutations. By blocking HIF-2alpha function, Belzutifan blocks tumor growth.

 

Theo Ross: 2024 Women in Biopharma R&D

Theo Ross, M.D., Ph.D. CPI’s, President and Chief Scientific Officer, was recognized as one of 20 women making an impact in Biopharma Research & Development in 2024 by Endpoints News. Dr. Ross serves as Vice President of Early Oncology R&D at AbbVie. Read about her journey from medical school to pharma and how empathy drives her work.

Link to full article

Conference BRCA 30 Years: Discovery to Impact

Damon Runyon Fellowship Award

CPI has partnered with Damon Runyon Research Foundation to promote research relevant to the development of molecular approaches (such as drugs and vaccines) for the prevention of inherited cancers. If an applicable proposal is selected by Damon Runyon’s award selection committee and approved by the Damon Runyon Board of Directors, CPI will co-fund the Fellowship Award.
Award Overview – https://www.damonrunyon.org/for-scientists/application-guidelines/fellowship
Application Guidelines – https://www.damonrunyon.org/for-scientists/application-guidelines/fellowship/forms

Projects considered for funding by CPI are those that have the potential to make significant contributions to the development of chemo- or immuno-prevention measures that could reduce the risk of cancer in germline mutation carriers. Discovery research that could increase the understanding of early, pre-cancer stages are also considered. Visit the link below for more information on CPI’s funding priorities.
https://www.cancerpreventioninitiative.org/apply-for-grants/funding-priorities/

We encourage postdoctoral researchers with novel and innovative ideas related to precision prevention of inherited cancer to take advantage of this opportunity. Please contact Grants@CancerPreventionInitiative.org with questions regarding the CPI-funded award.

In Memory of Dr. Charis Eng

Charis Eng 1962-2024

(more…)

A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity

A CPI grant funded Dr. Kotsopoulos at the University of Toronto, Toronto, Canada for Evaluating BRCA1 haploinsufficiency as a putative target for the prevention of BRCA1-associated cancer. She and her collaborators developed a cell-based test to screen for drugs, small molecules, or natural compounds that could alter BRCA1 levels. Following the screening of more than 6,000 compounds using this assay, they identified several agents that can decrease BRCA1 protein levels. Some of these compounds can sensitize breast cancer cells to the PARP inhibitor Olaparib and may therefore have future clinical utility.

Read the full article in iScience.

Li Fraumeni Syndrome and one family’s harrowing experience with this deadly disease

Li Fraumeni (LF) is a hereditary cancer syndrome due to deleterious inherited mutations in the TP53 gene that increases the risk for developing a wide range of cancers, mostly sarcomas, breast cancers, brain tumors, and leukemias.

In the Wall Street Journal article below, journalist Lawrence Ingrassia writes about the multiple deaths in his family from a then unknown cause, and the scientists whose dedicated research spanning decades that eventually unearthed the culprit.

Much has been learned about LF since the death of the author’s mother in the 1950’s; when the author’s brother died after developing multiple cancers in 2019, he knew that he carried a TP53 mutation. However, the disease is still managed in mutation carriers by frequent screenings and tests to catch the cancers as early as possible. There is currently no way to prevent the disease before cancer(s) have taken hold.

As such, CPI funded a project by Dr. Jos Jonkers that could lead to vaccines that prevent cancers with TP53 mutations.

Solving the Cancer Mystery That Devastated My Family

For decades, Lawrence Ingrassia wondered why so many of his loved ones got cancer. Then a team of dedicated researchers discovered the gene p53.

By Lawrence Ingrassia

My most enduring childhood memories of my mom are of her being sick. Of visiting her in the hospital with my older brother and two younger sisters. Of our grandmother staying with us while our mom recuperated from breast cancer surgery. Of seeing her in bed at home with a soulful, sad look on her face.

She had been ill, sometimes gravely, off and on while I was growing up. I’m pretty sure that she first had cancer as early as 1958, when she was 32, though my memory is vague because I was only 6.

Read the full article

2023 CPI Research Meeting

The second Cancer Prevention Initiative (CPI) Research Meeting was held on January 18^th, 2023. Following the success of the first meeting in 2021, this event was again held virtually and was moderated by Dr. Larry Brody, Director of the Division of Genomics at the National Human Genome Research Institute at the National Institutes of Health. He is a strong advocate for cancer prevention and has made pioneering discoveries of the genetic basis of breast cancer and the roles of the breast cancer genes BRCA1 and BRCA2.

CPI President and Chief Scientific Officer Dr. Theo Ross opened the meeting by welcoming the attendees and thanking Dr. Brody for moderating the event again this year. She reiterated the mission and the strategy of CPI, to accelerate the discovery and development of new medicines that prevent cancer by supporting research on the prevention of inherited cancers. She shared the good news that in addition to the progresses made in the scientific research front, CPI has successfully raised substantial funds to continue support of current projects as well to as start additional projects this year. She also spoke of new funding opportunities in the external cancer prevention front: concept proposals by the National Cancer Institute’s Division for Cancer Prevention in support of research related to immunoprevention and the discovery of natural compounds that may prevent cancer. This is a welcome change, as prevention research has historically received weak support from funding agencies. Even today, only a small fraction of the funding is devoted to prevention, and treatment remains the main focus. These new efforts, though small, may herald a rising interest in prevention by funding agencies.

The 2023 CPI research meeting featured a lineup of CPI-funded researchers who presented updates on their research projects. The first session of the meeting was dedicated to research projects on immunoprevention of cancer, harnessing the abilities of the immune system to stop precancerous lesions from developing into cancer. Dr. Peter Lee of the City of Hope Comprehensive Cancer Center discussed his project related to repurposing an FDA-approved antiparasitic drug that they showed could kill nascent tumor cells in a way that activates the immune surveillance system to prevent future cancer initiation.

The next presenter, Cleveland Clinic’s Dr. Charis Eng, started her presentation with a historical imperative for prevention from the ancient Chinese medical text Huang Dee Nai-Chang: “Superior doctors prevent the disease, mediocre doctors treat the disease before evident, and inferior doctors treat the full-blown disease”. This philosophy resonates with the mission and vision of CPI to shift the approach to cancer from treatment to prevention. Dr. Eng and her team are working on developing a vaccine that would specifically target BRCA1 mutated cells before they can proliferate into harmful tumors and can be given to BRCA1 mutation carriers to reduce their chance of developing cancer. Along the way, they have generated the first gene expression data comparing tumor and normal mammary tissue of BRCA1 mutation carriers. These data are an invaluable resource for all researchers studying breast cancer.

The second session was dedicated to projects exploring the earliest events that drive cancer initiation and understanding the mechanisms underlying these events. BRCA1 mutation carriers have only one “good” copy of BRCA1 instead of the normal two. It is well known that precancerous cells develop when the “good” copy of the BRCA1 gene is lost. Dr. Maria Jasin and her team at Memorial Sloan Kettering Cancer Center have generated a very elegant cell-based assay to identify compounds and signaling pathways that contribute to BRCA1 gene loss. Their work can lead to finding ways to intercept this early step necessary for transformation.

CPI-funded researchers at the Women’s College Research Center at University of Toronto, Drs. Joanne Kotsopoulos and Leonardo Salmena, and Ph.D. candidate Erin Sellars, attempt to prevent cancer development in BRCA1 mutation carriers by restoring BRCA1 expression levels to normal levels. They used a high-throughput screen they developed to identify drugs that increased BRCA1 expression, and they have hit upon some promising targets.

The CPI Research Meeting was an opportunity for CPI scientists to share their newest data and get productive feedback from fellow scientists. It was also an opportunity for cancer scientists with a shared interest in prevention to come together and have a larger conversation on the challenges of carrying out cancer prevention research – from limited funding and lack of enthusiasm from the medical community to restrictions posed by regulatory agencies. These are some of the challenges CPI attempts to address through its goals.

The meeting ended with closing remarks by Dr. Ross.

The meeting was supported by generous funding from Lyda Hill Philanthropies.

Meeting Participants

Moderator:

Lawrence Brody, Ph.D.
Director, Division of Genomics
National Human Genome Research Institute
National Institutes of Health

Participants:

Charis Eng, M.D., Ph.D. Presenter
Professor, Sondra J. and Stephen R. Hardis Endowed Chair in Cancer Genomic Medicine
Lerner Research Institute, Cleveland Clinic
“Transcriptome guided vaccine for BRCA1/2 germline mutation carriers”

Maria Jasin, Ph.D. Presenter
Professor, Lab Head
Memorial Sloan Kettering Cancer Center
“Preventing LOH in BRCA mutation carriers”

Joanne Kotsopoulos, Ph.D.
Scientist, Familial Breast Cancer Research Unit, Women’s College Research Institute
Associate Professor, Department of Pharmacology & Toxicology, University of Toronto
“Screening for modifiers of BRCA1 expression”

Peter P. Lee, M.D. Presenter
Chair, Department of Immuno-Oncology
Professor, Department of Hematology & Hematopoietic Cell Transplantation
City of Hope Comprehensive Cancer Center
“Chemo-immunoprevention for cancer via repurposing a low-cost, safe, anti-parasitic drug”

Steven Narod M.D., FRCPC, FRSC
Tier 1 Canada Research Chair in Breast Cancer, Women’s College Research Institute
Professor, Dalla Lana School of Public Health, University of Toronto

Ying Ni, Ph.D.

Assistant Professor, Cleveland Clinic Center for Immunotherapy and Precision Immuno-oncology

“Transcriptome guided vaccine for BRCA1/2 germline mutation carriers”

 

Leonardo Salmena, Ph.D.
Associate Professor, Department of Pharmacology and Toxicology, University of Toronto
Affiliate Scientist, Princess Margaret Cancer Centre
Canada Research Chair, Tier 2
“Screening for modifiers of BRCA1 expression”

Erin Sellars, M.Sc. Presenter
Ph.D. Candidate, Salmena Lab
Department of Pharmacology & Toxicology, University of Toronto
“Screening for modifiers of BRCA1 expression”

CPI team participants:

Doug Hager, Ph.D.
CPI Sr. Vice President, Project Management and Operations

Theo Ross, MD, Ph.D.
CPI President and Chief Scientific Officer

Marion Stewart-Thomas, M.S.
CPI Operations Manager

Angelique Whitehurst, PhD.
CPI Sr. Scientist and Advisor

Ranjula Wijayatunge, Ph.D.
CPI Project Manager

2023 CPI Research Meeting Summary

Expert Interview with Alan Venook, MD, on colorectal cancer and the promise of immunotherapy for prevention and treatment

Posted February 9, 2023 –

Dr. Alan Venook is a nationally renowned expert in gastrointestinal cancers such as colorectal cancer (CRC) and liver cancer. He is based at University of California, San Francisco (UCSF) and holds the Madden Family Distinguished Professorship in Medical Oncology and Translational Research. He is also the Shorenstein Associate Director for Program Development at UCSF’s Helen Diller Family Comprehensive Cancer Center. Dr. Venook has a deep interest in clinical trial designs for the treatment of gastrointestinal malignancies and served as the Chair of the Gastrointestinal Committee of the Alliance for Clinical Trials in Oncology.

Dr. Venook earned his bachelor’s degree from Rutgers University, and his medical degree from UCSF. He completed his residency in internal medicine at UC Davis. He joined the faculty of UCSF in 1988.

 
 
In this interview, Dr. Venook shares his thoughts on:

• His motivation to focus on gastrointestinal (GI) cancers
• A recent study that shows the promise of first-line immunotherapy for rectal cancer (Cercek et al., 2022. New England Journal of Medicine – NEJM) and its implications for future treatments and Lynch syndrome patients
• The relevance of the gut microbiome to CRC and cancer treatments
• The shifting demographic in colorectal cancer (CRC)
• Changes in screening recommendations
• How to be an informed patient
• His observations regarding the difference between right- and left-sided colon cancer

Dr. Venook, you specialize in gastrointestinal (GI) cancers and have been in the field for many years. What spurred your interest GI cancers and especially colorectal cancers (CRCs)?

I wanted to work in an area that was really underserved and underexplored, and GI cancer seemed like a good area. Frankly, it was a practical issue of where the opportunities were; finding an area that was open and had opportunities for me. Obviously, I find it very interesting. CRC, particularly, is unique in that it’s one of the very few cancers that can be cured even after it’s metastasized. We didn’t know that when I started and ours was one of the first groups to demonstrate it. We’ve learned a lot about the disease since I started. We have a lot of treatments for CRC now, but it’s a complex disease and we are still playing catch-up. It has been challenging especially with the limits of efficacy of immunotherapies.

On the topic of immunotherapy, what do you think about the recent study (Cercek et al., 2022, see summary below) that treated rectal cancer patients with neoadjuvent immunotherapy and saw complete remission in all patients?

 This is the first study I have seen that shows complete remission in every single patient. Nothing’s ever hundred percent, so they must not have treated enough patients to see non-responders. Nonetheless, it’s remarkable that every single patient treated went into remission. It is also remarkable that there was no toxicity. I believe that this may be the only journal paper I’ve ever seen on a clinical trial that had no toxicity. Again, they probably didn’t treat enough patients.

Memorial Sloan Kettering (MSKCC) has sort of led the field in what’s called “total neoadjuvant therapy” (TNT) for rectal cancer. In TNT, chemotherapy and radiation is done up front before surgery. Memorial had looked at TNT in dMMR/MSI-high patients and found that a surprising number of patients didn’t get the full benefit of neoadjuvant chemotherapy, about one out of three did not (Cercek et al., 2020). Based on those results, it seemed logical to flip the paradigm and go with the immune checkpoint inhibitors (ICIs) upfront.

A previous study from the Netherlands (NICHE study) (Chalabi et al., 2020) had looked at immunotherapy in patients with primary colon, not rectal, cancers in a neoadjuvant setting – ICIs given as primary treatment. They took the patients to surgery six weeks in, so, they really didn’t get a definitive glance, but they still saw really marked responses.

How long do you think it takes for different ways of treating patients to be adapted into to mainstream care?  With the low toxicity seen in this study by Cercek and others, there doesn’t seem to be a lot of harm in trying neoadjuvant ICI.

The short answer is that it depends. If it’s a subtle or nuanced difference, it can take a very long time. There’s harm if you’re not vigilant and miss opportunities. We have to follow the data, and when the data tells us to make changes, we should go ahead and make changes. But most oncologists don’t live and breathe one disease. Therefore they may go with what they’re used to, but it’s our job to be ready to turn on a dime.

A lot of cancer care is dictated by the National Comprehensive Cancer Network (NCCN) guidelines, rightly or wrongly. And I happen to be the vice chair of the NCCN panel for guidelines to colorectal cancer and this neoadjuvant immunotherapy will be in discussion. Do we change the guidelines? It’s all consensus. It’s unusual that a 12-15 patient study could change the standards of care, but I think this is one of the times where, in my opinion, it might. If you change the guidelines, you need to include the proper caveats about exactly what you have to do, the right follow up and surveillance, etc. You can’t be nonchalant about it.

A concern in moving ICI up front is that you may miss the opportunity with patients who don’t benefit from the ICI but may get substantial benefit from chemotherapy. I think that one of the problems with immunotherapy is that there is truly so much upside to immunotherapy that physicians don’t want to abandon it once they start it. Because they assume it’s going to work. They may start with a single agent and if it doesn’t work add in another. Then they may see so-called “Pseudoprogression.” I think there are more papers written about pseudoprogression than patients who’ve actually had pseudoprogression. It’s talked about a lot. The danger is that these patients may never get chemotherapy due to physician and patient bias, and that may disadvantage some patients who might benefit from chemotherapy.

Given the low toxicity, how feasible is it to use ICIs in primary prevention for high-risk individuals, such as Lynch syndrome patients who are at a high risk for developing CRC and other cancers?

It is an interesting question. The problem with the ICIs is that they could have major downsides. I have a patient who is a perfect candidate for everything else, got a single dose of the PD-1 blocker Pembrolizumab, an ICI, just one dose, and has essentially myasthenia gravis. The patient had to be intubated and has been in our rehab for four months. Myasthenia gravis is an autoimmune neurologic disease, which is admittedly very unusual, but it happens. Probably one in 25 patients on ICIs have a major consequence, therefore, going into healthy beings with that kind of risk is not tenable.

How good an indicator is the MMR/MSI status in predicting response to ICIs?

As seen in Keynote 177 (Andre et al., 2020; Diaz et al., 2022) and other studies, even dMMR/MSI-high colon cancer is not uniformly responsive to ICIs. However, in the recent Cercek et al., 2022 study, all dMMR/MSI-high rectal cancers responded. Why is that? There are many differences between the colon and the rectum. Memorial Sloan Kettering has collected a lot of biospecimens, so they’ll have a ton of molecular data and a real opportunity to figure out the differences.

Can you discuss the relevance of the gut microbiome to cancer therapy? What is your opinion on using the microbiome to predict treatment responses and direct treatments?

We’ve known that the gut microbiome influences treatment responses for a long time. One of the observations is with the conventional chemotherapy drug, Capecitabine, an oral chemotherapy drug that’s used frequently in patients with colon cancer. It was observed that patients in the US tolerate a much lower dose than patients in Europe. Now, we’ve got quite good evidence that that’s almost directly related to the microbiome. Capecitabine is a prodrug that has to be activated in a couple of steps by several enzymes in order to be effective. People can have biota with activating and/or inactivating enzymes. These enzymes can change how the drug is processed and can play havoc with the dosing and predictability of the drug.

The microbiome has a huge impact on the whole immune system. I think that’s why the immune therapies may not work well in colon cancer. It’s also probably why patients with liver metastases with MSI-high tumors are less likely to get benefits from ICI than those with other sites of metastasis. Because the liver is sort of an immune island.

 The problem with the microbiome is that it is very complex. Until the last decade we didn’t have the computational power to even sort through it. It is said that there are more microbiota in the microbiome than there are cells in the human body. I don’t know who counted them, but that alludes to the complexity of the microbiome.

In the future, I expect the gut microbiome to be incorporated into detection and treatment of cancer. I won’t be in the field by then. Jim Allison won the Nobel Prize for ICIs that he’d been fiddling with for 10 or 15 years before he really put two and two together. Hopefully, we will figure out the microbiome and how it influences the immune system and immunotherapies without taking so long.

What other immunotherapy approaches apart from ICIs do you see as promising? Where does adoptive T cell therapy stand for CRC?

Ideally, you would want to generate a unique CAR-T (chimeric antigen receptor T-cell) for each patient. One challenge is that it takes several months to prepare the T-cells. And you need patients who are Olympic athletes, patients to be in very good condition. These patients will already be having standard therapies, and you hope that they don’t deteriorate while the T-cells are being prepared. There is also the issue of efficacy with this therapy. Another problem, with any therapy actually, is that the nature of the disease changes from the time you put a patient on the study to the time you actually get to treat them. This could be a very daunting experience. However, we do have a program at UCSF, and we’ve got some patients who’ve made it through.

What are the major challenges in CRC space right now?

The biggest issue right now is the preponderance of young people with CRC. For the last decade or so, we’ve been seeing an influx of young people with CRC. The incidence of CRC in people over the age 60 has gone down dramatically because of screening, but I would say that it’s made-up for by the increase in younger people. So, the net incidence is about the same.

A vast majority of cases are at advanced stages like stage 4, because colon cancer symptoms take a while to develop. We probably have two dozen patients in our care at UCSF who are under the age of 40 with advanced CRC. If someone happens to have a cancer that bleeds that is good luck because that could lead to early detection. Otherwise, the cancer can be there for years before its detected. Then, there are times when there are symptoms, but it doesn’t occur to the patient or the doctors that it could be CRC.

Is this why some recent recommendations for CRC screening have been lowered from age 50 to 45? Do you think we should make the age even younger? 

Screening people starting at 45 is not going to improve early detection. I guess it’s better than starting at 50. But it’s not going to make a big impact because although there are some cases between the age of 45 and 50, for the most part, the real increase is in 30-to-35-year-olds. The problem with increased screening is that there aren’t enough gastroenterologists to do that. Also, when you do many colonoscopies, you’re going to increase the chance of complications.

We need to figure out a simple test that can be used to screen for CRC less invasively. For example, a test that would detect protein biomarkers in stool. Or oncRNAs (orphan noncoding RNAs) that are excreted by cancer cells. At a recent conference, I saw phenomenal data from assays that are so sensitive, they can find oncRNAs in the stool. They could be predictive of cancer and therefore can be used for screening and identifying those who then need to get a colonoscopy. But, if it’s too sensitive you’re going to be putting people through too many colonoscopies.

 Factors that increase the risk in the general population have a worse impact on high-risk individuals, such as lynch patients with inherited risk. What are some of the reasons for increasing CRC among young adults that they should know about?  

This increase of CRC in young individuals is really mind boggling. It doesn’t appear to have anything to do with heritable factors. Interestingly, it also does not appear to be due to the obesity epidemic. It’s not only people with bad diets or with fatty livers or metabolic syndromes; we also see otherwise healthy people. We even see patients who are marathoners or triathletes.

The other thing that’s even more distressing is the disproportionate impact it’s having on people of color. Recently, a famous African American actor died of colon cancer at age 43 – this is not an isolated incident.

Aside from screening to detect cancer early, what are (early) interventions or preventative measures that are available for high-risk individuals?

There is no preventive therapy so far. For people truly at high risk, like with familial polyposis, the only choice is to remove the colon. The problem is the rest of the bowels are at risk for polyps as well. These people will not infrequently succumb to small bowel or other problems.

You’ve run many clinical trials, what are some of the challenges in planning and running clinical trials?

One challenge is that large clinical trials can take a long time to complete. The CALGB/SWOG 80405 study was launched in 2004 and I presented the results at the American Association for Clinical Oncology (ASCO) meeting in 2014. It was an almost 20-year process with 2300 patients. So, you need to have patients and patience.

It is getting harder to recruit patients for large, randomized trials which is how you would like to ask a good scientific question and be vigorous. But patients will come already decided on what they want based on a relatives’ recommendation or an anecdote they’ve seen on social media. It is harder do a large trial with a control or placebo arm.

How can one be an informed patient?

You want informed patients, but you don’t want them to be poorly informed or misinformed. There’s so much misinformation on the internet and we are constantly battling with it. It’s a real challenge. To me, it’s interesting that people may know about pharmacogenetics, how an individual patient’s genes effect the way drugs are metabolized. A common chemotherapy for multiple types of cancer is Fluorouracil (5FU). There’s an enzyme responsible for metabolizing it called DPYD. Certain rare variants of this enzyme can put some people, maybe 2% or 3% of the population, at greater risk for complications. There’s an advocacy group of family members of people who had complications of 5FU who are pushing for everybody to be screened for variants in DPYD. If we test everyone, we will find high-risk variants, but we will mostly find variants that we have no idea what to do with. For patients with these variants, it will be unclear what to do. Do we reduce the dose and run the risk of having a reduced impact on the patient’s outcome?

Being informed also means understanding that there are a lot of unknowns. Doctors should be ready to explain to patients why they wouldn’t do a test, as opposed to more and more patients demanding tests and getting them done. You should only do a test if you’re prepared to do something with the results or know what to do with the results. I wrote an editorial a few months ago about a circulating tumor DNA (ctDNA) test (Venook et al., 2022). It was a blood test to find evidence that cancer was present in the body, but it couldn’t tell you where it was located, what you could do about it, etc. So, you are giving people a death notice with nothing to do about it.

 You’ve demonstrated the difference in outcome between colon cancers developing in the right vs. left side of the large intestine. Can you explain the process of figuring this out?

We carried out the biggest colon cancer study in the US, the CALGB/SWOG 80405 study (Venook et al., 2017). Some aspects of our results were different from a study that was done contemporaneously in Europe. I was trying to figure out the biological reasons to how this difference could be explained, and we put right vs left location of tumor as something to think about. However, to simplify the data sheets, we had not included the location of the primary tumor. So, we had to look through 2400 charts to collect this information, which took a while.

Coincidentally, I was invited to give a memorial lecture for a colleague who had passed away. Looking through his publications in preparation for the lecture, I came across a very old study that basically looked at a bunch of therapies that we’ve long since abandoned. But in that paper, there was just a line that commented that patients with right sided primary lived for ten months while patients with left sided primary lived for fifteen months. This was many years ago when we were not nearly as effective with the therapies for colon cancer. I thought “wow” that’s a big difference. I’ve never heard that. I was stunned that nobody followed up on it. So, this motivated us to look into the sidedness of the tumors.

In our study, we saw a stunning 15 – 16-month difference in survival between left- and right-side patients. And genetically it makes sense because the right and left colon come from different embryonic structures – the right colon comes from the midgut and the left colon comes from the hind gut. We are trying to understand the molecular features that make the right vs left colon cancer different, but we don’t have an answer yet.

I love to talk about this observation that the right and left side cancers are different, for which I am credited for figuring out. But it’s embarrassing that I’ve been taking care of patients for all these years and hadn’t figured it out before. It’s very humbling.

Dr. Venook, it has been such a pleasure talking with you. Many thanks for sharing your insights.

 

 Promise of immunotherapy for DNA repair deficient rectal cancer, Cercek et al. 2022 NEJM

 Summary: This small but significant study establishes the efficacy of immunotherapy as first line/primary treatment for a type of DNA repair-deficient rectal cancer. The patients received a type of immunotherapy known as immune checkpoint inhibitors (ICIs). ICIs act by releasing the molecular breaks put on by cancer cells on the immune cells to stop the immune system from identifying and destroying them. The ICI given in this study was dostarlimab. It was given to the patients every three weeks for six months. This was different from standard practice in that immunotherapy was given as the first line treatment i.e., in a neoadjuvant setting before the main treatment. Surgery was planned for after immunotherapy. At the end of the six-month treatment cancer had disappeared in all 18 patients, and they avoided the need for surgery.

All the cancers in this study were deficient for a type of DNA repair called mismatch repair (MMR). Inability to repair errors in DNA due to deficiency in MMR (dMMR) results in high microsatellite instability (MSI-H) and the expression of cancer-specific proteins that help immune system identify the cancer cells.

This study is of particular interest to Lynch syndrome patients because they carry inherited mutations in MMR genes that put them at a high risk for CRC among other cancers. It raises the possibility of immunotherapy as first line therapy for Lynch patients with rectal cancer.

This study was conducted by Memorial Sloan Kettering Cancer Center (MSKCC) in New York with Dr. Luis A. Diaz Jr. as lead investigator.

 

 Glossary:

Adoptive T cell therapy: A type of immunotherapy in which T cells (a type of immune cell) are given to a patient to help the body fight diseases, such as cancer. CAR-T is a type of adoptive T cell therapy, where the T cells are modified to better target and kill cancer cells before giving to the patient.

Familial adenomatous polyposis (FAP): A type of hereditary colorectal cancer, caused by pathogenic mutations in the APC gene. Many polyps (abnormal growths) form in the colon and the rectum and these may develop into cancer.

Immunotherapy: A type of treatment that uses a patient’s own immune system to fight cancer. Treatments may stimulate/activate the immune system to better identify and attack cancer. Includes checkpoint inhibitors, CART-cell therapy, cancer vaccines.

Immune Checkpoint inhibitor (ICI): A type of immunotherapy. Although the immune system can recognize many cancers and destroy them, the cancer cells develop ways to evade the immune system. They can produce “immune checkpoints” that can suppress the immune response, to put “breaks” on the immune response. Immune checkpoints are normally used to prevent autoimmune reactions against healthy cells of the body. ICI drugs like PD-1/PD-L1 and CTLA-4 inhibitors take these breaks off the immune system, to help it recognize and attack cancer cells.

Lynch syndrome: The most common inherited CRC syndrome caused by germline pathogenic variants in DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and EPCAM. Affected individuals have an elevated risk of developing CRC as well as certain other cancers.

Mismatch repair (MMR) and Microsatellite instability (MSI): Mismatch repair (MMR) is a type of DNA repair pathway that is present in the cell. MMR pathway components are encoded by genes such as (MLH1, MSH2, MSH6, and PMS2). MMR-deficient (dMMR) tumors have mutations in MMR genes and are thus unable to correct certain errors, resulting in tumors with high microsatellite instability (MSI-high) and mutational burden.

Neoadjuvant therapy: Treatment given first before the main treatment such as surgery.

Pseudoprogression: A phenomenon in which an initial increase in tumor size is observed, followed by a decrease in tumor burden. This phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false judgment of progression.

 

References:

Andre et al., 2020. NEJM. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

Cercek et al., 2020. Clin Cancer Res. Mismatch Repair-Deficient Rectal Cancer and Resistance to Neoadjuvant Chemotherapy.

Cercek et al., 2022. NEJM. PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer.

Chalabi et al., 2020. Nat Med. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers.

Diaz et al., 2022. Lancet Oncol. Pembrolizumab versus chemotherapy for microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): final analysis of a randomised, open-label, phase 3 study.

Venook et al., 2017. JAMA. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Venook et al., 2022. JAMA. Colorectal Cancer Surveillance with Circulating Tumor DNA Assay.