Challenge Awards – Class of 2023

The PCF Challenge Award Winners – Class of 2023 recipients are:

2023 J.C. Kennedy Foundation, GTSN-PCF Challenge Award

Targeting Neuroendocrine Cells in Prostate Cancer with Small Molecule and Targeted Radionuclide Therapies

Principal Investigators: Andrew Armstrong, MD (Duke University), Jiaoti Huang, MD (Duke University)

Co-Investigators: Michael Zalutsky, PhD (Duke University), Susan Halabi, PhD (Duke University), Kent Weinhold, PhD (Duke University)

Young Investigators: Fan Zhang, PhD (Duke University), Yutian Feng, PhD (Duke University)

Description:

• Lineage-plastic and neuroendocrine prostate cancer (NEPC) are highly aggressive subtypes of metastatic castration-resistant prostate cancer (mCRPC) that develop as mechanisms of resistance to androgen receptor (AR)-targeted therapies. Approximately 1/3 of patients with lethal prostate cancer have lineage-plastic and/or NEPC phenotypes. New treatments for these subtypes are urgently needed.
• Drs. Andrew Armstrong and Jiaoti Huang and team have identified the chemokine receptor CXCR2 as a critical regulator of NEPC and lineage plasticity, and others have identified CXCR2 as important for immune evasion in prostate cancer, suggesting it may have potential as a therapeutic target.
• Preclinical studies suggest that co-targeting AR and CXCR2 may have synergistic efficacy for the treatment of mCRPC. A phase 2 clinical trial (SYNERGY-201) testing the combination of the AR inhibitor enzalutamide and the CXCR1/2 inhibitor SX-682 (Syntrix) is underway and will be conducted through the US Department of Defense Prostate Cancer Clinical Trials Consortium (DOD PCCTC).
• In this project, Dr. Armstrong and team will use samples from this trial to identify and validate tumor and immune biomarkers that predict which patients with mCRPC are most likely to benefit from treatment with enzalutamide plus SX-682.
• The team has also identified the GPC3 protein as a promising new cell surface therapeutic target on NEPC cells and has developed a new GPC3-targeted alpha particle radioligand therapy. In this project, the team will perform preclinical studies to evaluate the efficacy of combining AR and GPC3 targeted therapies in CRPC to provide data to support a first-in-human phase 1 trial of this therapy.
• If successful, this team will develop two new treatment strategies for patients with the most aggressive and lethal forms of prostate cancer.

What this means to patients: New treatments are urgently needed for patients with lineage-plastic and neuroendocrine prostate cancer (NEPC), which are highly aggressive forms of CRPC with no effective therapies available.  Drs. Armstrong and Huang and team are studying the efficacy and developing biomarkers for two new treatment approaches for NEPC, which target CXCR2 and GPC3, and may have synergy with AR-targeted therapy in patients with mCRPC. These studies may result in significant clinical benefit for patients with mCRPC who have progressed on AR blockade, addressing a major unmet need encompassing precision immunotherapy and reversing the lethal treatment-resistant, lineage-plastic phenotype of aggressive prostate cancer.

2023 Republic National Distributing Company (RNDC)-PCF Challenge Award

Development of a CBP/p300 Degrader for the Treatment of Castration-Resistant Prostate Cancer

Principal Investigators: Arul Chinnaiyan, MD, PhD (University of Michigan), Shaomeng Wang, PhD (University of Michigan), Ulka Vaishampayan, MBBS (University of Michigan), Abhijit Parolia, PhD (University of Michigan)

Young Investigator: Jie Luo, PhD (University of Michigan)

Co-Investigators: Jeremy Taylor, PhD (University of Michigan), Yuanyuan Qiao, PhD (University of Michigan)

Description:

• During prostate cancer progression, tumor cells become dependent on an aberrant genomic 3D organization that enables high expression of critical oncogenes.
• Two key proteins that regulate this process are CBP and p300. Preclinical studies have shown that CBP/p300 inhibitors can decrease oncogenic signaling pathways and inhibit prostate cancer tumor growth in animal models. However, previously developed CBP/p300 inhibitors are unable to fully inhibit the proteins, and subpar activity has been seen in clinical trials.
• Chinnaiyan and team are developing a new class of drugs, called PROTACs, that target CBP/p300 and cause complete degradation of these proteins. The team has already developed an oral treatment candidate CBP/p300-PROTAC called CBPD-409.
• In this project, the team will determine the mechanism of action of CBPD-409, comprehensively profile its efficacy in preclinical models of castration-resistant prostate cancer (CRPC), and perform correlative studies in a phase 1/2 clinical trial of CBPD-409 alone and in combination with enzalutamide in metastatic CRPC patients.
• If successful, this project will identify the mechanism of action of CBP/p300-PROTACs and determine features of prostate cancer cells that make them more susceptible to this therapy. These studies will also position CBPD-409 for further clinical development and highlight the potential of CBP/p300 degraders as new treatment options for mCRPC.

What this means to patients: New and more effective treatments are needed for mCRPC. Dr. Chinnaiyan and team are developing a new therapy that targets and fully degrades the prostate cancer oncogenes CBP and p300. This project will provide preclinical data for the efficacy of this new treatment, and analyze biomarkers of response from a phase 1/2 clinical trial in mCRPC patients, paving the way for further clinical development and a new treatment for mCRPC.

2023 Bayer-PCF Health Equity Research Award

Incorporating Patient Education into Germline Genetic Testing in Black Patients with Prostate Cancer

Principal Investigator: Burcu Darst, PhD (Fred Hutchinson Cancer Center)

Young Investigator: Hiba Khan, MD, MPH (University of Washington)

Co-Investigators: Heather Cheng, MD, PhD (University of Washington), Manoj Menon, MD, MPH (Fred Hutchinson Cancer Center), Yaw Nyame, MD, MS (University of Washington)

Collaborator: Veda Giri, MD (Yale University)

Description:

• Prostate cancer represents one of the largest health disparities in the US, with Black patients having the highest incidence and mortality rates. Prostate cancer is also one of the most heritable cancers, estimated to be ~57% heritable, and differences in social, environmental, lifestyle, and germline genetic risk factors are thought to contribute to disparities in incidence and mortality rates.
• Despite the established effectiveness of genetic factors for stratifying disease risk, predicting disease aggressiveness, and informing disease management, Black patients are less likely to receive genetic testing results. This could exacerbate the existing health disparities of prostate cancer, as genetic testing is now a standard of care for patients with advanced disease.
• Burcu Darst and team will determine whether a tailored educational program improves the participation of Black patients in prostate cancer germline genetic testing and evaluate the impact of receiving genetic testing results on prostate cancer management among Black patients.
• This will be accomplished by establishing a cohort of Black patients with recently diagnosed prostate cancer and evaluating whether an educational program increases the likelihood of deciding to undergo genetic testing and whether this information ultimately impacts decisions around disease management.
• The team will also determine how educational information was used, including whether patients shared their results with family members or healthcare providers, the perceived utility of this information, and whether it impacted decisions around disease management.
• If successful, this research will improve our understanding of how to engage Black patients in prostate cancer genetic testing and how genetic testing subsequently impacts disease management in Black patients.

What this means to patients: Despite disparately higher prostate cancer incidence and mortality rates among Black patients, they are less likely to undergo genetic testing for prostate cancer risk, which may further exacerbate health disparities outcomes. Dr. Darst and team will determine whether a tailored education program increases the likelihood of Black patients to undergo genetic testing and how this information impacts disease management decisions. This could improve engagement of Black patients in prostate cancer genetic testing and improve patient outcomes, ultimately reducing prostate cancer health disparities.

2023 PCF Challenge Award

Personalizing Treatment Decisions Through Composite Next Generation Imaging and Liquid Biomarker Development Within a Phase II Randomised Trial of Enzalutamide (+/-¹⁷⁷Lu-PSMA-617) (ENZAp)

Principal Investigator: Louise Emmett, MD, MBBS (St Vincent’s Hospital Sydney, Australia)

Young Investigators: Edmond Kwan, MBBS, PhD (University of British Columbia), Megan Crumbaker, MD, PhD (St Vincent’s Hospital Sydney), Andrei Gafita, MD (Johns Hopkins University), Narjess Ayati, MD (St Vincent’s Hospital Sydney)

Co-Investigators: Michael Hofman, MBBS (Peter MacCallum Cancer Centre), Ian Davis, MBBS, PhD (Monash University), Alexander Wyatt, PhD (University of British Columbia), Andrew Martin, PhD (University of Sydney), Shahneen Sandhu, MD, PhD (Peter MacCallum Cancer Centre), Martin Stockler, MBBS, PhD (University of Sydney), Felix Feng, MD (University of California, San Francisco), Martin Sjostrom, MD, PhD (University of California, San Francisco), Nathan Papa, MBBS, PhD (Garvan Institute of Medical Research)

Description:

• LuPSMA (Pluvicto^®; ¹⁷⁷Lu-PSMA-617 is a new life-extending treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). LuPSMA works by targeting radiation to prostate cancer cells, which uniquely express the PSMA protein. However, this treatment remains non-curative. How to overcome treatment resistance and increase efficacy is of critical importance.
• The efficacy of LuPSMA requires sufficient levels of PSMA on the surface of prostate cancer cells. PSMA levels are regulated by the androgen receptor (AR), and can be increased by AR-targeted therapies such as enzalutamide. These data suggest that therapeutic synergy may be achieved by combining LuPSMA with enzalutamide.
• Louise Emmett is leading the ENZA-p trial, a fully recruited randomized phase II trial testing LuPSMA plus enzalutamide versus enzalutamide alone as first-line therapy in patients with mCRPC.
• In this project, Dr. Emmett and team will utilize data and samples from the ENZA-p trial to investigate whether enzalutamide can impact PSMA levels, determine mechanisms of synergy of LuPSMA + enzalutamide, and develop biomarkers to determine whether individual patients are more likely to benefit from enzalutamide alone vs. with LuPSMA.
• Patients on the trial will undergo serial PSMA PET imaging before, during and after treatment. These images will be studied to determine how PSMA PET levels are changed by enzalutamide, and whether sites of resistance to enzalutamide can be identified by PSMA PET.
• Combined PSMA PET and blood-based tests will be developed to better predict patients most likely to benefit from enzalutamide monotherapy vs. combination therapy.
• Circulating tumor DNA from blood will be used to study tumor genomics and identify mechanisms of response and resistance to the different therapy options.
• Finally PSMA SPECT, a molecular imaging technique that can directly visualize LuPSMA in the body, will be investigated as a method to evaluate and predict the efficacy of LuPSMA treatment.
• If successful, this project will answer key questions about how to use imaging and molecular biomarkers to improve personalization of treatment decisions in patients with mCRPC being considered for enzalutamide +/- LuPSMA.

What this means to patients: Several treatments are now available for patients with mCRPC, including AR-targeted therapies and LuPSMA. However, none of these are curative alone, and how to sequence and combine them to optimize efficacy is of critical importance. Dr. Emmett and team are leading a phase 2 trial testing LuPSMA plus enzalutamide versus enzalutamide alone as first-line therapy in patients with mCRPC. In this project, the team will study molecular imaging and liquid biopsy biomarkers from patients on this trial, to understand mechanisms of synergy and resistance, and develop optimal biomarkers to guide individual treatment selection decisions for patients with mCRPC.

2023 Sun Pharma-PCF VAlor Special Challenge Award

A Phase 2 Randomized Study of YONSA® (Abiraterone Acetate), Enzalutamide or Apalutamide as First Line Therapy in Veterans with Castrate-Sensitive Prostate Cancer

Principal Investigators: Antonio Tito Fojo, MD (James J. Peters Veterans Affairs Medical Center), Susan Bates, MD (James J. Peters Veterans Affairs Medical Center)

Description:

• Prostate cancer is a serious health problem among Veterans and was the second leading cause of cancer death in American men in 2019. Although many patients in the past seven years have experienced improved survival with novel hormonal therapies (abiraterone acetate and enzalutamide), most patients experience treatment failure as the cancer develops resistance and disease progresses. Whether earlier treatment may improve ultimate outcomes remains to be determined. Also uncertain is the order in which drugs should be administered.
• Dr. Antonio Tito Fojo and team are conducting a randomized phase 2 clinical trial in Veterans with prostate cancer to determine if the efficacy of YONSA® (abiraterone acetate) is the optimal and non-inferior first-line therapy for Veterans with castrate-sensitive prostate cancer at the time a recurrence of their disease is first documented, as compared with enzalutamide or apalutamide.
• Prior studies have also found that the efficacy of abiraterone is superior in African American compared to Caucasian Veterans. This study also aims to demonstrate that abiraterone acetate is more effective in African American than in Caucasian Veterans with castrate-sensitive prostate cancer as initial therapy when a recurrence is first detected.
• If successful, this study will reinforce an abiraterone-first strategy in the management of Veterans (and all patients) with castrate-sensitive prostate cancer at the time a recurrence is first documented, which is further supported by prior data that enzalutamide is a better salvage (second-line) therapy than abiraterone.

What this means to patients: Abiraterone acetate is a standard of care therapy for advanced prostate cancer, but the loss of patent protection for Zytiga® resulted in a curtailing of its development and slowing of clinical trials to optimize the timing and use of abiraterone in the prostate cancer disease course. As a result, medical oncologists have increasingly been administering enzalutamide or apalutamide before abiraterone, while prior data suggest that abiraterone should precede enzalutamide to achieve maximum benefit and is also a superior choice for African Americans with prostate cancer. This study will provide support for YONSA®, a newer alternative formulation of abiraterone acetate, as part of the first treatment given to patients with a recurrence of prostate cancer, and will lead to new regulatory filings and treatment guidelines for patients with advanced prostate cancer.

2023 PCF Challenge Award

Identifying Drivers of Aggressive Prostate Cancer and Racial Disparities in Patients Presenting with Low-Grade Disease

Principal Investigators: Vanessa Hayes, PhD(The University of Sydney),Gail Prins, PhD (University of Illinois at Chicago), Riana Bornman, MD (University of Pretoria)

Co-Investigators:Massimo Loda, MD (Weill Cornell Medicine), Daniel Moreira, MD (University of Illinois at Chicago), Weerachai Jaratlerdsiri, PhD (The University of Sydney)

Young Investigators: Ikenna Madueke, MD, PhD (University of Illinois at Chicago), Pamela Soh, PhD (The University of Sydney)

Description:

• African ancestry individuals are at significantly elevated risk for prostate cancer and associated death compared to other ethnic/racial groups. For African ancestry individuals, risk for prostate cancer mortality is further increased with younger age (<65 years) and low-grade disease. What causes this disparity is unknown.
• Most preclinical and clinical research on prostate cancer biology and treatments has been done in European ancestry populations. The lack of knowledge about prostate cancer biology in African ancestry populations exacerbates prostate cancer racial disparities.
• This disparity – in which African ancestry patients diagnosed with low-grade disease or at a younger age are at significantly increased risk for lethal disease — raises important concerns with applying current clinical guidelines for managing African ancestry patients. As of now, clinical guidelines exclude divisive action for “low-grade” disease and result in undertreatment and worse outcomes in African ancestry patients.
• Dr. Vanessa Hayes and team are investigating the etiology of “low-grade” and early onset prostate cancers in African ancestry patients that are ultimately lethal.
• In this project, the team will define a new classification of African ancestry-relevant “low-grade” and early-onset lethal prostate cancer, to establish a framework and criteria for prostate cancer precision medicine and germline testing for African ancestry patients.
• The team will perform genomic sequencing on tumors from African ancestry patients from the U.S. and South Africa presenting with low-grade and/or early-onset prostate cancer, to identify cancer driver mutations and inherited genetic cancer risk variants.
• The impact and relationship of these genomic factors on pathogenicity, oncogenic status and clinical outcomes will be determined.
• If successful, this project will identify genetic and genomic factors that drive early-onset or “low-grade” prostate cancer that are actually lethal in African ancestry patients. This will enable the development of biomarkers that indicate lethal disease risk in patients diagnosed with “low-grade” disease and clinical guidelines to appropriately manage these patients.

What this means to patients: Identifying the underlying causes of racial prostate cancer health disparities has significant implications for minority inclusion in the benefits of precision medicine, advancing our understanding of the etiology, early detection and ultimately prevention and treatment of lethal prostate cancer. Dr. Hayes and team will identify genetic and genomic risk factors of lethal prostate cancer in African ancestry patients presenting with low-grade or early-onset disease, ultimately translating this into new criteria for classifying, managing and treating prostate cancer in African ancestry patients, and reducing racial health disparities.

2023 Bayer-PCF Health Equity Research Award

Impact of Genetic Ancestry and DNA Methylation on Prostate Cancer in African and African American Patients

Principal Investigator: Brian Joyce, PhD (Northwestern University)

Young Investigators: Zequn Sun, PhD (Northwestern University)

Co-Investigators: Adam Murphy, MD (Northwestern University), Mamoudou Maiga, MD, PhD (Northwestern University), Lifang Hou, PhD, MD (Northwestern University)

Description:

• Prostate cancer disparities are the highest cancer disparity in the US, with Black individuals facing significantly higher incidence and mortality rates than White individuals, as well as a higher likelihood of being diagnosed with more aggressive prostate cancer and at younger ages.
• Better understandings of the factors that drive racial disparities in prostate cancer will aid int eh development of improved and equitable prostate cancer screening and treatment approaches.
• DNA methylation is a chemical modification to DNA that can be altered in response to environmental, lifestyle, and sociocultural factors, and regulates gene expression. DNA methylation has been identified as a potential biomarker of prostate cancer and is associated with racial disparities. However, Black populations have been underrepresented in prostate cancer genomic and molecular studies.
• In this project, Dr. Brian Joyce and team will investigate whether differences in DNA methylation from patient samples can predict prostate cancer risk and outcomes, and whether these features contribute to prostate cancer racial disparities.
• The team will profile and compare DNA methylation in samples from African American and West African patients, and determine modification effects by percentage of West African ancestry and by specific West African ancestry subgroups.
• This data will be used to data to construct an ancestry-specific prostate cancer risk calculator and examine its predictive utility.
• If successful, this study will advance health equity by identifying new prostate cancer biomarkers in Black patients, establishing a less-invasive method for studying prostate cancer DNA, and revealing mechanisms of prostate carcinogenesis to inform new efforts at precision prevention and earlier diagnosis of prostate cancer in Black patients.

What this means to patients: Black patients are underserved and at elevated risk of prostate cancer in general and aggressive prostate cancer specifically, yet they tend to be under-represented in clinical research studies. Dr. Joyce and team will investigate whether DNA methylation profiling of patient samples could be a useful tool for the early detection and risk stratification of prostate cancer and a more accurate diagnostic method for prostate cancer, particularly in Black patients, to reduce prostate cancer disparities.

2023 John Black Charitable Foundation-PCF Challenge Award

Metabolic Imaging and Targeted Radionuclide Combination Treatment of Prostate Cancer Bone Metastases

Principal Investigators: Edward O’Neill, PhD (University of Oxford), Claire Edwards, PhD (University of Oxford)

Co-Investigator: Ian Mills, PhD (University of Oxford)

Collaborators: Massimo Loda, MD (Weill Cornell Medicine), Josephine Bunch, PhD (National Physical Laboratory), Mark Konijnenberg, PhD (Erasmus MC), Gail Risbridger, PhD (Monash University), Renea Taylor, PhD (Monash University), Peter Croucher, PhD (Garvan Institute of Medical Research), James McCullagh, PhD (University of Oxford), Daniel McGowan, PhD (Oxford University Hospitals NHS Trust), Neel Patel, MD, PhD (Oxford University Hospitals NHS Trust), Price Jackson, PhD (Peter MacCallum Cancer Centre)

Description:

• The PSMA-targeted radionuclide therapy LuPSMA has recently been approved for the treatment of patients with mCRPC whose tumors are positive on PSMA PET imaging. LuPSMA consists of a radioactive isotope attached to a small molecule targeting PSMA, a protein expressed on most prostate cancer cells.
• Despite the promising activity of LuPSMA, all patients eventually progress. Understanding the mechanisms of resistance to LuPSMA is critical for improving the efficacy of this treatment.
• PSMA is an enzyme that regulates folate metabolism. Dr. Edward O’Neill and team hypothesize that PSMA’s folate metabolism activity, which can be used to create antioxidants, may contribute to resistance to LuPSMA.
• In this project, the team will investigate whether FDG PET imaging, which visualizes tumors with high metabolic activity, can predict radiation sensitivity of tumors and responsiveness to LuPSMA.
• Whether increased PSMA levels can contribute to resistance to LuPSMA through increasing anti-oxidant metabolism will be determined.
• The team will investigate whether treatments that inhibit folate or anti-oxidant metabolism increase the efficacy of LuPSMA. The role of FDG PET + PSMA PET for predicting and monitoring responses to this treatment combination will be investigated.
• Finally, the impact of these metabolic pathways on prostate cancer cell dormancy will be investigated. Whether metabolic inhibitors combined with LuPSMA can prevent reactivation of dormant prostate cancer cells will be determined.
• If successful, this project will define the role of tumor metabolism in resistance to LuPSMA, determine an optimal way to use PSMA PET and FDG PET to select patients for treatment with LuPSMA, and identify metabolically directed combination therapies to overcome metabolic radiation-resistance.

What this means to patients: Understanding resistance to LuPSMA is critical for improving treatment of patients with advanced prostate cancer. This team will determine the role of tumor metabolism in treatment responses to LuPSMA, and the potential for these tumor metabolic pathways as biomarkers and therapeutic targets in prostate cancer.

2023 Bayer-PCF Health Equity Research Award

Molecular Evaluation of Prostate Saturation and Progression Biopsies for Risk Assessment and Early Intervention

Principal Investigator: Nallasivam Palanisamy, PhD, MSc (Henry Ford Health System)

Young Investigator: Wei Zhao, MD, PhD (Henry Ford Health)

Co-Investigators: Pin Li, PhD (Henry Ford Health), Nilesh Gupta, MD (Henry Ford Health),  Daniel Isaac, DO, MSc (Michigan State University), Craig Rogers, MD (Henry Ford Health)

Description:

• Prostate cancer incidence and mortality rates are disparately higher among Black patients compared with White patients. Understanding the factors that contribute to these disparities and developing improved methods to diagnose and treat Black patients is critical to reducing prostate cancer health disparities.
• Nallasivam Palanisamy and team as well as others have previously observed significant differences in the expression of oncogenic factors such as ERG, SPINK1, ETV1 and ETV4 in localized prostate cancers from Black vs. White patients, that associate with clinical outcomes. Palanisamy and team hypothesize that these factors may be useful as prognostic markers that can be incorporated into clinical risk stratification models, to improve personalized therapy recommendations in patients with newly diagnosed, localized prostate cancer.
• In this project, the team will study saturation biopsy samples to determine molecular heterogeneity in spatially distinct tumors and estimate the prevalence of ERG, SPINK1, ETV1, ETV4, and PTEN molecular markers in prostate cancers from Black vs. White patients.
• Longitudinal biopsy samples from patients who had two or more biopsies will also be evaluated to understand tumor clonal evolution and the role of molecular markers in disease progression.
• If successful, this project will help to unravel prostate cancer’s genetic and molecular heterogeneity from a racial disparity perspective and its impact on disease progression and risk assessment.

What this means to patients: Prostate cancer incidence and mortality is disparately higher in Black patients, but the contributing factors as well as optimal patient management strategies remain unclear.  Dr. Palanisamy and team will perform in-depth molecular assessments of localized tumor samples from Black vs. White patients, to understand racial differences in prostate cancer molecular biology and disease progression. This may ultimately lead to improved biomarker-based prostate cancer risk assessment tools for Black patients, that will improve individualized patient management strategies and reduce disparities in health outcomes.

2023 Digital Science Press-PCF Challenge Award

Intercepting the Cancer Endocycle to Cure Lethal Prostate Cancer

Principal Investigators: Kenneth Pienta, MD (Johns Hopkins University), Sarah Amend, PhD (Johns Hopkins School of Medicine), Emma Hammarlund, PhD (Lund University)

Young Investigators: George Butler, PhD (Johns Hopkins School of Medicine), Christopher Carroll, PhD (Lund University), Bryan Lee, PhD (Johns Hopkins School Medicine), Chi-Ju Kim, PhD (Johns Hopkins School of Medicine)

Co-Investigators: Angelo DeMarzo, MD, PhD (Johns Hopkins School of Medicine), Bruce Trock, PhD (Johns Hopkins School of Medicine), Alexander Wyatt, PhD (University of British Columbia), Michael Haffner, MD, PhD (Fred Hutchinson Cancer Research Center)

Description:

• Metastatic prostate cancer is resistant to all systemic therapies and the cause of therapeutic resistance remains undefined. For almost a century, therapeutic resistance has been explained either by mutational changes that lead to resistant clones or by a rare population of therapy-resistant cells (often referred to as cancer stem cells) giving rise to a recurrent population. However, none of these models have yet been definitively proven. More importantly for cancer patients, no intervention has yet been designed that specifically targets the underlying biological mechanism that emerges as universal therapeutic resistance. Therefore, metastatic prostate cancer remains a lethal incurable disease.
• Kenneth Pienta and team propose a novel hypothesis of therapy resistance: that cancer cells survive cancer therapy via “endocycling,” a normal cellular stress-survival mechanism where cells replicate their DNA and proteins but don’t divide, instead entering a dormant state.
• In this project, Dr. Pienta and team will determine whether endocycling is responsible for treatment resistance in prostate cancer and develop therapeutic strategies to target this mechanism.
• The team is conducting a phase 2 clinical trial where patients with localized prostate cancer receive ADT + abiraterone + an endocycle targeting therapy, belzutifan, for 3 months, followed by radical prostatectomy. Surgical samples will be evaluated for whether all cancer was eliminated by the treatment or not.
• The team will also set up a pipeline to discover new candidate endocycle-targeting therapies and rapidly test them in a series of pilot clinical trials.
• The team will perform comprehensive genomic and molecular analyses on tumor cells in the endocycle state from blood and tumor tissue samples from patients, to better understand the biology of the endocycle state and identify targetable features associated with disease progression and treatment resistance.
• If successful, this project will determine whether the cancer endocycle state drives therapy resistance, and will identify therapeutic strategies to intercept the cancer endocycle state that will be tested in clinical trials, ultimately reducing cancer lethality.

What this means to patients: The mechanisms that drive treatment resistance in prostate cancer remain unclear, but must be identified in order to develop improved treatment approaches. Dr. Pienta and colleagues will determine whether a dormant “endocycling” state underlies the ability of cancer cells to survive and resist anti-cancer therapies. In this project, they will define the biology of the endocycling state, and identify and clinically test new therapeutic strategies to target cancer cells in this state, to reduce treatment resistance and disease lethality.

2023 Bayer-PCF Darolutamide Challenge Award

Darolutamide to Augment Radiotheranostic Therapy in Biochemically Recurrent Prostate Cancer (DART-BCR)

Principal Investigators: Praful Ravi, MD (Harvard: Dana-Farber Cancer Institute), David Einstein, MD (Beth Israel Deaconess Medical Center)

Young Investigator: Daniel Fein, MD (Beth Israel Deaconess Medical Center)

Co-Investigators: Heather Jacene, MD (Dana-Farber Cancer Institute), Mary-Ellen Taplin, MD (Dana-Farber Cancer Institute), Jacob Berchuck, MD (Dana-Farber Cancer Institute), Steve Balk, MD (Beth Israel Deaconess Medical Center)

Description:

• The PSMA-targeted radioligand therapy ¹⁷⁷Lu-PSMA-617 is approved for use in patients with advanced metastatic castration-resistant prostate cancer (mCRPC), and is now being evaluated in clinical trials in earlier disease settings.
• Short-term treatment with androgen receptor signaling inhibitors (ARSI) such as darolutamide may increase PSMA expression. This suggests that darolutamide may synergize with PSMA-targeted radioligand therapy and could also increase the sensitivity of PSMA PET imaging for visualizing micro-metastatic tumors.
• Praful Ravi and team will conduct a novel clinical trial to test the efficacy of darolutamide + ¹⁷⁷LuTLX591 (a new PSMA-targeted radioligand therapy) versus darolutamide alone, in patients experiencing a rising PSA after initial therapy, who have at least 1 metastatic lesion detected by PSMA-PET but none by conventional imaging.
• This trial will also evaluate whether and how darolutamide increases PSMA expression, and whether PSMA PET imaging or other molecular biomarkers can be used to identify patients who are most likely to benefit from the addition of PSMA-targeted radioligand therapy to darolutamide.
• The impact of this treatment combination on tumor and immune biology will also be investigated.
• If successful, this project will determine the efficacy of darolutamide alone vs. in combination with PSMA-targeted radioligand therapy in patients at the earliest stages of prostate cancer recurrence after initial treatment. This combination could delay or prevent the onset of metastatic disease and/or the need for long-term anti-androgen therapy.

What this means to patients:  It is possible that improved therapies given at the earliest sign of prostate cancer recurrence after initial surgery or radiation could prevent tumor metastasis and ultimately death from prostate cancer. Dr. Ravi and team will investigate the efficacy of darolutamide alone vs. in combination with PSMA-targeted radioligand therapy in patients experiencing a rising PSA after initial therapy, as well as identify biomarkers for selecting patients most likely to benefit from this therapy combination. This project will also resolve the biology of this treatment and determine how PSMA, the target of prostate cancer treatments and PET imaging, is regulated in prostate cancer, expanding opportunities for new patient treatment and management strategies.

2023 Durden Foundation-PCF Challenge Award

Characterizing Imaging, Genomic and Immune Predictors of ¹⁷⁷Lu-PSMA (Lu-PSMA) and Olaparib Response in Patients with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Principal Investigators: Shahneen Sandhu, MBBS (The University of Melbourne), Belinda Parker, PhD (University of Melbourne)

Co-Investigators: Michael Hofman, MBBS (University of Melbourne), Nicole Haynes, PhD (University of Melbourne), David Quigley, PhD (University of California San Francisco), Alexander Wyatt, PhD (University of British Columbia), Anna Trigos, PhD (University of Melbourne), Louise Emmett, MD (St Vincent’s Hospital), Anis Hamid, MBBS (Peter MacCallum Cancer Centre), Ramyar Molania, PhD (University of Melbourne), Anthony Joshua, MBBS, PhD (St Vincent’s Hospital), Andrei Gafita, MD, PhD (Johns Hopkins University), Felix Feng, MD (University of California San Francisco), William Chen, MD (University of California San Francisco), Paul Neeson, PhD (University of Melbourne)

Young Investigator: Richard Rebello, PhD (University of Melbourne)

Description:

• LuPSMA (¹⁷⁷Lu-PSMA-617) and olaparib are standard therapies for certain patients with metastatic castration resistant prostate cancer (mCRPC) that can significantly extend patient survival. However, even among eligible patients, not all will benefit from these treatments, and they are not curative. New ways to improve efficacy and better identify which patients will benefit are urgently needed.
• Dr. Shahneen Sandhu is leading the phase 1b LuPARP trial, which is testing the combination of LuPSMA and olaparib in patients with mCRPC. The rationale for this trial is based on knowledge that LuPSMA delivers DNA-damaging radiation to tumor cells, while olaparib prevents DNA repair, thus combining these may deliver therapeutic synergy, as tumor cells that receive extensive DNA damage but cannot repair it are more likely to die.
• In this project, Dr. Sandhu will leverage patient samples and data from the LuPARP trial to define imaging and molecular biomarkers that predict response vs. resistance to LuPSMA + Olaparib and to understand the mechanisms of action of this treatment.
• The performance of PSMA PET imaging, circulating tumor DNA, and circulating tumor cell numbers for measuring treatment efficacy and disease burden will be investigated.
• How the treatment combination impacts the molecular and genomic evolution of the tumor will be investigated.
• Whether and how this treatment combination changes the tumor microenvironment, including anti-tumor immune responses will be studied. These data may help to uncover novel strategies to increase the efficacy of LuPSMA-based therapy by targeting the altered tumor immune microenvironment.
• If successful, this project will characterize the tumor and immune impacts of LuPSMA + Olaparib combination treatment, and will define biomarkers to guide selection of patients who will most benefit from this combination.

What this means to patients:LuPSMA and Olaparib are two new treatments for certain patients with mCRPC that may work even better when combined. Dr. Sandhu and team are leading a clinical trial to test this combination. In this project, the team will develop biomarkers to measure combination treatment efficacy and help to select patients who will most benefit from. The team will also define the biological impacts of this combination, which will help to refine how best to use these treatments for maximal efficacy.

2023 John and Daria Barry Foundation- PCF VAlor Challenge Award

Germline Influence on Prostate Cancer Metastasis and Response to Androgen Deprivation Therapy

Principal Investigators: Tyler Seibert, MD, PhD (University of California San Diego), Rana McKay, MD (University of California San Diego), Paul Boutros, PhD, MBA (University of California Los Angeles)

Young Investigators: Roni Haas, PhD (University of California Los Angeles), Sophia Kamran, MD (Massachusetts General Hospital)

Co-Investigators: Felix Feng, MD (University of California San Francisco), Phuoc Tran, MD, PhD (University of Maryland), Alan Pollack, MD, PhD (University of Miami), Daniel Spratt, MD (University Hospitals / Case Western), Elai Davicioni, PhD (Veracyte),  Isla Garraway, MD, PhD (University of California Los Angeles), Jason Vassy, MD, MPH (VA Boston Healthcare System)

Description:

• Prostate cancer is the second most heritable solid malignancy, and inherited (germline) genetic factors play a major role in disease development and progression. While certain rare gene variants, such as BRCA2 alterations, increase the risk of metastatic prostate cancer, most patients inherit risk via the combination of many common genetic variants.
• Polygenic risk scores (PRS) are genetic tools that can predict overall prostate cancer risk based on the combination of many common genetic variants. However, modifications are needed to use PRS tools to identify individuals at highest genetic risk for developing aggressive prostate cancer.
• Tyler Seibert and colleagues have identified germline variants that can directly modulate tumor evolution and development of aggressive phenotypes, and are associated with clinical outcomes – these are called driver quantitative trait loci (dQTLs).
• dQTLs also vary across ancestry groups and may explain some of the differences in tumor behavior across racial and ethnic groups. Thus, the use of dQTLs in clinical tools could improve patient management strategies and reduce racial/ethnic health disparities.
• In this project, Dr. Seibert and team will determine whether a new “driver polygenic risk score” that uses dQTLs can predict the development of metastatic prostate cancer, as well as molecular and genomic prostate cancer features. This will be done using data and samples from VA patients and randomized phase 3 clinical trials with long-term follow-up data.
• Whether dQTLs can predict tumor mutations and gene expression patterns or predict clinical outcomes after initial therapy with surgery or radiation, will also be investigated.
• If successful, this project will result in a new clinical tool that can identify individuals at highest genetic risk for metastatic prostate cancer and help to guide treatment approaches in patients.
• These studies will also help to improve understanding of the effects of inherited genetic features on prostate cancer clinical outcomes, elucidate biological contributions to health disparities, and prompt new lines of investigation to close ancestry-based gaps in our basic knowledge and clinical care.

What this means to patients: Prostate cancer is highly heritable, and tools that can identify individuals at highest genetic risk for aggressive disease will help to improve patient care and outcomes.  Dr. Seibert and team have identified genetic variants that increase prostate cancer aggressiveness and are using these to develop a new genetic test that can predict individuals at high risk for developing lethal prostate cancer and their responses to treatments. Ultimately, this new clinical tool will improve prostate cancer screening and treatment approaches and patient management, and help to reduce prostate cancer racial disparities.

2023 PCF Hamptons Coalition-PCF Challenge Award

Targeting Gut Bacterial Androgen Production to Reverse Therapeutic Resistance in Metastatic Prostate Cancer

Principal Investigators: Karen Sfanos, PhD (Johns Hopkins University), Cathy Marshall, MD, MPH (Johns Hopkins Medicine), Mark Markowski, MD, PhD (Johns Hopkins Medicine), Jason Ridlon, PhD (University of Illinois Urbana-Champaign), Young Investigator: Angélica Cruz-Lebrón, PhD (Johns Hopkins University)
Co-Investigators: Hao Wang, PhD (Johns Hopkins University), Isaac Cann, PhD (University of Illinois), Joseph Irudayaraj, PhD (University of Illinois)
Collaborators: Samuel Denmeade, MD (Johns Hopkins Medicine)

Description:

• The gut microbiome – the community of microorganisms that live in the intestines – can significantly impact host biology, including regulating metabolism and shaping the immune system.
• The team and others previously discovered that the gut microbiome can be an unforeseen source of androgens that may contribute to insensitivity to androgen receptor (AR)-targeted therapies in patients with progressive metastatic prostate cancer.
• In this project, Dr. Sfanos and team will investigate bacterial androgen metabolites, to determine their role in driving treatment resistance to AR-targeted therapy.
• The team previously found that a bacterial “desmolase” can create androgens from prednisone, a corticosteroid commonly given with abiraterone to help manage side-effects.
• The team is conducting a clinical trial to test whether patients progressing on abiraterone + prednisone can have a renewed response if prednisone is switched to dexamethasone. Additionally, this trial will test if patient outcomes are further improved if patients also receive an antibiotic that selectively kills the gut bacteria most likely to produce androgens.
• The team will also develop gut-targeted therapeutic strategies towards additional bacterial enzymes that can produce androgens (DesF and DesG), and test these in preclinical prostate cancer models.
• If successful, this project will result in new therapeutic strategies to extend the efficacy and prevent primary resistance to anti-androgen therapies in individuals with mCRPC.

What this means to patients: Dr. Sfanos and team have discovered that androgen metabolism by gut bacteria could interfere with the anti-androgen therapies given to treat metastatic castration resistant prostate cancer. In this project, the team will develop and test therapeutic strategies to prevent androgen production by gut bacteria, to prolong the clinical response to anti-androgen therapies.

2023 Regeneron – PCF Special Challenge Award

A Pilot Presurgical Trial of REGN5678 (Anti-PSMAxCD28) In Patients with High-Risk, Localized Prostate Cancer Followed by Radical Prostatectomy

Principal Investigators: Padmanee Sharma, MD, PhD (The University of Texas MD Anderson Cancer Center), Sumit Subudhi, MD, PhD (The University of Texas MD Anderson Cancer Center), Brian Chapin, MD (The University of Texas MD Anderson Cancer Center), Bilal Siddiqui, MD (The University of Texas MD Anderson Cancer Center)

Description:

• PSMA is a protein that is highly expressed on prostate cancer cells and is a promising therapeutic and imaging target.
• Prostate cancer is typically “immunologically cold,” meaning the immune system does not effectively recognize prostate cancer and immunotherapies are rarely effective. New approaches are needed to harness the immune system to recognize and target prostate cancer.
• Anti-PSMAxCD28 (REGN5678) is a new experimental immunotherapy treatment that simultaneously targets PSMA on prostate cancer cells and CD28 on T cells. This treatment brings T cells into direct contact with tumor cells, activating the T cells to kill tumor cells.
• Drs. Sumit Subudhi, Bilal Siddiqui, Brian Chapin and team are conducting a phase 1/2 clinical trial testing the safety and tolerability of REGN5678 in patients with high-risk localized prostate cancer who are scheduled for radical prostatectomy.
• In this project, Dr. Padmanee Sharma and her team will use samples from this trial to identify biomarkers of response and mechanisms of treatment resistance to REGN5678.
• Mechanisms of action and how the treatment impacts immune responses in the prostate tumor microenvironment and peripheral blood will be investigated.
• The potential for PSMA PET/CT and FDG PET/CT as molecular imaging biomarkers to identify patients who are more or less likely to benefit from the treatment will be explored.
• If successful, this project will establish the safety and preliminary efficacy of REGN5678 in patients with high-risk localized prostate cancer and identify biomarkers for selecting patients for this treatment and mechanisms of treatment response or resistance.

What this means to patients: Dr. Sharma and team are studying the efficacy of a new immunotherapy treatment, anti-PSMAxCD28 (REGN5678), that enables T cells to directly bind and kill prostate cancer cells. The team is conducting a clinical trial testing REGN5678 and in this project, will perform correlative studies to understand mechanisms of action or resistance and identify biomarkers for identifying patients who may benefit from REGN5678. This may result in a new curative treatment approach for patients with high-risk localized prostate cancer.

2023 PCF Challenge Award

Modulation of Anti-Androgen Response by NSD2 in Castration-Resistant Prostate Cancer

Principal Investigators: Michael Shen, PhD (Columbia University Medical Center), Andrea Califano, PhD (Columbia University Medical Center), Johann de Bono, MD, PhD (The Institute of Cancer Research), Charles L. Sawyers, MD (Memorial Sloan Kettering Cancer Center)

Young Investigators: Jia Li, PhD (Columbia University Medical Center), Zhen Sun, PhD (Memorial Sloan Kettering Cancer Center), Alessandro Vasciaveo, PhD (Columbia University Medical Center)

Collaborators: Cory Abate-Shen, PhD (Columbia University Medical Center), Kristian Helin, PhD (The Institute of Cancer Research Cancer), Massimo Loda, MD (Weill Cornell Medicine), Chao Lu, PhD (Columbia University Medical Center)

Description:

• Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal form of metastatic castration-resistant prostate cancer (mCRPC), for which new treatments are urgently needed.
• Dr. Michael Shen and colleagues have identified NSD2 as a key driver of NEPC, and have found that inhibiting NSD2 restores sensitivity of CRPC models to anti-androgen therapy. They propose that NSD2 is a highly promising therapeutic target in CRPC and NEPC.
• In this project, the team will comprehensively define the mechanisms by which NSD2 drives NEPC development and progression, and test various drug development approaches to determine an optimal strategy for therapeutic inhibition of NSD2.
• If successful this project will provide rationale and a path forward for the development of NSD2-inhibitors, which could be a new, effective treatment for patients with NEPC.

What this means to patients: Dr. Shen and team have identified NSD2 as a critical driver and promising therapeutic target in NEPC, one of the most aggressive forms of prostate cancer. This team will establish the fundamental conceptual basis for rational targeting of NSD2 in NEPC, elucidate the mechanisms of NSD2 action, and provide a foundation for early-phase clinical trials of NSD2 inhibitors.

2023 Bayer-PCF Darolutamide Challenge Award

Darostep: Evaluating Step Counts as a Biomarker and its Relationship on Treatment Outcomes in Vulnerable Patients with Metastatic Hormone-Sensitive Prostate Cancer on Darolutamide and Androgen Deprivation Therapy

Principal Investigators: Russell Szmulewitz, MD (The University of Chicago), Nabiel Mir, MBBS (The University of Chicago), Megan Huisingh-Scheetz, MPH, MD (The University of Chicago)

Description:

• Prostate cancer predominantly affects older adults aged ≥ 65, but current treatments like intensified androgen deprivation therapy (ADT) often exacerbate physical and cognitive decline.
• Darolutamide exhibits improved tolerability in fitter older adults recruited for clinical trials, but has not been studied in vulnerable older adults. Participation in drug trials often burdens vulnerable older adults with expanded monitoring requirements for an expanded set of potential treatment effects.
• Nabiel Mir and team will conduct a novel clinical trial, DAROSTEP, to assess the effects of darolutamide + ADT on age-related outcomes in vulnerable older patients with metastatic hormone sensitive prostate cancer (mHSPC).
• Patients will be provided with a wrist accelerometer as a non-invasive digital biomarker, to remotely monitor cancer treatment tolerability.
• This trial will measure the impact of darolutamide + ADT on patient-reported outcomes (PROs), wrist accelerometry-determined daily step counts, physical activity, physical and cognitive function, body composition, and adverse events in vulnerable patients ≥70-years-old with mHSPC.
• This study will be performed within a diverse array of care centers, to focus inclusion on older/minority populations who bear a heightened burden of metastatic prostate cancer development and mortality.
• If successful, this project will determine the impact of darolutamide on health outcomes and quality of life in vulnerable older adults with mHSPC, an understudied group often overlooked in clinical trials. This information will be used to guide therapeutic decisions, improve care, and enhance outcomes of older adults with prostate cancer.
• The study’s innovative incorporation of wrist accelerometry could also pave the way for inclusion of digital monitors in clinical trials and practice for geriatric prostate cancer patients, to remotely monitor adverse events and ultimately improve patient outcomes.

What this means to patients:  The impact of prostate cancer treatments is understudied in older, more frail patients, as they are often excluded from or overburdened by inclusion in clinical trials. Dr. Mir and team will evaluate the impact of darolutamide, a treatment with improved tolerability in fitter patients, on age-related outcomes in vulnerable older patients with mHSPC. This trial will also evaluate the ability of a wrist accelerometer to remotely monitor adverse events in patients, which could greatly increase the ability to monitor side effects in frail patients in clinical trials or undergoing real world treatment.

2023 Movember, Todd Boehly, Shmuel Meitar, Richard Merkin, MD, Marcel Claure-PCF Challenge Award

Identification of Patients at High-Risk of Metastatic Disease after Neoadjuvant Intensive Androgen Signaling Inhibition

Principal Investigators: Mary-Ellen Taplin, MD (Dana-Farber Cancer Institute), Steven Balk, MD, PhD (Beth Israel Deaconess Medical Center)

Young Investigators: Praful Ravi, MD (Dana-Farber Cancer Institute), Joshua Russo, MD, PhD (Beth Israel Deaconess Medical Center), Zijun Frank Zhang, PhD (Cedars-Sinai Medical Center)

Co-Investigators: Eliezer Van Allen, MD (Dana-Farber Cancer Institute), Corey Arnold, PhD (University of California at Los Angeles), Huihui Ye, MD (Cedars-Sinai Medical Center), Stephanie Harmon, PhD (National Cancer Institute), Adam Sowalsky, PhD (National Cancer Institute)

Description:

• Recent prostate cancer clinical trials have demonstrated that treatment with androgen receptor signaling inhibitors (ARSI) earlier in the disease course can significantly extend patient survival. Even earlier usage of ARSI, given prior to radical prostatectomy (“neoadjuvant”), may further improve outcomes in certain patients.
• Mary-Ellen Taplin and colleges have completed several phase 2 clinical trials testing ARSI combinations prior to surgery in patients with high-risk localized prostate cancer. Thes trials have suggested that more intense ARSI neoadjuvant combinations may improve outcomes compared to standard of care prostatectomy. However, confirmatory phase 3 trials, as well as biomarkers to identify patients most likely to benefit from this approach, are needed.
• In this project, Dr. Taplin and team will identify biomarkers that predict which patients are at higher risk of recurrence and would benefit from intense neoadjuvant ARSI therapy, vs. patients with good prognosis who can be spared from further therapy. These biomarkers will be validated in an ongoing phase 3 trial testing neoadjuvant intense ARSI (ADT + apalutamide) followed by prostatectomy vs. prostatectomy alone.
• If successful, this project could lead to a new paradigm for the management of patients with high-risk localized prostate cancer and a decrease in the number of patients who progress to lethal prostate cancer.

What this means to patients: A large proportion of patients with high-risk localized prostate cancer will eventually recur after initial treatment with prostatectomy or radiation therapy +/- ADT. Phase 2 trials have suggested that some of these patients may benefit from neoadjuvant intensive ARSI.  Dr. Taplin and team are leading a confirmative phase 3 trial testing neoadjuvant ARSI in patients with high-risk localized prostate cancer and will develop biomarkers to identify patients most likely to benefit from this more intense treatment approach. This could lead to a new treatment paradigm that will cure more patients at the localized disease stage.

2023 Igor Tulchinsky-PCF Challenge Award

ctDNA Determinants of Resistance to ¹⁷⁷Lu-PSMA-617 versus Taxane-Based Chemotherapy

Principal Investigators: Alexander Wyatt, PhD (Vancouver Prostate Centre), Arun Azad, MD (Peter MacCallum Cancer), Kim Chi, MD (BC Cancer), Michael Hofman, MBBS (Peter MacCallum Cancer Centre)

Young Investigators: Heidi Fettke, PhD (Peter MacCallum Cancer Centre), Edmond Kwan, MBBS, PhD (University of British Columbia), Corinne Maurice-Dror, MD (BC Cancer), Martin Sjostrom, MD, PhD (University of California San Francisco)

Co-Investigators: Fred Saad, MD (University of Montreal Hospital Center), Francois Bernard, MD (BC Cancer), Ian Davis, MBBS, PhD (Monash University), Matti Annala, BS (Tampere University), Felix Feng, MD (University of California, San Francisco), Wendy Parulekar, MD (Queen’s University)

Description:

• The prostate-specific membrane antigen (PSMA) radioligand therapy LuPSMA (177–Lutetium-PSMA-617; Pluvicto®) is a promising new treatment for metastatic castration-resistant prostate cancer (mCRPC).
• However, it is unclear how to use LuPSMA in settings where taxane-based chemotherapy (docetaxel or cabazitaxel) is also a proven life-prolonging option. Importantly, neither treatment elicits benefit for all patients, and both can result in significant health and/or financial toxicity.
• Alexander Wyatt and team have previously developed blood plasma circulating tumor DNA (ctDNA) tests that can track treatment response and disease progression.
• In this project, they will develop ctDNA-based biomarker tests to determine differential responses of patients with mCRPC to LuPSMA versus taxane chemotherapy, and identify tumor subclones that drive acquired treatment resistance.
• The team have assembled serial blood samples from over 600 patients enrolled in clinical trials testing LuPSMA versus docetaxel or cabazitaxel or receiving standard-of-care treatment with taxane chemotherapy or LuPSMA.
• In this project, the team will perform genomic and epi-genomic sequencing on circulating tumor DNA from pre-treatment samples from all patients, and use custom computational and AI tools to identify genomic and epi-genomic tumor biomarkers that can predict probability of response and survival on each therapy.
• The team will also analyze samples from patients at the time of disease progression on therapy to identify drivers of acquired resistance to LuPSMA versus taxane chemotherapy.
• If successful, this project will identify new drivers of treatment resistance and provide new biomarkers to help guide treatment selection for patients with mCRPC, reducing the use of futile therapy, and improving quality and length of life.

What this means to patients: There are now several treatment options for patients with mCRPC, including LuPSMA and taxane chemotherapy. However, these treatments are not effective in all patients and can cause side effects that severely reduce patient quality of life. Biomarkers to predict which treatment a patient is likely to benefit more from are urgently needed. Dr. Wyatt and team will develop new blood-based biomarker tests that can predict how well individual patients with mCRPC will respond to LuPSMA vs taxane chemotherapy, and will also identify new mechanisms that drive treatment resistance. This will help to guide treatment selection and greatly improve patient outcomes.

2023 Richard Solomon, Igor Tulchinsky, Darius Bikoff, John Paulson, Richard Sandler, Bill Mack, Jason Safriet-PCF Challenge Award

New Targeted Epigenetic Therapy for Androgen Receptor-Negative Prostate Cancer

Principal Investigators: Ming-Ming Zhou, PhD (Icahn School of Medicine at Mount Sinai), Kunhong Xiao, MD, PhD (Allegheny Health Network Cancer Institute)

Young Investigator: Zuqiang Liu, PhD (Allegheny Health Network Cancer Institute)

Collaborators: Bharath Kumar Gajjela, PhD (Icahn School of Medicine at Mount Sinai), Michael Appiah, PhD (Icahn School of Medicine at Mount Sinai), Anurupa Ghosh, PhD (Icahn School of Medicine at Mount Sinai), Qiangmin Zhang, PhD (Allegheny Health Network Cancer Institute), Xi Peng, PhD (Allegheny Health Network Cancer Institute), Yunxiang Fu, BA (Allegheny Health Network Cancer Institute), David Bartlett, MD (Allegheny Health Network Cancer Institute)

Description:

• The androgen receptor (AR) is a crucial driver for prostate cancer, and AR-targeted therapies are standard of care for prostate cancer patients. However, resistance to these therapies inevitably develops in most patients, leading to the progress of the disease to metastatic castration-resistant prostate cancer (mCRPC), which is highly lethal.
• While the majority of mCRPC cases remain driven by AR alterations (“AR-positive”), approximately 20% are deemed “AR-negative”, encompassing highly aggressive and incurable subtypes such as neuroendocrine prostate cancer (NEPC) and double-negative prostate cancer.
• Currently, there are no treatment options for AR-negative prostate cancers, underscoring the urgency of the development of targeted therapies for this unmet medical need. Moreover, many patients’ cancers exhibit heterogeneity, coexisting with both AR-positive and AR-negative mCRPC subtypes. Therefore, it is critical to develop therapeutic strategies that address multiple subtypes of mCRPC and/or prevent emergence of AR-negative subtypes.
• BRD4, a major transcription regulator, has been recognized as a novel drug target for prostate cancer. However, despite promising results in preclinical studies, BRD4 inhibitors have proven ineffective in mCRPC clinical trials and virtually non-responsive against AR-negative prostate cancer.
• Dr. Zhou and colleagues discovered that standard BRD4 inhibitors repress oncogenes that drive AR-positive prostate cancer but activate these pathways in AR-negative prostate cancer. This property likely underlies the failure of these drugs in mCRPC clinical trials.
• The team has developed a new class of “bivalent” BRD4 inhibitors capable of preventing growth of both AR-positive and AR-negative prostate cancer subtypes.
• In this project, the team will elucidate the mechanisms of resistance of AR-negative prostate cancer to prior “monovalent” BRD4 inhibitors. The study will also investigate the mechanisms of action and efficacy of the new bivalent BRD4 using in preclinical models representative of currently uncurable mCRPC subtypes.
• If successful, this innovative approach could lead to the development of a new treatment that is effective in both AR-positive and AR-negative mCRPC, potentially offering a significant clinical impact, as no current therapies are effective in both subtypes.

What this means to patients: mCRPC represents a lethal and incurable advanced prostate cancer. Treatment failure in this context often stems from disease heterogeneity, where diverse molecular subtypes of mCRPC emerge. Dr. Zhou and colleagues have developed a novel therapy targeting BRD4, demonstrating preclinical efficacy in both AR-positive and AR-negative mCRPC subtypes. This project aims to establish the mechanisms of action and preclinical efficacy of this new treatment, laying the groundwork for future clinical trials.