“Multi-omic Analysis Guides the Decisions of Brian McCloskey”

“Multi-omic Analysis Guides the Decisions of Brian McCloskey” (Rana McKay, MD, and BostonGene) [#98] Brian McCloskey and Brad Power May 22, 2024 “For the next four days, Dr. McKay completely quarterbacked my care across the emergency department, the urology team, the radiation oncology team, her team, and orthopedic surgery.

” – Brian McCloskey, Cancer Patient Lab “First, we noticed that a lot of tumor cells demonstrate expression of Synaptophysin in the metastatic sample, nearly 38%, and only 3% expression in the primary sample. We then reviewed H&E slides and images and revealed that in the metastatic sample, we also can find areas with neuroendocrine-like features.

” – Kirill Kryukov, BostonGene “The salient thing that I pulled from this report is the striking angiogenesis signature. There are multiple different VEGF pathway genes that are dysregulated. What's important to pull is that there are multiple different targets here, as opposed to just one that could all be targeted with a drug.

When I see that, that's a very nice thing as a clinician to say, ‘Hey, this is not just one thing out of a sea of many; there are multiple targets in this pathway… This pathway seems to be off, and that may present a greater vulnerability for the tumor.’” – Rana McKay, MD, UCSD Health “That's what precision medicine can do.

It can help try to identify a specific vulnerability that we can take advantage of with drugs that we otherwise would not be able to.” – Rana McKay, MD, UCSD Health Meeting Summary Advanced prostate cancer patients want to know what their next treatment option should be if their current regimen fails.

However, this is a moving target as new treatments are approved, clinical trials for new treatments begin, and experience is gained in old and new treatments. It is important to occasionally scan the field for newly approved treatments and research on treatments currently in clinical trials.

For example, a number of new drug combinations and sequencing of systemic therapies in metastatic castrate-resistant prostate cancer can hit the cancer harder and earlier. Dr. Rana McKay is uniquely qualified to discuss the latest personalized approaches to treating men with prostate cancer.

She leads a multi-disciplinary prostate cancer clinic at UC San Diego Health, focused on delivering advanced cancer care. Her research interests include the design and implementation of clinical trials and novel biomarkers and therapeutic outcomes for patients with genitourinary (reproductive and urinary system) malignancies.

She is interested in understanding mechanisms of response and resistance to specific cancer therapies. Before joining UC San Diego Health, Dr. McKay was a medical oncologist at the Dana-Farber/Brigham and Women's Cancer Center in Boston and an assistant professor at Harvard Medical School.

“Multi-omic Analysis Guides the Decisions of Brian McCloskey” (Rana McKay, MD, and BostonGene) [#98] Kirill Kryukov presented

San Diego Health, Dr. McKay was a medical oncologist at the Dana-Farber/Brigham and Women's Cancer Center in Boston and an assistant professor at Harvard Medical School.

“Multi-omic Analysis Guides the Decisions of Brian McCloskey” (Rana McKay, MD, and BostonGene) [#98] Kirill Kryukov presented BostonGene’s analysis of Brian’s cancer, demonstrating the power of transcriptomic (RNA) analysis in identifying key biomarkers. Dr.

McKay discussed her interpretation of the test results and considerations of various therapeutic approaches, illustrating the issues and art and science of treatment navigation. What is Brian McCloskey’s situation? ●Advanced prostate cancer, diagnosed in 2016.

●Has had many tests over the years and has been through multiple lines of treatments including a radical prostatectomy, salvage radiation, six lines of systemic therapy, and two additional surgeries to remove metastatic lesions.

●Constriction of his right ureter (the tube that transports urine from the kidneys to the bladder) leading to kidney hydronephrosis (kidney swelling that happens when urine can't drain from a kidney and builds up in the kidney) and kidney damage, which affects his ability to pursue treatments that require full kidney function.

●Has had five operations since February 2023 to replace the ureter stent used to preserve as much kidney function as possible.

●In April 2024 the cancer spread to bone (typical for prostate cancer) in his spine (in the L2 vertebra, the second uppermost of the five lumbar vertebrae toward the lower end of the spinal column, within the lower back) leading to a compression fracture and spinal stenosis (the space inside the backbone is too small) requiring surgery to separate his spinal column from the spinal cord.

He is recovering from that surgery. ●Suspended his most recent systemic therapy, a chemotherapy (docetaxel), in February to take a break from the side effects of a cytotoxic treatment. ●BostonGene completed extensive testing on Brian’s tumors in early 2024 and identified several targets to pursue. What did the BostonGene analysis uncover?

●Some alterations were uncovered from the latest biopsy sample (amplification of androgen receptor, and co-amplification of KIT/PDGFRA/VEGFR2, along with a PTEN gene mutation), suggesting evolutionary divergence and potential targets as the disease progresses.

●A transcriptomic (RNA) analysis looked for biomarkers that are valuable as antibody- drug conjugates (ADCs bind to the tumor cell, a chemical linker takes a cytotoxic drug inside the tumor cell, which kills the cancer cell while sparing healthy tissue.) for therapy (TROP2, Nectin4, and SLFN11), and all of these markers in both samples demonstrated a medium or a high level of RNA expression.

●RNA analysis also uncovered a medium or high level of expression of some other potential biomarkers ( HER2, HER3, and TGFb) .

all of these markers in both samples demonstrated a medium or a high level of RNA expression. ●RNA analysis also uncovered a medium or high level of expression of some other potential biomarkers ( HER2, HER3, and TGFb) . ●The immune microenvironment has changed from an immune desert in Brian’s primary prostate sample to fibrotic in his metastatic sample.

“Multi-omic Analysis Guides the Decisions of Brian McCloskey” (Rana McKay, MD, and BostonGene) [#98] low and high grades of malignancy) and in the metastatic sample near 38%, and only 3% expression in the primary sample. What are the treatment options being considered for Brian?

●Chemotherapies: Brian’s synaptophysin (neuroendocrine marker) points to platinum therapies (such as carboplatin) and cabazitaxel. ●Targeted drugs: Drugs targeted at his gene mutations (e.g.

, VEGF and HER2), especially targeting the VEGF expression (KIT/PDGFRA/VEGFR2) with a tyrosine kinase inhibitor (cabozantinib) combined with an immune checkpoint inhibitor (nivolumab/Opdivo), which increases the efficacy over cabozantinib alone ●Antibody drug conjugates : to target Brian’s RNA biomakers (TROP2, NECTIN4, and HER2) ●AR (androgen receptor) degraders (a type of drug which interacts with the androgen receptor to downregulate this hormone activity, which feeds prostate cancer) ●Radionuclides (drugs that contain radiation that bind to tumor targets) : Alpha particle radionuclides (like actinium) are possible, but beta particle radionuclides (like Pluvicto) are not because of Brian’s kidney obstruction, which would hold the radiation in his kidneys for too long.

(Actinium is not processed through the kidney.) What are the strategic principles being applied to make a decision on Brian’s next treatment? ●Outcome Goals: Consider two main outcome goals: quality of life and delaying disease progression.

●Integrate: Balance and integrate data from the research and the test reports, considering patient history, current treatments and clinical context when interpreting reports. ●Target: Identify specific vulnerabilities in the tumor (VEGF, angiogenesis signature – formation of new blood vessels in cancer growth) and insights on the disease (neuroendocrine) to target with drugs.

Consider possible agents and their compatibility with other agents. ●Immune system: Prefer immunotherapy over chemotherapy to maintain the strength of the immune system. ●Safety: Look at FDA approval evidence in other cancers and where there is evidence of safety and efficacy in prostate cancer. Avoid drug combinations that have high toxicity risks (such as two VEGF drugs).

●Access: Favor treatments with easy access. ●Plan ahead: Keep treatments in reserve for future rounds and allow for new, better therapies to come to market.

cacy in prostate cancer. Avoid drug combinations that have high toxicity risks (such as two VEGF drugs). ●Access: Favor treatments with easy access. ●Plan ahead: Keep treatments in reserve for future rounds and allow for new, better therapies to come to market.

●Validate: Validate the test results and findings: If decisions are being made based on the increased expression of synaptophysin, VEGF pathway, etc. and these decisions are based on a single data point/test (there is a confidence risk for RNA expression tests.

“Multi-omic Analysis Guides the Decisions of Brian McCloskey” (Rana McKay, MD, and BostonGene) [#98] (1) confirmation by IHC (immunohistochemistry - tissue staining) or a proteomic test, (2) a biological replicate showing the same signature (confirms the expression but does not unambiguously demonstrate a corresponding protein expression), and (3) molecular matching to similar patients who have shown increased expression and translation of the gene of interest.

●Disease burden: Keep the disease burden as low as possible. What is Brian’s next treatment going to be? Brian is planning to get a drug (cabozantinib) for inhibition of one of his biomarkers (VEGF) combined with an immunotherapy drug (nivolumab, brand name Opdivo, an immune checkpoint inhibitor). This combination has shown good efficacy in other cancers.

Brian hopes to access this combination through a clinical trial being offered at UCSD. What are Brian’s next steps? ●Procure nivolumab and cabozantinib for his treatment, either through a clinical trial or, if he fails the eligibility criteria, through patient assistance programs.

●Monitor his response to treatment and disease progression through various tests, including scans, PSA (prostate-specific antigen blood test), radiographic progression, blood tests for molecular changes and assessments of his symptoms and quality of life.

PSA is a tricky marker to follow in castrate-resistant prostate cancer, especially with AR (androgen receptor) amplification and it's not as reliable as in metastatic hormone- sensitive settings. There are several ways to monitor disease progression with blood draws, using various approaches (e.g.

, minimum residual disease testing), such as fragmentomics, which looks at fragmentation patterns of cell-free DNA from a blood draw and identifying interesting markers (such as DLL3, a ligand highly expressed in neuroendocrine tumors, and STEAP, a prostate-specific cell-surface antigen highly expressed in human prostate tumors). What can you learn from Brian that you can apply to your own care?

●Get an extensive diversity of tests to examine your cancer from different perspectives over time. ●Choose a quarterback for your care who is well-versed in the research and connected with you. (It may be hard to find medical oncologists like Dr.