Prostate Cancer Lab Updates

  Full Transcript (Google Doc)

Meeting Summary

Advanced prostate cancer patient and bioinformatician Rick Stanton introduced the treatment options he and his medical team are considering, using the standard (NCCN) treatment guidelines as a way to tell the story of how he got here. This built on Rick’s previous session (see the notes from meeting #6 here), in which he walked through his and Brian McCloskey’s medical history. We have discussed potential enhancements to the guidelines, such as:

• Bring testing forward in the guidelines to help people at each decision point.
• Embed more real world evidence in the decisions.
• Add more structure and explicit guidance for decisions in the late stages.
• Make the guidelines more dynamic and predictive.

 

Put a treatment strategy with guiding principles on top of it.

To guide his treatment decision, Rick shared his test results (DNA sequencing, immunohistochemistry, and RNA sequencing). The DNA sequencing identified two CDK12 mutations. The RNA sequencing identified three biomarkers which were overexpressed: AR, PSMA, and B7-H3.

Based on the test results and his medical history, Rick and his medical team have identified this list of treatment options:

• Pluvicto (radioligand attacking PSMA, currently unavailable due to production issues)
• Olaparib (targeting CDK12) + CTLA4 inhibitor + PDL1 blockade
• PSMA CAR-T from Poseida (targeting PSMA)
• PSMA bispecific from Calibr (targeting PSMA)
• ASRV-766 AR degrader (targeting AR)
• Daiichi antibody drug conjugate to B7-H3 (targeting B7-H3)
• Cabazitaxel (chemotherapy)

 

Requests

Do you have any feedback on Rick’s testing and treatment options?

Upcoming Meetings

• May 18: Bob Gatenby, MD, Co-Director, Center of Excellence for Evolutionary Therapy, Moffitt Cancer Center, on "An Evolutionary Biology Approach to Advanced Cancer Treatment Strategy"
• May 25: Karin Rodland, PhD, Director, Precision Medicine Innovation CoLaboratory, Pacific Northwest National Laboratory, on "Proteomics to Guide Advanced Cancer Treatment"
• June 1: Tony Letai, MD, PhD, Professor at Dana Farber Cancer Institute, and President, Society for Functional Precision Medicine, on "Functional Precision Medicine for Advanced Cancer"
• June 22: Selin Kurnaz, PhD, Co-founder and CEO, Massive Bio, on "Finding the Best Clinical Trial"

 

If you have other priorities at this time, we will send out a meeting summary that you can read at your convenience.

Best,
Brad

Meeting Recording

 

👉  Full Transcript (Google Doc)

Meeting Summary “We have done many simulations on genomic data, and all of them show that using more drugs is better than fewer drugs, and less concentration is better than more concentration.” - Saed Sayad In our meeting on May 4 we discussed the strengths and weaknesses of using combinations of approved drugs to better fit a patient’s unique molecular profile and thereby achieve better outcomes, and the use of off-label drugs targeted at molecular biomarkers. The main concerns were around toxicity from combinations and the possibility that off-label drugs might behave differently in different disease contexts (something that worked in one cancer might not in another). (For more background, please see the notes from our meeting #5 on April 20, where Ally Perlina, Chief Science Officer at CureMatch, presented combinations of approved drugs that are the best fit for advanced prostate cancer patient Brian McCloskey based on his cancer’s unique molecular profile.) Should a combination of drugs be administered sequentially vs. all at once?

• Leaving mutations untargeted enables progression.
• Higher matching results in better outcomes.

Are drug combinations more expensive than monotherapies?

• Providing the molecular rationale is evidence that can persuade payers to reimburse.
• Alternative drugs are identified that affect the same pathway. Some will be cheaper yet have the same effect.
• Dosages for drugs within a combination can be reduced vs. when the drug is administered as a monotherapy.
• By targeting the molecular profile, better outcomes are achieved, which are cheaper.

Do you have any experience or data in having patients cycle on and off drugs?

• We don’t.
• It’s hard enough getting physicians to consider drug combinations.

Do you include therapies that are in clinical trials in your recommendations?

• We don’t.
• Adding drugs that are in clinical trials would be too complicated and too risky for most physicians

Is there evidence to support using a MEK inhibitor for a BRAF mutation?

• I will have to look it up to find the evidence.
• It depends on the situation whether to use the indirect MEK pathway.

Is off-label use of a drug potentially a mistake? What about the example of a BRAF drug not working in colon cancer?

• If a drug that targets a mutation didn’t work, it was because the whole molecular picture wasn’t taken into account.

How should a physician manage doses with a novel drug combination?

• There is dosage advice provided in the report.
• We will provide report reviews on request.

Brian McCloskey asked about on-off cycling through drugs, an idea promoted by Dr. Bob Gatenby. Saed Sayad and Dr. John Laird observed that our guidelines, which push to maximum tolerated doses, are driving cancers to resistance – a flawed strategy. Saed Sayad presented a hypothesis that RCC1 could be a biomarker to predict cancer recurrence after prostate surgery. Requests: Do you have any feedback on drug combinations and off-label uses of approved drugs? Upcoming Meetings

• May 11: A Roadmap for Advanced Prostate Cancer Decisions (Enhancements to the NCCN Guidelines)
• May 18: Bob Gatenby, MD, Co-Director, Center of Excellence for Evolutionary Therapy, Moffitt Cancer Center, on "An Evolutionary Biology Approach to Advanced Cancer Treatment Strategy"
• May 25: Karin Rodland, PhD, Director, Precision Medicine Innovation CoLaboratory, Pacific Northwest National Laboratory, on "Proteomics to Guide Advanced Cancer Treatment"
• June 1: Tony Letai, MD, PhD, Professor at Dana Farber Cancer Institute, and President, Society for Functional Precision Medicine, on "Functional Precision Medicine for Advanced Cancer"

Meeting Recording

  Full Transcript (Google Doc)

Meeting Summary

Advanced prostate cancer patient Rick Stanton walked through a one-page summary of the NCCN (National Comprehensive Cancer Network) guidelines for advanced prostate cancer and illustrated it with his and Brian McCloskey’s treatment journeys. The NCCN guidelines are the “standard of care” - the evidence-based protocol for deciding on treatments for patients with prostate cancer. Rick started his summary of the NCCN guidelines after the prostatectomy step since he is focusing on the journey for advanced prostate cancer. From there, most branches in the NCCN decision tree depend on whether the patient’s PSA (prostate specific antigen, a blood test result), is rising or not, and whether their cancer has spread outside the prostate (metastasized).

Rick and Brian’s PSA rose after their prostatectomy, so they switched from observation (“watchful waiting”) and had the next recommended treatment: radiation and drugs (Lupron and bicalutamide/Casodex) that suppress androgen, the hormone that feeds the cancer. This androgen suppression treatment worked for about a year for Rick and Brian. Brian was doing so well, he and his medical team decided to take a holiday from the androgen suppressing drugs, and then after several months his PSA started rising rapidly. Rick’s PSA started rising rapidly after about a year. At this point for both, with PSA rising, and now both with metastases (cancer in other places besides their prostate), the NCCN treatment recommendation is to try one of several drug options. Rick chose a next generation androgen blocker (darolutamide). After a few months, it was clear that this wasn’t working for him, so he joined a clinical trial that had two arms: one for chemotherapy (docetaxel) and another with that same chemotherapy plus two other drugs (a PD1 inhibitor and an adenosine inhibitor). Unfortunately, Rick got the clinical trial control arm with chemotherapy only, which he has stayed on until today. It has knocked down his PSA. Brian chose another androgen-suppressing drug (abiraterone), which he is on now. It is keeping his PSA at a very low level.

The first four or five rounds of decisions in the NCCN guidelines are largely not personalized. They depend on whether the cancer has metastasized and the PSA level. It is only in the very advanced stages of prostate cancer that personalization (decisions which draw on genomic tests) enters.

In our next meeting Rick and Brian will continue to talk about ways to (a) enhance the NCCN guidelines to refine this overview of the whole journey - a roadmap for communication between patients and doctors, (b) bring more testing and associated personalization earlier in the decision process, (c) add data on the efficacy of the treatment options, and (d) add a roadmap for steps beyond the end of the current guidelines.

Requests

• Do you have any feedback on Rick’s presentation on the decision tree for advanced prostate cancer testing and treatments? How could we improve it?
• Do you have contacts at the NCCN whom we could contact to explore the possibility of collaboration?

 

Meeting this Week

Please join us for our next video chat on Wednesday, May 3, at noon Eastern.

Our meeting agenda is:

• A continuation of discussion of the testing and treatment decision roadmap (led by Rick Stanton)
• Feedback on the CureMatch presentation (led by Ally Perlina)
• Further discussion of the inclusion of hypotheses and insights from public data sets for prostate cancer guidance (led by Saed Sayad)

Meeting Recording

👉  Full Transcript (Google Doc)

Meeting Summary

At our last meeting on April 20, Ally Perlina, Chief Science Officer at CureMatch, presented combinations of approved drugs that are the best fit for advanced prostate cancer patient Brian McCloskey based on his cancer’s unique molecular profile. CureMatch is a San Diego-based company which takes biomarkers identified by most any diagnostic sequencing test and matches them with approved drugs in combinations. Their distinctive value is using multiple drugs in combination to achieve a better fit with the unique characteristics of a patient’s cancer, and therefore better patient outcomes.

The CureMatch system starts with input from a patient’s molecular profile, derived from DNA and/or RNA sequencing of a patient’s tumor tissue or liquid biopsy sample. The test will identify biomarkers or variants of interest (variants from normal cells, potential drivers of the cancer), usually 4 to 6. Not all biomarkers or variants go into the algorithm. Some may be rejected because they are not pathogenic (don’t drive the disease), and some because there are no therapies targeting that biomarker. The physician has latitude to include or exclude biomarkers or treatment options due to any reason, such as medical history. For example, Brian had pembrolizumab, so he might decide to remove it as a treatment option. Then CureMatch analyzes the patient’s selected biomarkers against the roughly 300 drugs that the FDA has approved in combinations of 3, 2, or 1 drugs. They do not include clinical trials in their recommendations. For example, Brian has a variant (B7-H3/CD276) which has several clinical trials targeting this pathway, but it would not be included in a CureMatch recommendation because there are no approved drugs for it yet. Off-label uses of drugs (drugs that have been approved but for a different indication) are included in the treatment combinations.

The roughly 4.5 million possible combinations of the roughly 300 approved drugs are then scored on the extent to which they address the patient’s selected biomarkers. If a drug combination addresses 4 of 6 biomarkers, the score is 67%, 3 of 6 would be 50%, and 2 of 6 would be 33%. The drug combinations are ranked on their scores, with explanations and links to support the choices. For example, Brian had 6 actionable markers, 16 on compendia drugs, 54 matching drugs, and 24,857 relevant combinations. CureMatch’s top option, with a score of 32%, was a 3-drug combination of apalutamide (FDA approved, AR target), olaparib (FDA approved, FANCA target via PARP-1, PARP-2), and trametinib (off-label, BRAF target via MAP2K1, MAP2K2, and MAP2K2 target).

As Emma Shtivelman, an experienced PhD molecular biologist and Chief Scientist at Cancer Commons summed up,

“... someone like me looks more for clinical trials rather than off-label treatment options. And when I look for clinical trials, I keep in mind the previous treatments... CureMatch has this assumption that a physician will be able to prescribe off-label combinations of two or three drugs. This happens rarely, even with the best specification. I know two patients who had recommendations from CureMatch and their physicians worked with the recommendations, and it worked great. But it's an exception... It's unfortunate and very frustrating.”

Advanced Prostate Cancer Patient Panel Report

Brian McCloskey shared highlights from a meeting of advanced prostate cancer patients who have registered with the Prostate Cancer Lab community.

Four themes emerged that they would like to see if they could change one thing about their care:

• Better physician-patient communication: Providing patients with simple language they can use to understand their disease and treatment options.

• Better diagnostics for personalizing treatments: Tailoring treatments uniquely to the profile of each individual.

• Medical guide partner: Finding a trusted medical advisor who will be an expert partner on the journey.

• Access to experts: Achieving a high quality of care in rural locations.

Requests

• Do you have any feedback on the CureMatch presentation? Would you recommend their approach to a friend or family member?
• Do you know anyone who would be a good candidate to serve on our Prostate Cancer Lab patient board? The candidate should be very active in wanting to learn more about his advanced prostate cancer and treatment options.

👉  Full Transcript (Google Doc)

Meeting Summary

Saed Sayad, MD, professor of computer science at Rutgers, and founder of Bioada Lab, presented a bioinformatics analysis of prostate cancer using public databases.

His main claim is that there is lots of useful data in the public domain which is under-utilized.

He shared several examples in prostate cancer where public data can be used to generate hypotheses for treatment options, including:

• Several drugs that could address a common gene (HOX) in prostate cancer (HXR9, sunitinib, aphidicolin, resveratrol).
• Only two sessions of radiation therapy may achieve the same result as the standard, which includes more sessions.
• Copper, in combination with other drugs, has been shown to kill prostate cancer cells.
• Prostate cancer with poor outcomes has a number of biomarkers, one of which (YOD-1) has been targeted by an oncogene (MicroRNA-373) in cervical cancer.
• Proteins found in a blood analysis (related to P53) could predict whether patients will respond to expensive therapies (anti-CTLA-4).
• A serum analysis can predict risk for 11 cancers, including prostate cancer.

 

His group is building a platform to make it easier for healthcare professionals to directly query these public databases, without having to use bioinformaticians or data scientists.

A rich - and at times heated - debate ensued about the merits of efforts to develop research hypotheses (especially for repurposed drugs) vs. getting them to clinical use for patients who need treatments today. The process of developing evidence to get promising treatments into the standard of care for patients can be expensive and hard to fund if it can't be funded by a pharmaceutical company with a proprietary drug that could benefit. Government and advocacy groups like the Leukemia and Lymphoma Society or Prostate Cancer Foundation were mentioned as the most likely avenues for funding.

👉  Full Transcript (Google Doc)

Meeting Summary

Advanced prostate cancer patient Rick Stanton shared details on his testing and medical history, treatment options being considered, and the tests he would like to see to inform his future treatment decisions. 

• Medical history: Rick shared a table with his PSA measurements and treatment history. His PSA is currently under control, and he is looking to have his next treatment ready to go.
• Treatment options: Rick listed the treatment options that have been recommended to him. Dr. John Laird suggested that trying chemotherapy combinations in the lab of Bob Nagourney at the Nagourney Cancer Institute would have a greater assurance of efficacy (80-90%) than clinical trials (15%). Rick Davis endorsed treatments with more evidence, and recommended that Rick revisit his initial diagnosis, as well as considering Pluvicto (PSMA-targeted radiation nanoparticles).
• Tests requested and analysis desired: Rick has requested IHC stains that will provide indications on his likely responsiveness to immunotherapies. He is offering his extensive medical data to anyone who would like to hack on it.
  
  

We continue work on “right to see” – finding ways for patients to be able to access data from “research use only” tests run on them.

Requests

• Please let us know if you know anyone who might be interested in being a principal investigator, or any potential funding organizations, for an observational feasibility study on providing data from emerging (research use only) tests to patients to guide their prostate cancer treatment decisions (“right to see”).
• If you would like access to Rick or Brian’s data, please contact them.
• Please join our online discussion forum on Discord for 24/7 conversation.

Next Meeting Agenda- Bioinformatics, the Prostate Cancer Foundation, and an Advanced Prostate Cancer Roadmap

Please join us for our next video chat on Wednesday, April 13, at noon Eastern, where we plan to discuss:

• Saed Sayad will present a bioinformatics analysis of prostate cancer using public databases. Dr. Sayad is an MD by training, and currently a professor of data science in the computer science department at Rutgers, and founder of Biodata.
• Brian McCloskey will update us on conversations he is having with the Prostate Cancer Foundation about collaboration.
• Rick Stanton will share a roadmap and guidelines he is developing for advanced prostate cancer.

👉  Full Transcript (Google Doc)

Meeting Summary 

👉  Full Transcript (Google Doc)

Meeting Summary

Advanced prostate cancer patients Brian McCloskey and Rick Stanton introduced themselves, their medical history, and their objectives for the Prostate Cancer Lab.

• Brian McCloskey: 56-year-old tech marketing executive; diagnosed 5.5 years ago; on abiraterone; sees the challenge of personalizing his treatment as hinging on data and analytics; wants to bring cutting edge diagnostic data and integrate it to understand his disease and guide his treatment.
• Rick Stanton: bioinformatician with many years in the pharmaceutical industry, including at Human Longevity, Inc., and Amgen; Stage IV; on chemo; wants to bring emerging research diagnostic technologies to his treatment decisions.

 

CancerHacker Lab founder Brad Power moderated and shared an overview of the Prostate Cancer Lab and its purpose.

• Building on the hackathon for advanced prostate cancer patient Bryce Olson in 2021.
• Lab process: attract patients, gather data, analyze data and find treatment options, define treatment strategy.
• Have attracted diverse companies and individuals willing to help: diagnosticians, bioinformaticians, treatment matching, patient advocates, and clinicians.
• Focus on accelerating the use of cutting edge diagnostics (RNA, proteomics, single cell, spatial analysis), which are currently “Research Use Only”, for clinical decision-making.

 

Several of the participants introduced themselves, including:

• Nik Schork: of TGen, an organization bridging between health data and clinical guidance - has developed a protocol, approved by an IRB, to grant patients access to research data about them.
• Rick Davis: leader of AnCan, a community of cancer patients - clarified treatment options.
• Lea Ann Biafora: oncology nurse, founder of Beacon Associates; Jason Sager: pediatric oncologist; Stacy Hurt: patient advocate, colorectal cancer survivor; Jeff Waldron: healthcare community connector; Jan Sobieralski: advanced prostate cancer patient.