Young Investigator Award- Class of 2023

The PCF Young Investigator Award-Class of 2023 recipients are:

2023 Lowell Milken – PCF Young Investigator Award

MMUVE Prostate Cancer: Multi-Omic Evaluation of Micro-Ultrasound VisiblE Prostate Cancer

Wayne Brisbane, MD

University of California, Los Angeles

Mentors: Leonard Marks MD, Robert Reiter MD, Paul Boutros PhD

Description:

• Diagnosis of prostate cancer begins with PSA screening, often followed by multiparametric MRI imaging or a biomarker test to confirm suspicion (and location, if MRI) of cancer, before biopsy. However, these procedures are not optimal, as MRI is costly and not widely available, while biomarker tests cannot provide information such as cancer location and disease staging.
• Micro-Ultrasound is a high-resolution transrectal ultrasound method that may offer a promising alternative prostate cancer diagnostic, as it retains similar cancer visualization sensitivity as MRI, at 6% of the cost. However, dense benign tissue appears cancerous on Micro-Ultrasound, resulting in low cancer specificity. Further refinement of this method is required for widespread clinical adoption.
• Wayne Brisbane is investigating methods to improve Micro-Ultrasound specificity and evaluate Micro-Ultrasound versus MRI for prostate cancer visualization.
• In this project, Dr. Brisbane and team will create a machine learning-based image analysis algorithm to improve cancer specificity following PSA screening. This model will use data including age, PSA, DRE findings, prostate volume, and whole gland Micro-Ultrasound images to risk stratify patients following PSA screening.
• The team will also compare the specificity and sensitivity of Micro-Ultrasound versus MRI and evaluate if a urine-based biomarker test can further improve specificity for cancer diagnosis.
• MRI and Micro-Ultrasound employ different physical mechanisms for visualizing tissue. The team will compare the biological differences in what these imaging methods detect, the molecular characteristics of tumors visible on MRI and Micro-Ultrasound vs. tumors visible by only one modality.
• If successful, this project will improve understanding of tumor visibility by Micro-Ultrasound, and result in a 3-minute prostate scan and urine sample test that identifies patients at risk for prostate cancer and improves decisions on whether patients should undergo prostate biopsy or not.

What this means to patients:  Current prostate cancer screening methods either lack specificity (PSA tests) or are costly and not widely available (MRI), thus many more patients undergo invasive prostate biopsies than are necessary. Dr. Brisbane and team are investigating methods to improve the use of a rapid and cheap alternative, Micro-Ultrasound, possibly with a urine biomarker test, to accurately determine a patient’s risk for prostate cancer and aid in decisions about whether to undergo prostate biopsy.

2023 Michael & Lori Milken – PCF Young Investigator Award

Breaking Barriers in Prostate Cancer: Novel Clinical Uses of PSMA Radioligand Therapy and Imaging with PSMA PET/CT

James Buteau, MD

The University of Melbourne

Mentors: Michael Hofman, Declan Murphy, Arun Azad

Description:

• There is a need for improved therapeutic approaches for patients with advanced metastatic castration-resistant prostate cancer (mCRPC), whilst on the other extreme, there is a need to accurately identify clinically significant prostate cancer in individuals presenting with elevated PSA levels or inconclusive MRI results.
• James Buteau proposes to address both these unmet needs with two first-in-field clinical trials testing PSMA-targeted theranostic approaches.
• VIOLET is a phase I/II trial that will test a new PSMA-targeted radionuclide therapy, 161-Terbium-PSMA-I&T, in patients with progressive mCRPC. This treatment is similar in concept to the recently approved radionuclide therapy 177-Lutetium-PSMA-617 (Pluvicto®), but uses 161-Terbium instead of 177-Lutetium as the radioactive-emitting isotope. 161-Terbium emits Auger electrons, depositing higher concentrations of radiation to micrometastases, and has shown superior preclinical results in comparison with 177-Lutetium. Dr. Buteau and team will determine the maximum tolerated dose, safety profile and preliminary anti-tumor activity of 161-Terbium-PSMA-I&T.
• PRIMARY2 is randomized phase III trial that will determine whether the addition of PSMA PET/CT prior to diagnostic prostate biopsy could improve earlier diagnosis of clinically significant prostate cancer, improve biopsy targeting, and help patients without clinically significant prostate cancer to avoid unnecessary biopsies.
• If successful, this project will benefit two populations of patients by improving survival in men with mCRPC and improving the early diagnosis of prostate cancer when there is a higher chance of cure.

What this means to patients: PSMA-targeted therapy and diagnostic imaging (theranostics) has revolutionized the landscape of prostate cancer in recent years. In this project, Dr. Buteau and team will investigate the potential for new PSMA theranostic applications at both extremes of the disease course. If successful, this project will demonstrate the ability for PSMA PET/CT imaging to specifically detect clinically significantly prostate cancer earlier, while reducing overdiagnosis and overtreatment, as well as determine whether a novel PSMA-targeted radionuclide therapy improves survival in patients with mCRPC.

2023 American Cancer Society (ACS) – PCF Young Investigator Award

Rural Outpatient Advanced Diagnostics to Maximize Access to Prostate Health (ROADMAP)

Alexander P. Cole, MD

Harvard: Brigham and Women’s Hospital (BWH)

Mentors: Quoc-Dien Trinh, Caroline M.Moore, Adam S. Kibel

Description:

• Patients with prostate cancer who live in rural communities face unique challenges, including reduced access to advanced diagnostics and targeted interventions. The extent and magnitude of this disparity, as well as whether these disparities are due to referral patterns, patient preferences, or other health systems factors, are unknown.
• Dr. Alexander Cole is investigating the nature of disparities in access to modern prostate cancer care in rural settings.
• In this project, Dr. Cole and team will use Medicare and the American Hospital Association (AHA) databases to assess geographic disparities (urban vs. rural) in utilization of diagnostics and targeted interventions, such as image-guided biopsies, image-guided treatments, and molecularly targeted therapies, such as PARP inhibitors for patients with germline mutations. The role of geography, hospital type, insurance type, and health systems factors in receipt of advanced testing and targeted interventions will be determined.
• The contribution of regional, hospital, and patient level variables on race-specific likelihood of receiving advanced testing and targeted interventions will also be investigated. Barriers to advanced testing and targeted interventions at community practices treating underserved minority patients will be identified.
• If successful, this project will identify modifiable factors that impact receipt of advanced imaging and molecular diagnostics by rural prostate cancer patients. Ultimately, this proposal aims to yield a policy and implementation roadmap to facilitate the equitable dissemination of prostate cancer diagnostic and treatment modalities with a particular emphasis on rural populations.

What this means to patients:  Patients in rural communities tend to have reduced access to advanced diagnostics and targeted interventions for prostate cancer, which contributes to disparities in health outcomes. Dr. Cole and team aim to determine the nature of disparities in access to modern prostate cancer care in rural settings and develop a policy and implementation roadmap for equitable diffusion of advanced diagnostics and targeted interventions. This will contribute to more equitable and high-quality cancer care for all patients with prostate cancer regardless of race, ethnicity, or geographic location.

2023 Clay Hamlin, Metropoulous Family Foundation, William and Cary Singleton -PCF Young Investigator Award

Investigating how Prostate Cancer causes Sclerotic Metastatic Bone Lesions and Impact Fracture Risk using Cellular and Materials Sciences Approaches

Felipe Eltit Guersetti, DDS, PhD

University of British Columbia (UBC)

Mentors: Michael Cox, Colm Morrissey, Raphaele Charest-Morin

Description:

• About 20% of patients diagnosed with prostate cancer will eventually develop incurable metastatic prostate cancer, with bone being the most common metastatic site.
• Prostate cancer bone metastases cause abnormal hardening or thickening of bone that increases a patient’s risk for fractures and spinal cord compression, which can cause severe pain or even paralysis These risks are exacerbated by standard-of-care androgen deprivation therapy (ADT). The mechanisms that drive development of abnormal bone density and increase fracture risk in metastatic lesions remain unclear.
• Felipe Eltit Guersetti is investigating the bone structure of prostate cancer bone metastases, to identify the cause of bone metastasis development and identify at-risk patients based on tumor phenotype and bone architecture.
• In this project, Dr. Eltit and team will characterize bone architecture, mineral composition, and fracture sensitivity in bone metastatic samples from patients treated for pathologic fracture or spinal cord compression.
• Single cell and spatial analyses will be performed on bone metastases samples to identify tumor cell profiles and bone microenvironment features that relate to fracture-prone pathologic bone architecture.
• Preclinical bone-tumor models will be studied to evaluate how various subtypes of prostate cancer cells interact with and impact bone cell activities.
• If successful, this project will improve understandings of how prostate cancer metastases impact bone architecture and biology and increase fracture risk. This is crucial to developing new intervention strategies to block formation of abnormal bone lesions and improve quality of life for patients with metastatic prostate cancer.

What this means to patients:  Nearly all patients with metastatic prostate cancer develop bone metastases, which increase risk for fractures and spinal cord compression, causing pain and reduced quality of life.  Dr. Eltit and team will characterize bone microenvironment and prostate cancer features that enable bone metastases and cause fracture-prone pathologic bone architecture. These studies will help to identify patients at risk for bone fractures and enable development of new therapeutic interventions that decrease morbidity from bone metastases.

2023 Rob & Cindy Citrone – PCF Young Investigator Award

Precision Prevention and Treatment for Aggressive Prostate Cancer with PTEN Loss

Sinéad Flanagan, MB BCh BAO, MPH.

Harvard T.H. Chan School of Public Health

Mentors: Lorelei Mucci ScD, Konrad Stopsack MD MPH, Tamara Lotan MD.

Description:

• Phosphatase and tensin homolog (PTEN) is the most commonly inactivated tumor suppressor gene in prostate cancer and its loss is strongly associated with increased risk for metastases and death from prostate cancer.
• PTEN is also a critical negative regulator of insulin signaling through its role in the phosphoinositide 3-kinase (PI3K) pathway. Abnormally high insulin levels (hyperinsulinemia) induced by diet and lifestyle are associated with increased risk of prostate cancer development and progression.
• In terms of PTEN, hyperinsulinemia has also been shown to accelerate prostate cancer progression in PTEN-deficient mouse models. Moreover, cholesterol metabolism and PI3K signaling are tightly linked, and statin therapy post-diagnosis may be specifically beneficial in the presence of PTEN loss.
• Dr. Flanagan hypothesizes that tumors with PTEN loss are amenable to primary prevention and responsive to precision interventions involving insulin-modulating dietary and lifestyle changes and/or statin therapy following a prostate cancer diagnosis.
• An ongoing, well-annotated, US population-based cohort study, with over three decades of long-term follow-up, along with an associated tumor biorepository, will be leveraged. Since 1986, this cohort study has prospectively collected clinical, dietary, and lifestyle data at regular intervals from more than 50,000 men initially free of cancer. Prostate tumor samples have been obtained from over 1,800 participants diagnosed with prostate cancer during this period and will undergo evaluation for genetically validated PTEN status.
• The impact of a low-insulinemic diet and lifestyle on the incidence of prostate cancer with PTEN loss and whether such insulin-modulating dietary and lifestyle changes, along with statin use, can prevent progression to metastasis and death in prostate cancer patients with PTEN loss will be investigated.
• If successful, this project will determine the potential benefits of a low-insulinemic diet and lifestyle for the primary prevention of prostate cancer with PTEN loss, while evaluating PTEN as a biomarker to identify patients with prostate cancer who are more likely to benefit from an insulin-lowering diet and lifestyle or statin therapy.

What this means to patients:  Prostate cancers commonly lose PTEN, a critical tumor suppressor gene that negatively regulates the insulin signaling pathway. Dr. Flanagan and team will determine whether a low-insulinemic diet and lifestyle, and/or statin use, can prevent the development or progression of prostate cancer with PTEN loss. This will set the stage for clinical trial testing of diet and lifestyle-based strategies, which have also shown proven cardiovascular benefits, for the prevention and treatment of this highly aggressive form of prostate cancer.

2023 Society of Urologic Oncology (SUO) – PCF Young Investigator Award

Defining Modifiable Components of the Immune Microenvironment in Patients with Prostate Cancer Nodal Metastases

Christopher Gaffney, MD

Memorial Sloan Kettering Cancer Center (MSKCC)

Mentors: Howard Scher, David Knorr, Behfar Ehdaie

Description:

• Lymph nodes are small structures located throughout the body that help to initiate immune responses against cancer and infections. Prostate cancer commonly spreads to the lymph nodes, increasing the risk for distant metastases and death from prostate cancer.
• Lymph nodes have an important role generating anti-tumor immunity which is increasingly important with the development of immunotherapies that activate the immune system against cancer.
• However, the types of immune cells, their locations within the immune microenvironment, and their interactions with other immune cells in the lymph nodes of patients with prostate cancer lymph node metastases is unclear.
• Dr. Christopher Gaffney is studying the biology of lymph nodes with prostate cancer metastases and their role in responses to androgen deprivation therapy (ADT) and a novel immunotherapy.
• In this project, Dr. Gaffney and team will investigate the immune microenvironment of lymph nodes with prostate cancer metastases from patients who underwent surgery to remove the prostate and nearby involved lymph nodes to discover if the immune system appears suppressed within these lymph nodes.
• ADT is hypothesized to enhance anti-tumor immunity by activating immune cells. Lymph node samples from patients who were treated with ADT prior to surgery will be studied to determine the impact of ADT on immune features and functions.
• The team developed a clinical trial testing ADT in combination with a novel immunotherapy, anti-CD40, which is hypothesized to further activate immune responses against cancer. As a part of this project, the efficacy of this combination will be investigated in samples from a subgroup of patients with node-positive prostate cancer, to determine whether and how ADT + anti-CD40 modifies the immune microenvironment.
• If successful, this project provide a comprehensive description of the immune microenvironment of lymph nodes with prostate cancer metastases, and determine how they are impacted by ADT alone or with immunotherapy. This information may be used to define aspects of the immune microenvironment that are modifiable with new classes of immunotherapies.

What this means to patients:  Prostate cancer commonly metastasizes to lymph nodes, an event associated with distant spread and death from disease. These lymph nodes are immune organs that are hypothesized to be immunosuppressed in patients with cancer. Dr. Gaffney and team will comprehensively profile prostate cancer-infiltrated lymph nodes from patients and determine how immune features are changed by treatment with ADT alone or in combination with a novel immunotherapy, anti-CD40.  These studies will provide critical insights into the immune mechanisms underlying prostate cancer progression and inform the development of novel therapeutic strategies.

2023 John Black Charitable Foundation – PCF Young Investigator Award

Optimal Methods for Identifying and Communicating which Treatments are Best for which People with Metastatic Hormone-Sensitive Prostate Cancer

Peter Godolphin, PhD

University College London

Mentors: Jayne Tierney, Susan Halabi, Noel Clarke

Description:

• Recently, several new life-prolonging therapies and combinations have become available for patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, which treatment option is best for which patients remains unclear.
• Peter Godolphin is investigating methods to determine which treatments work best for which people with mHSPC, and ways to communicate information on treatment selections in practice.
• In this project, Dr. Godolphin and team will analyze mHSPC clinical trial data and perform simulations to identify optimal patient-level, clinical, imaging, and/or molecular biomarkers that can identify which treatments work best for which patients. This will be used to develop a framework of recommendations on which methods to use in practice, and in trials and meta-analyses in mHSPC.
• Workshops will be held with patients, clinicians, statisticians and trialists to understand communication challenges. Tools for improving communication of interaction results will be developed and tested for effectiveness.
• If successful, this project will produce a framework of recommendations on optimal methods for selecting treatments for patients with mHSPC and for use in clinical trials and meta-analyses in mHSPC, as well as provide tools to communicate results from such methods.

What this means to patients:  Multiple treatment options are now available for patients with mHSPC, such as docetaxel, abiraterone, enzalutamide, apalutamide and darolutamide, but uncertainty remains about precisely which people benefit, which is critical to determining how therapies should be used in practice, whether ongoing trials need to adapt, and how future trials should be designed and analyzed. Dr Godolphin will identify optimal clinical biomarkers for matching patients with mHSPC to treatments, and develop tools for communicating these methods and their results clearly to stakeholders, including patients with mHSPC, clinicians, trialists, and statisticians. This will help to ensure that treatments are targeted appropriately and de-escalated when they are not required, ultimately improving outcomes for people with prostate cancer.

2023 Todd Boehly – PCF Young Investigator Award

Discovering Combination Therapeutic Targets in Castration-Resistant Prostate Cancer using Highly Multiplexed CRISPR Chromatin Perturbations

Chris Hsiung, MD, PhD

Stanford University

Mentors: Luke Gilbert, Felix Feng, Howard Chang

Description:

• Castration-resistant prostate cancers (CRPC) can exhibit significant phenotypic plasticity. In one extreme form of this plasticity, CRPC can acquire treatment resistance by adopting the lineage identity of another cell type, neuroendocrine cells. This plasticity creates highly aggressive prostate cancer subtypes for which new treatment approaches are urgently needed. Whether these aggressive CRPC phenotypes can be reprogrammed to more benign states or eliminated without toxicity to other tissues remains uncertain.
• Dr. Chris Hsiung is developing and applying novel combinatorial functional genomics approaches to efficiently screen millions of combinations of targets in the genome of CRPC cell models to identify combinations that when targeted can prevent or reverse the transition to aggressive forms of CRPC.
• Using a conceptually related approach for nominating combination therapeutic targets, Dr. Chris Hsiung is developing next-generation CRISPR therapeutic strategies with the goal of targeting key oncogenes driving aggressive CRPC while minimizing off-tissue toxicity.

What this means to patients:  New treatments are needed for patients with aggressive forms of CRPC, including neuroendocrine prostate cancer. Dr. Hsiung and team will develop and apply a novel CRISPR gene targeting approach that enables efficiently testing millions of combinations of potential therapeutic targets discover specific combinations that can prevent or reverse the development of aggressive forms of CRPC. This efficient large-scale discovery approach can lead to the development of next-generation combination therapeutics for treating aggressive forms of CRPC.

2023 Milken Scholars, Merkin Family Foundation – PCF Young Investigator Award

Defining Mechanisms of AR Transcriptional Regulation to Improve Outcomes in Advanced Prostate Cancer

Sarah Hsu, MD, PhD

University of California, San Francisco (UCSF)

Mentors: Luke Gilbert, Franklin Huang, Eric Small

 Description:

• Metastatic castration resistant prostate cancer (mCRPC) is a lethal disease that invariably becomes resistant to existing therapies targeting androgen signaling.
• Persistent or increased androgen receptor (AR) activity is thought to be a major driver of treatment resistance. As such, there is an urgent need to understand how AR expression is controlled in mCRPC to identify better therapeutic strategies.
• AR expression can be supported through the activity of an enhancer – a genomic element with the capacity to activate gene expression over large distances. The genomic region containing the AR enhancer is frequently amplified in mCRPC and likely plays a key role in sustaining AR expression in advanced and treatment resistant disease.
• Dr. Sarah Hsu is defining the mechanisms regulating AR expression and enhancer activity in mCRPC, which may lead directly to new therapeutic strategies.
• In this project, Dr. Hsu will define protein factors that control AR enhancer activity and modulate AR expression, with the goal of identifying potentially druggable targets.
• Dr. Hsu will also aim to characterize additional or alternative AR enhancers that may be active in different contexts and disease states, and that could also contribute to disease progression and treatment resistance.
• If successful, this project will define mechanisms of AR expression in advanced prostate cancer and identify new approaches for treating mCRPC.

What this means to patients: Androgen signaling and AR activation are key drivers of prostate cancer, and AR is the primary therapeutic target in patients with advanced disease. Importantly, AR is also frequently central to the development of treatment resistance, through a variety of adaptive mechanisms that can increase AR levels and/or activity. In this project, Dr. Sarah Hsu aims to comprehensively characterize how the AR gene is regulated, with the goal of identifying druggable targets that circumvent resistance mechanisms.

2023 Ben Franklin – PCF Young Investigator Award

Optimizing Outcomes in Survivors of Prostate Cancer with Diabetes

Amanda Leiter, MD

Icahn School of Medicine at Mount Sinai Hospital

Mentors: Juan Wisnivesky, Chung Yin Kong, Matthew Galsky

Description:

• Approximately 20% of prostate cancer survivors have type 2 diabetes, often with worse control of blood sugars. In prostate cancer survivors, type 2 diabetes is associated with increased mortality.
• While prostate cancer progression is a concern for prostate cancer survivors, the majority die of comorbid illness, particularly cardiovascular disease.
• Optimizing type 2 diabetes treatment can have a major beneficial impact in clinical outcomes for prostate cancer survivors, but data regarding the optimal type 2 diabetes treatment strategies is limited. The harm/benefit ratio of different diabetes treatment approaches is likely significantly different for prostate cancer survivors due to differences in competing risks of death from prostate cancer, hyperglycemia from androgen deprivation therapy, increased risk of type 2 diabetes and cardiovascular disease caused by treatments, and differences in baseline quality of life.
• Dr. Amanda Leiter is investigating optimal type 2 diabetes treatment strategies for advanced prostate cancer survivors with type 2 diabetes.
• In this project, Dr. Leiter and team will develop a validate a model that simulates the unique natural history and outcomes of type 2 diabetes in advanced prostate cancer survivors.
• This model will be used to identify the most effective first-line medications and glycemic control goals for advanced prostate cancer survivors with varying clinical characteristics in regard to reducing complications, reducing adverse events, and maximizing quality-adjusted life expectancy.
• If successful, this project will provide tailored type 2 diabetes care recommendations for prostate cancer survivors and aid with decision-making regarding type 2 diabetes treatment approaches for clinicians, patients, and caregivers, thereby improving quality of life in prostate cancer survivors.

What this means to patients:  In prostate cancer survivors, type 2 diabetes is a common comorbidity that is linked to increased mortality and is a risk factor for cardiovascular disease, a major cause of death in prostate cancer survivors. Dr. Leiter and team will develop a simulation model to assess optimal type 2 diabetes treatment approaches in prostate cancer survivors. This study will generate tailored diabetes care recommendations for prostate cancer survivors and aid with decision-making regarding diabetes treatment approaches. This will ultimately improve long-term prostate cancer outcomes by optimizing survival and quality of life in prostate cancer survivors with type 2 diabetes.

2023 Igor Tulchinsky – PCF Young Investigator Award

A Novel CBP/p300 PROTAC Degrader Suppresses Prostate Cancer Progression via Re-Shaping the Chromatin Landscape and Acetylome

Jie Luo, PhD

University of Michigan

Mentors: Shaomeng Wang, Arul Chinnaiyan

Description:

• CBP and p300 are proteins that regulate gene transcription and the 3D structure of the genome, and have been demonstrated as prostate cancer oncogenes and promising therapeutic targets in prostate cancer. However, most previously developed p300/CBP-inhibitors have performed poorly in prostate cancer clinical trials.
• Jie Luo and team are developing a p300/CBP-targeted “PROTAC,” an emerging class of treatments that causes complete degradation of the protein target. This agent, named CBPD-409, appears highly promising in preclinical studies.
• In this project, Dr. Luo will delineate the comprehensive roles of p300/CBP in prostate cancer and generate preclinical data on CBPD-409 to position it for clinical translation.
• The effects of CBPD-409 treatment on the 3D genomic landscape and transcription factor activity in prostate cancer cells will be investigated. Results will be compared between CBPD-409 and other p300/CBP inhibitors to gain insights into their differential mechanisms of action.
• Non-genomic, protein targets of p300/CBP activity will be identified and assessed for their role in prostate cancer.
• The anti-tumor efficacy and biological effects of CBPD-409 alone and in combination with enzalutamide will be investigated in multiple preclinical prostate cancer models.
• If successful, this project will define the full spectrum of the biological roles of p300/CBP in prostate cancer and generate preclinical data needed for the orally bioavailable PROTAC degrader, CBPD-409, which has potential to be quickly translated to early-phase clinical trials.

What this means to patients:  p300/CBP is a promising therapeutic target for patients with advanced prostate cancer, yet prior drugs targeting these proteins have underperformed. Dr. Luo and team are developing a novel p300/CBP-degrading treatment, CBPD-409. This project will define the biological roles of p300/CBP in prostate cancer and provide preclinical data necessary for rapid translation of CBPD-409 into clinical trials.

2023 Royalty Pharma – PCF Young Investigator Award

Investigating Tumor and Immune Cell Dysregulation for the Treatment of Prostate Cancer Bone Metastases

Shenglin Mei, PhD

Harvard: Massachusetts General Hospital (MGH)

Mentors: David Sykes, Philip Saylor

Description:

• The bone and bone marrow are metastatic sites in ~90% of patients with metastatic castration-resistant prostate cancer (mCRPC), and show poor responses to second-generation anti-androgen treatments and immunotherapies. There is an urgent need to better understand the processes underlying prostate cancer bone metastases, and to use this information to develop better treatments for our patients.
• An important feature that accompanies the progression of prostate cancer is the remodeling of the tumor and immune cell microenvironment, ultimately leading to dysregulated and tumor-supporting immune cell populations.
• Dr. Shenglin Mei is using single cell and spatial gene expression data from primary prostate cancer and bone metastatic tumor samples to investigate the role of tumor and immune cell remodeling and their specific cell to cell interactions in bone metastasis.
• The characteristics of functionally distinct tumor subclusters in the progression from localized to metastatic disease will be determined.
• Immune cell dysregulation and key cell-to-cell nodes of communication with each tumor cell cluster will be investigated.
• The clinical implications of tumor sub- clustering and immune cell interactions in prostate cancer and other malignancies will be determined.
• If successful, this project will provide deeper understandings of tumor cell and immune cell heterogeneity, dysregulation, and interactions that contribute to prostate cancer bone metastasis and disease progression. These mechanistic insights will aid in the development of new therapeutic strategies for patients with prostate cancer bone metastases.

What this means to patients: Prostate cancer commonly metastasizes to the bone, and these lesions are often highly resistant to standard and experimental therapies. Dr. Mei and team are comprehensively characterizing the tumor and immune cell types, locations, functions, and cell-cell interactions in bone metastases. These studies will provide new insights into prostate cancer biology and enable the development of new, improved treatment strategies.

2023 John and Amy Phelan – PCF Young Investigator Award

Modulation of Oxidative Stress Responses to Augment Prostate Cancer Radiation Therapy

Katherine Morel, PhD

The University of Adelaide

Mentors: Chris Sweeney, Lisa Butler

Description:

• Recently, a novel prostate-specific membrane antigen (PSMA)-targeting radioligand treatment (RLT) was approved for treating patients with metastatic castration-resistant prostate cancer (mCRPC).
• While PSMA-RLT can reduce tumor burden and increase life expectancy in patients with mCRPC, it is not curative. The limiting factor in PSMA-targeted RLT is normal tissue toxicity; efforts to reduce toxicity would enable higher and more effective doses to be given to patients.
• Katherine Morel and team have identified a naturally occurring anti-inflammatory compound, dimethylaminoparthenolide (DMAPT), that can reduce radiation-induced damage in normal cells, while increasing tumor cell sensitivity to radiation damage in preclinical models.
• In this project, Dr. Morel and team will investigate whether DMAPT treatment can increase the anti-cancer efficacy of different forms of PSMA-RLT while protecting normal tissues, in preclinical models.
• The key mechanisms by which DMAPT differentially affects cancer versus normal cell responses to radiation will be defined. These studies will specifically investigate the role of the NRF2-KEAP1 pathway, which modulates antioxidant activity and is one of the main cellular defense mechanisms against oxidative stress.
• Whether baseline NRF2-KEAP1 activity can predict efficacy of RLT treatment alone will be investigated.
• If successful, this project will investigate a novel strategy to reduce radiation toxicity in normal tissues while potentially having the added benefit of increasing tumor killing from RLT. In addition, understanding the role of baseline NRF2-KEAP1 activity on PSMA-RLT efficacy will increase the number of patients receiving appropriate therapy for advanced prostate cancer and identify further strategies to try and improve the efficacy of RLT.

What this means to patients:  PSMA-targeted radioligand therapy is a new class of treatments for mCRPC that delivers radiation directly to tumor cells. Dr. Morel and team are investigating whether a naturally occurring anti-inflammatory compound can both increase the efficacy of PSMA-targeted RLT and significantly improve the quality of life for patients after therapy. In addition, this project aims to develop novel biomarkers and improved understandings of RLT mechanisms of action, which will improve treatment optimization and the selection of patients who will most benefit from this treatment approach.

2023 Leerom & Karolina Segal – PCF Young Investigator Award

Epigenetic and Metabolomic Vulnerabilities in ASCL1-Driven NEPC Subtype

Shaghayegh Nouruzi, PhD

University of British Columbia (UBC)

Mentor: Amina Zoubeidi

Description:

• Androgen receptor signaling inhibitors (ARSIs) are newer, more potent treatments for advanced prostate cancer. Unfortunately, prostate cancers commonly develop treatment resistance to ARSIs, often through the emergence of AR-independent phenotypes, including neuroendocrine prostate cancer (NEPC). Alarmingly, no targeted therapies exist for NEPC, which stems from our poor understanding of the mechanisms underlying this lethal disease.
• Shaghayegh Nouruzi and team have recently found that the transition of castration-resistant prostate cancer (CRPC) to NEPC is accompanied by an extensive epigenetic and transcriptional rewiring, governed by ASCL1. Further, ASCL1-high NEPC tumors have a distinct metabolic profile.
• In this project, Dr. Nouruzi and team will evaluate the interplay between ASCL1, metabolism and epigenetic alterations, in the transition of CRPC to NEPC.
• The epigenetic and metabolic landscape of CRPC, ASCL1-high NEPC, and ASCL1-low NEPC will be characterized, to determine the contribution of ASCL1 and metabolic rewiring in NEPC and identify epigenetic/metabolomic-based treatment vulnerabilities.
• The mechanism by which ASCL1 alters metabolism to alter the epigenetic landscape in favor of the NEPC lineage will be determined.
• The efficacy and biological effects of treating ASCL1-high NEPC with metabolic inhibitors will be investigated.
• If successful, this project will define the role of ASCL1 and metabolic alterations in driving progression to NEPC and identify promising new metabolism-based treatment strategies for NEPC.

What this means to patients:  NEPC is a highly aggressive form of CRPC, for which no effective treatments are currently available. Dr. Nouruzi and team will define the role of a novel driver of NEPC, ASCL1, and determine whether metabolic alterations underlie transition of CRPC to NEPC. This project will also define whether NEPC is sensitive to certain metabolic inhibitors, which could accelerate new treatment paradigms for patients with this otherwise lethal form of prostate cancer.

2023 Jeff & Loyd Zisk – PCF Young Investigator

Conditionally Activated Membrane Binding Probes for Improved Targeted Radiotherapy in Metastatic Castration Resistant Prostate Cancer

Apurva Pandey, PhD

University of California, San Francisco (UCSF)

Mentors: Michael Evans, Charles Craik, Felix Feng

Description:

• Radioligand therapy (RLT) is a new class of treatments that consist of a tumor-targeting molecule attached to a radioactive isotope, that deliver cell-killing radiation directly to tumor cells. The same tumor-targeting molecules can also be attached to less powerful isotopes that enable tumor imaging with PET machines. The pairing of therapeutic + diagnostic agents (“theranostics”) allows clinicians to determine if patients’ tumors express the target, and aids in optimal matching of patients with treatments.
• Pluvicto (¹⁷⁷Lu-PSMA-617) is a PSMA-targeted RLT that recently received FDA approval for treatment of metastatic castration-resistant prostate cancer (mCRPC). However, several factors limit the efficacy of PSMA-targeted RLTs, and improved RLT strategies are needed to cure patients with advanced prostate cancer.
• Dr. Apurva Pandey and team are developing a new class of RLTs called “restricted interaction peptides” (RIPs). RIPs are small protein fragments attached to radioactive isotopes, that have a unique chemistry which allows them to emit radiation only once inside tumor cells.
• In this project, Dr. Pandey and team will develop and test the first RIPs that target a tumor associated protease specifically and highly expressed by prostate cancer cells, making it a promising therapeutic target.
• This project will develop and optimize these tumor targeted RIPs for both prostate cancer imaging and therapy. They will test preclinical anti-tumor efficacy, biodistribution, and investigate the mechanism of action of targeted RIPs in preclinical prostate cancer models.
• If successful, this project will develop a new class of theranostic agents for prostate cancer, that are both safer and more effective than PSMA-targeted RLT.

What this means to patients: ¹⁷⁷Lu-PSMA-617 is a highly promising new radioligand therapy for patients with mCRPC, but unfortunately, it is not curative. Dr. Pandey and team will develop a new RLT and accompanying molecular imaging agent specific to prostate cancer, which uses a novel chemistry approach in which the agent becomes activated only upon entering tumor cells. This approach may lead to a more effective and safer treatment for prostate cancer, thus improving both the length and quality of life for patients.

2023 National Cancer Institute – PCF Young Investigator Award

Artificial Intelligence-Based Lesion Kinetics Assessment for the Selection of Therapeutic Targets for Focal SBRT in Patients with Oligoprogressive Metastatic Castration Resistant (mCRPC) and Biochemically Recurrent (BCR) Prostate Cancer

Krishnan Patel, MD

National Cancer Institute (NCI)

Mentors: Ravi Madan, Deborah Citrin

Description:

• Advances in molecular imaging and radiotherapy have enabled the development of metastasis-directed radiation therapy techniques. Clinical trials have demonstrated that metastasis-directed radiation therapy can improve progression-free survival times in patients with “oligometastatic” (up to 5 metastases) prostate cancer.
• However, studies are needed to understand whether metastasis-directed radiation therapy would benefit any patients with more advanced or wide-spread metastatic disease, and how many/which tumors would need to be radiated in these patients for benefit.
• Krishnan Patel is studying whether patients with an oligo-progressive phenotype (in which the minority of lesions drive progression) would benefit from metastasis-directed radiation therapy to “active” lesions alone.
• Patel and team are conducting a phase 2 clinical trial testing a whether an AI-based strategy can identify progressing lesions from PET scans, and if targeting metastasis-directed radiation therapy to only these lesions can prolong progression-free survival in patients with metastatic castration-resistant prostate cancer (mCRPC) on first-line therapy.
• Whether immune cell-based blood biomarkers can predict which patients will benefit from this approach will be investigated.
• The team will also analyze data from an ongoing trial to determine whether a subset of patients experiencing a biochemical recurrence (rising PSA after initial therapy) may benefit from the same AI-based target selection strategy.
• If successful, this project will develop a new AI-based approach to optimize the use of metastasis-directed radiation therapy in patients with biochemical recurrence and mCRPC. This may serve to reduce the toxicity from metastasis-directed radiation therapy by limiting the total treatment volume, as well as allow patients with biochemical recurrence to avoid initiating ADT or delay the need for further lines of therapy in patients with mCRPC.

What this means to patients:  Metastasis-directed radiation therapy is a treatment strategy that can delay disease progression in patients with a small number of metastatic tumors, but how to apply it in patients with more widespread disease is unknown. Dr. Krishnan Patel is developing an AI-based approach to identify active tumor lesions and determine whether radiation to only active lesions can prolong disease progression in patients with more advanced prostate cancer. This project will define a means by which to rationally and appropriately select lesions to treat with metastasis-directed radiation therapy, that will delay disease progression in patients with advanced prostate cancer who largely have stable disease on systemic therapy.

2023 Michael & Lori Milken – PCF Young Investigator Award    

Non-Invasive Prediction of Tumor Phenotypes, Therapeutic Targets, and Treatment Response in CRPC using ctDNA  

Robert Patton, PhD

Fred Hutchinson Cancer Center

Mentors: Peter Nelson, Gavin Ha

Description:

• Patients with metastatic castration-resistant prostate cancer (mCRPC) exhibit variable outcomes to most therapeutics. Intra-patient tumor phenotype heterogeneity is a likely driver of treatment resistance and the emergence of plastic tumor subtypes, such as neuroendocrine prostate cancer (NEPC), in patients that fail to respond to these therapies.
• There is an urgent and unmet need for novel diagnostics and biomarkers which can quantify intra-patient tumor heterogeneity, predict treatment outcomes, and predict the emergence of NEPC and other aggressive tumor subtypes. Cell-free tumor DNA (ctDNA) found in patients’ blood has the potential to noninvasively meet these needs, as it allows for frequent testing to monitor therapy efficacy and potential progression.
• Dr. Robert Patton is investigating the use of ctDNA biomarkers to monitor for additional prostate cancer phenotypes and to predict outcomes and treatment responses.
• In this project, Dr. Patton and team will determine the ability of ctDNA profiling to quantify the burden of NEPC in patients beginning treatment with androgen receptor signaling inhibitors (ARSI) and use this information to develop predictive tools.
• A novel genome-scanning tool will be developed to evaluate ctDNA for the emergence of alternate prostate cancer phenotypes.
• A methodology will be developed to use ctDNA to evaluate the expression of therapeutic targets such as PSMA and predict responses to treatments such as PSMA-targeted radioligand therapy.
• If successful, this project will result in the development of novel biomarkers and multi-omic approaches to monitor phenotype heterogeneity and clinically relevant molecular subtypes and predict treatment outcomes using ctDNA.

What this means to patients: Prostate cancer is highly heterogenous and also changes during therapy and disease progression. The development of noninvasive biomarkers to predict these changes and treatment responses will improve precision medicine treatment strategies. Dr. Patton and team will develop ctDNA-based biomarkers and prediction models with the ability to actively monitor treatment, influencing accurate clinical decisions in real time and providing a set of non-invasive, liquid biopsy-based tools to better cater treatment plans to a patient’s individual needs.

2023 Kovler Family Foundation – PCF Young Investigator Award         

Validation and Integration of Optimized Risk Stratification and Novel Biomarkers for the Personalization of Prostate Cancer Treatment

Soumyajit Roy, MBBS, MSc

Rush University Medical Center

Mentors: Daniel Spratt, Felix Feng, Alison Tree

Description:

• Prostate cancer is the leading cause of cancer treatment-associated disability worldwide. Despite multi-modality treatment approaches, half of the deaths from prostate cancer are due to failure to cure patients with presumed non-metastatic disease at diagnosis.
• To avoid both under- and over-treatment, more accurate ways are needed to distinguish patients who need aggressive therapy from those who don’t are needed.
• While novel strategies to better risk-stratify patients at the time of diagnosis are being developed, they require validation.
• Soumyajit Roy is working to validate the STAR-CAP system, a newly built prostate cancer prognostication model that uses more granular information on patient’s age, clinical stage, tumor grade, biopsy results, and PSA levels, to divide patients into nine stages each of which has different outcome probability compared to others. This system has outperformed current classification systems in preliminary studies for predicting patients’ long-term chances of dying from prostate cancer with standard curative treatments.
• In this project, Dr. Roy will validate the STAR-CAP system for adoption in national guidelines and compare it to existing risk stratification criteria, using data compiled from phase III randomized trials and will see how the trial results are translated in the context of STAR-CAP prognostic model.
• Further, he aims to integrate the STAR-CAP system with other risk-stratification and treatment selection biomarkers such as Decipher and Artera AI (an AI-based pathological feature-based biomarker), to optimize treatment selection for individual patients.
• If successful, this project will result in new national guidelines for prostate cancer prognostication and treatment selection at the time of diagnosis with localized disease. This will improve patient outcomes by better matching patients to the most appropriate treatment or management plans, reducing both under- and over-treatment.

What this means to patients: Prostate cancer prognostication models are used to guide treatment and management strategies at the time of diagnosis, and are meant to identify patients who can safely undergo active surveillance from those needing more aggressive and immediate treatment. However, these models are not highly accurate, and many patients end up being either over- or under-treated. Dr. Roy’s project will validate a new prostate cancer prognostication model that will improve the ability to tailor individualized risk-directed treatment, which will not only help reduce the burden of recurrent metastatic prostate cancer but also avoid undue treatment related morbidities in long-term prostate cancer survivors across the world.

2023 John Black Charitable Foundation – PCF Young Investigator Award      

N-Acetyl Aspartate Sustains Castration Resistant Prostate Cancer through Glucocorticoid Induced Sphingolipid Metabolism

Mark Salji, PhD, MB, Bchir 

University of Glasgow – Cancer Research UK Beatson Institute

Mentors: Hing Leung, Nima Sharifi, Ruth Morgan

Description:

• Castration-resistant prostate cancer (CRPC) is an advanced form of prostate cancer that has developed resistance to standard hormonal therapy. Understanding the mechanisms that drive the development of CRPC are critical to developing new and more effective treatments.
• The glucocorticoid receptor (GR) is related to the androgen receptor (AR) with some overlap in metabolism pathways and function, and may act as a bypass mechanism for tumors to overcome AR-inhibition in some patients with CRPC. Aberrant activation of GR may also account for the aggressive nature of CRPC in patients with advanced prostate cancer and obesity. However, targeting the GR pathway directly has resulted in side effects that have limited drug development; novel approaches to target GR are needed.
• Mark Salji and team are investigating the role of metabolites that may be downstream of GR in CRPC. They hypothesize that N-acetyl aspartate (NAA), a metabolite product of the prostate cancer enzyme PSMA, may be driven by GR activation and drive CRPC.
• In this project, Dr. Salji and team will identify the major source of NAA in CRPC and determine whether NAA supports sphingolipid metabolism. Whether this is a mediator of GR pathway activation, driving CRPC, will be investigated in preclinical models.
• Whether the NAA pathway can be inhibited by targeting PSMA and sphingolipids will be determined in preclinical models of CRPC, to provide the rationale for future clinical trials.
• If successful, this project will characterize the role of NAA in CRPC and identify therapeutic approaches to target the NAA pathway as a potential downstream mediator of GR in CRPC. This may lead to new treatment approaches for patients with GR-driven CRPC.

What this means to patients:  The glucocorticoid receptor (GR) appears to drive the development of treatment resistance in some patients with CRPC, and may play a role in the links observed between obesity and more aggressive disease.  Dr. Salji and team will determine the role of NAA as a potential downstream mediator of GR activation in CRPC, and identify approaches for targeting the NAA pathway. This could lead to new treatments for CRPC as well as be of interest to cardiovascular and metabolic research areas and the wider cancer metabolism research community.

2023 Alison and Jim Casey – PCF Young Investigator Award    

Rational Antibody-Drug Conjugate (ADC) Combinations for Metastatic Castration-Resistant Prostate Cancer (mCRPC)           

Galina Semenova, MD, PhD 

Fred Hutchinson Cancer Center

Mentors: John Lee, Peter Nelson

Description:

• Antibody-Drug Conjugates (ADC) are a class of treatments that consist of cancer antigen-targeting antibody attached to a cytotoxic drug (payload) via a chemical linker.
• While single agent ADC therapies are established treatments for several tumor types, none have been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Challenges associated with ADC therapy in mCRPC include tumor heterogeneity, treatment resistance, and toxicity.
• Dr. Galina Semenova and team have found that these challenges can be addressed by co-targeting multiple mCRPC cell surface antigens and using complementary payload combinations.
• In this project, Dr. Semenova and team will rationally design combinatorial ADC therapies for CRPC.
• To identify which tumor targets may be optimally co-targeted, the landscape of tumor antigen expression in lethal mCRPC specimens will be characterized. Antigen pairs that are present in different prostate cancer subsets but are not expressed together in normal tissues will be prioritized for subsequent therapeutic development.
• ADCs against prostate cancer antigen pairs such as PSMA and CEACAM5 will be evaluated as single agents and together in heterogeneous mCRPC models.
• ADCs bearing different classes of payloads will be tested in combinations to identify those that achieve synergistic cytotoxicity in a variety of prostate cancer models, without increasing side effects. The mechanisms of drug synergy will be investigated, and molecular markers of response will be determined.
• If successful, this project will result in the development of rationally designed ADC combination treatments that target multiple tumor antigens and carry different payloads, setting the stage for testing these in clinical trials.

What this means to patients:  Prostate cancer commonly develops resistance to targeted therapies by losing expression of the therapeutic target. Dr. Semenova and team are developing an assortment of rationally designed combination ADC treatments that target multiple tumor antigens and deliver complementary payload combinations. This could lead to new treatment strategies for patients that have increased efficacy with reduced toxicity.

2023 John Curtius – PCF Young Investigator Award

Development of a Novel Molecular-Based Treatment Strategy for De Novo Metastatic Castration-Sensitive Prostate Cancer using Long-Read Transcriptome Sequencing  

Takayuki Sumiyoshi, MD, PhD       

Kyoto University

Mentors: Takashi Kobayashi, Shusuke Akamatsu, Akihiro Fujimoto

Description:

• The standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC) is combination treatment with androgen deprivation therapy (ADT) plus docetaxel or androgen receptor pathway inhibitors. Individual patient outcomes can be variable due to inter-patient tumor heterogeneity, however, treatment selection remains largely empirical based on radiographic and pathologic assessment of disease.
• Improved predictive or prognostic biomarkers based on biology are needed to enable optimal treatment selection for each patient and improve treatment outcomes.
• Takayuki Sumiyoshi and team are using new “long read” RNA sequencing technology to develop novel biomarkers for optimally selecting treatments for patients from Japan with mCSPC.
• In this project, Dr. Sumiyoshi and team are using RNA sequencing data from a cohort of patients with mCRPC to identify novel gene-splice variants and fusion genes that associate with prostate cancer progression, and full-length gene transcripts that characterize the disease state.
• The association between molecular features and clinical outcomes will be characterized, to develop new biomarkers and subtype classifications.
• If successful, this project will result in the development of new biomarkers to better understand the biology of mCSPC and guide optimal treatment selection for patients with mCSPC.
• This project will also provide a comprehensive understanding of the molecular biology of prostate cancer among less well studied Japanese/Eastern Asian population, and allow deeper understandings of shared and ethnic-specific characteristics of prostate cancer.

What this means to patients:  Multiple standard-of-care treatment options are now available for patients with mCSPC, yet biomarkers to optimally match patients with treatments are lacking. Dr. Sumiyoshi and team will apply new RNA sequencing technology to mCSPC samples to provide further understanding of cancer genes associated with disease progression and develop novel risk stratification frameworks for patients diagnosed with mCSPC.

2023 Debbie & Mark Attanasio – PCF Young Investigator Award          

Targeting Disparities in Prostate Cancer via Liquid Biopsies: Novel Biomarkers and Therapeutic Targets

Amy Taylor, MD

University of Wisconsin

Mentors: Joshua Lang, Kosj Yamoah, Elisabeth Heath

Description:

• Black patients experience a dramatic disparity in prostate cancer incidence and mortality compared to White patients, yet Black patients have been the least represented in studies on molecular mechanisms that drive prostate cancer progression and treatment resistance.
• Disparities in equitable molecular testing have a cascading impact and create a knowledge gap that reinforces inaccurate assumptions regarding genomic testing and diminishes the odds of identifying crucial biomarkers needed to identify new therapeutic targets and features of aggressive disease in underrepresented populations.
• Amy Taylor and team are conducting a clinical trial to perform comprehensive genomic and molecular analyses of metastatic prostate cancer from Black patients to identify pathways driving tumor progression and treatment resistance and identify new therapeutic targets. These studies will use circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) from liquid biopsy (blood) samples collected over time.
• Baseline genomic alterations that predict aggressive disease will be identified.
• Comprehensive molecular profiling performed after progression on first line therapy will be used to establish a biomarker predictive of treatment resistance. Clinical features of resistant disease will also be identified.
• Molecular testing results will be compared between liquid biopsy and tumor tissues samples, to evaluate for data concordance.
• This trial will include patients from the VA, and the team will evaluate whether tissue testing frequency in this VA patient population differs from the VA National Precision Oncology Program.
• If successful, this project will provide rationale for longitudinal liquid biopsy analysis in the management of prostate cancer and will establish an approach that serves to eliminate disparities in access to molecular testing for Black patients Additionally, this project will identify blood-based biomarkers that are predictive of treatment resistance and will be the first large multi-institution study to evaluate molecular drivers of treatment resistance in this patient population.

What this means to patients:  Black patients experience disparately higher rates of prostate cancer incidence and mortality, yet are underrepresented in molecular testing and molecular profiling studies. Dr. Taylor and team are leading a clinical trial to enroll black patients with metastatic prostate cancer and perform molecular analyses of liquid biopsy samples, to identify molecular drivers and biomarkers of disease progression, outcomes, and treatment resistance. This will increase knowledge of genomics in prostate cancer, and provide a durable means by which to eliminate access barriers to molecular testing and reduce health disparities in underserved patient populations.

2023 The Stewart J. Rahr Foundation-PCF VAlor Young Investigator Award

Impact of Androgen Receptor Signaling Inhibitors on Depression and Anxiety in Veterans with Metastatic Hormone-Sensitive Prostate Cancer           

Phoebe Tsao, MD     

University of Michigan        

Mentors: Megan Caram, Joshi Alumkal

Description:

• Androgen receptor signaling inhibitors (ARSIs) have recently become the standard of care for treatment of metastatic hormone-sensitive prostate cancer (mHSPC). Prior work in castration-resistant prostate cancer (CRPC) demonstrated an association between ARSIs and incident depression, but little is known about the impact of ARSIs on depression and anxiety in patients with mHSPC.
• Patients with mHSPC receive ARSIs continuously for on average three years – over twice as long as patients with CRPC – increasing the potential for mental health toxicity. Experiencing depression while living with cancer has significant implications including decreased clinical trial participation, worse quality of life, and increased health care utilization, cost, and mortality.
• Depression and anxiety are of particular importance to Veterans with mHSPC as they tend to have higher rates of mental health symptoms and suicide than non-Veterans.
• Phoebe Tsao and team are investigating the extent and predictors of depression and anxiety in Veterans with mHSPC undergoing treatment with ARSIs, to identify optimal interventions that will not only help patients maintain their quality of life, but also remain on critical, standard of care therapy.
• In this project, Dr. Tsao and team will use the VA’s extensive electronic health records database to determine the frequency and severity of depression, anxiety, and suicide in Veterans with mHSPC beginning ARSIs.
• The association between experiencing depression or anxiety and prostate cancer outcomes will be determined.
• Mental health care practice patterns linked with improved mental health outcomes, prostate cancer outcomes, and overall survival will be identified.
• If successful, this project will elucidate the impact of long-term ARSI treatment on mental health and determine which mental health care delivery systems are most effective for mitigating mental health side effects. This will lay the foundation for future clinical trials testing interventions for reducing depression and anxiety in patients with mHSPC, ultimately helping all patients treated with ARSIs to live both longer and better.

What this means to patients:  ARSIs are standard-of-care therapies for patients for advanced prostate cancer but may increase risk for mental health toxicities including depression and anxiety. Dr. Phoebe Tsao and team are investigating the prevalence of mental health toxicities and identifying optimal mental health care interventions in Veterans with mHSPC undergoing treatment with ARSIs. These studies will help to identify optimal mental health care delivery systems that reduce depression and anxiety and increase adherence rates to ARSI therapy, ultimately improving survivorship in Veterans and all men with advanced prostate cancer.

2023 Kovler Family Foundation – PCF Young Investigator Award         

Defining Lineage-Specific PRC2 Action and Rational Co-Targeting of EZH1/2 in Prostate Cancer 

Varadha Balaji Venkadakrishnan, PhD

Harvard: Dana-Farber Cancer Institute (DFCI)

Mentors: Himisha Beltran, Myles Brown

Description:

• Neuroendocrine prostate cancer (NEPC) is an aggressive form of advanced prostate cancer for which there are limited therapeutic options.
• The development of NEPC is driven by lineage plasticity, a phenomenon in which cells change identity by losing features of one cell type (prostate luminal cells) and gaining those of another (neuroendocrine cells). Lineage plasticity is enabled by alterations in epigenetics – chemical modifications on DNA determining what genes a cell can and cannot express.
• EZH1 and EZH2 are major epigenetic regulators playing an important role in cell identity. EZH2 is dysregulated in prostate cancer, however, the role for EZH1 in prostate cancer is not known. While treatments that target EZH2 alone are being tested in trials, studies suggest that EZH1+2 inhibitors may be more effective.
• Dr. Varadha Balaji Venkadakrishnan is studying the role of EZH1 vs. EZH2 in NEPC and the impact of therapeutically targeting EZH1+2.
• In this project, Dr. Venkadakrishnan and team will elucidate the specific roles of EZH1 and EZH2 in gene regulation and cell fate determination during lineage plasticity in prostate cancer preclinical models.
• Mechanisms that increase sensitivity or drive resistance to EZH1+2-inhibitors will be identified, in order to nominate new combinatorial strategies to co-target with EZH1/2 in NEPC.
• If successful, this project will define the roles of EZH1 and EZH2 in the development of NEPC and identify optimal combinatorial strategies to target with EZH1/2.

What this means to patients:  NEPC is a highly aggressive form of advanced prostate cancer, for which new treatments are urgently needed. Dr. Venkadakrishnan and team will determine the role of EZH1 and EZH2 in NEPC and define optimal ways to target this pathway to reverse or prevent the development of NEPC. This will lead to new understandings of NEPC and new treatments for this lethal form of prostate cancer.

2023 Michael & Lori Milken – PCF Young Investigator Award    

Molecular Correlates with Prostate-Specific Membrane Antigen (PSMA) in Prostate Cancer          

Adam Weiner, MD    

University of California, Los Angeles (UCLA)

Mentors: Rob Reiter, Paul Boutros, Jeremie Calais

Description:

• Prostate cancer is heterogeneous in both biology and clinical phenotypes. Since treatment options and efficacies vary from one patient to another, current efforts to better characterize prostate cancer have resulted in new imaging strategies including positron emission tomography (PET) based on the protein prostate-specific membrane antigen (PSMA).
• While PSMA PET is expected to increase in use, PSMA expression can vary and no studies have evaluated cancer phenotypes for primary tumors detected or not detected by PSMA PET prior to treatment. Thus, there is an unmet need to correlate tumor biology with PSMA PET to optimize prostate cancer imaging and define individual treatment susceptibilities.
• Weiner and team are assessing the molecular and clinical profiles of primary prostate cancer with high vs low/no PSMA expression to derive PSMA PET thresholds that may be biologically and clinically relevant and to improve understanding of the mechanisms underlying PSMA expression.
• Gene expression analyses will be performed on primary prostate cancer samples to investigate the differences in molecular pathways in tumors with high vs low PSMA expression. Tumor samples from several clinical trials will be studied to investigate associations with various treatments for prostate cancer.
• The associations between tumor histology, molecular profiles, and PSMA PET levels will be investigated to determine whether PSMA PET positive tumors differ in aggressiveness based on tumor histology and molecular profiles, that are suggestive of treatment susceptibilities. These relationships will then be studied prospectively in a clinical trial, in patients with a high suspicion for prostate cancer undergoing imaging PSMA PET prior to prostate biopsy.
• If successful, this project will define and validate the molecular biology and clinical features of primary prostate cancer that is PSMA high vs low on PSMA PET imaging. This will help clinicians to better use PSMA PET imaging at the time of diagnosis to risk stratify patients and identify optimal treatment strategies.

What this means to patients:  Prostate cancer is highly heterogeneous with variations in aggressiveness and treatment susceptibilities. These biological variations are likely somewhat reflected in differences in PSMA uptake on PET which is an increasingly used technology for staging and detecting prostate cancer. Dr. Weiner and team will define the biological differences associated with differences in PSMA PET levels, which will help augment individualized cancer care for many future patients.

2023 Tom Murphy – PCF Young Investigator Award       

A Rapid Molecular Imaging Diagnostic for Neuroendocrine Prostate Cancer

David Wise, MD, PhD          

New York University  

Mentors: Shohei Koide, J.T. Poirier

Description:

• Androgen receptor signaling inhibitors (ARSIs) have revolutionized treatment of metastatic castration resistant prostate cancer (mCRPC) patients by significantly extending their survival and improving their quality of life. However, 10-20% of these patients will eventually develop neuroendocrine prostate cancer (NEPC), a highly aggressive mCRPC subtype that is resistant to all current treatments.
• NEPC expresses low/no levels of PSMA, and therefore cannot be imaged with PSMA PET, which is the current gold standard for imaging prostate cancer. The current approach to diagnosing NEPC lesions is limited to biopsies, which are not always feasible and carry inherent risk. There is an urgent need to develop non-invasive diagnostics for NEPC and novel NEPC-directed treatment approaches to improve outcomes in these patients.
• Neuroendocrine cancers have previously been shown to express delta-like ligand 3 (DLL3), a cell surface protein that can be detected with antibody-based imaging agents.
• In this project, Dr. Wise and team will develop a novel monobody-based DLL3-targeted PET imaging probe for identifying the presence of NEPC lesions.
• Monobody scaffolds, invented by the Koide Lab at NYU, because of their small size have more favorable kinetic features that lead to improvements in imaging performance.
• The team will conduct a phase 1 trial to evaluate the safety, feasibility, and performance of the DLL3-targeted PET agent in patients with NEPC.
• If successful, this project will result in a new PET imaging agent to diagnose the presence of NEPC in patients with advanced prostate cancer.

What this means to patients:  NEPC is a highly aggressive, untreatable form of advanced prostate cancer, for which both diagnostic agents and new treatments are urgently needed.  Dr. Wise and team will develop and clinically validate a new DLL3-targeted monobody-based PET imaging agent for the diagnosis of NEPC in patients. This will enable clinicians to more easily identify patients with NEPC, and help to guide treatment decisions in these patients.

2023 Chris and Katia Oberbeck – PCF Young Investigator Award

Uncovering Novel Biomarkers in Localized Prostate Cancer Through Radiomics and Digital Pathology

David D. Yang, MD

Harvard: Dana-Farber Cancer Institute (DFCI)

Mentors: Eliezer Van Allen, Paul Nguyen, Martin King

• Current guidelines for risk-stratifying patients with localized prostate cancer are based on clinical and pathologic data. This information is used to identify patients at elevated risk of disease recurrence and guide treatment recommendations.
• However, the performance of current clinical risk-stratification systems, even when combined with information from molecular biomarker tests, is limited, and many patients experience overtreatment or undertreatment. Improved biomarker strategies to guide treatment decisions in patients with localized prostate cancer are urgently needed.
• David D. Yang is investigating the application of AI methods to medical imaging and digitized histopathology slides to improve risk stratification in patients with localized prostate cancer.
• In this project, Dr. Yang and team will develop and utilize AI methods that can predict the risk of prostate cancer recurrence from multi-parametric MRI scans and digitized histopathology slides from prostate tumors.
• In addition, whether AI algorithms can be developed to predict the presence of certain genomic alterations from multi-parametric MRI scans and pathology slides will be investigated. Specifically, Dr. Yang will study whether these models can identify tumors with DNA damage repair alterations, which may identify patients who could benefit from treatment with PARP inhibitors or other therapies.
• If successful, this project will result in new AI-based biomarkers that use MRI or pathology images to better risk-stratify patients at the time of diagnosis and improve personalized management plans.

What this means to patients: Current clinical tools for risk-stratifying patients with localized prostate cancer are suboptimal, resulting in patients being overtreated or undertreated, which negatively impacts their disease outcomes or quality of life. Dr. Yang and team will develop new AI-based tools that use MRI scans or digitized histopathology images to better identify patients at elevated risk for disease recurrence and with DNA-repair defects, for whom treatment intensification strategies may be worthwhile to investigate. This could greatly improve outcomes for patients with localized prostate cancer.

2023 Michael & Julie Wirth – PCF Young Investigator Award     

Characterizing cPRC1 as a Mediator of Enzalutamide Resistance in Advanced Prostate Cancer   

Noah Younger, MD, PhD

University of California, San Francisco (UCSF)

Mentors: Felix Feng, David Quigley

Description:

• Androgen receptor signaling inhibitors (ARSIs) such as enzalutamide robustly increase patient survival in advanced prostate cancer. However, not all patients respond to treatment, and resistance inevitably develops with prolonged treatment exposure.
• Noah Younger and team have identified the canonical Polycomb Repressive Complex 1 (cPRC1), an epigenetic regulatory complex which represses target gene expression through several mechanisms, as a key mediator of resistance to enzalutamide.
• Among other biological roles, cPRC1 can repress expression of multiple lineage-specific genes to maintain a de-differentiated state in a variety of cell types. Prostate cancer de-differentiation and the accompanying loss of dependence on androgen signaling for cellular growth and survival is a known mechanism driving resistance to therapies targeting the androgen signaling pathway.
• In this project, Dr. Younger is investigating the role of cPRC1 in prostate cancer biology and resistance to treatment with ARSIs.
• To clarify the mechanisms by which cPRC1 promotes resistance to enzalutamide, the team will evaluate changes in gene expression and cell state caused by loss of cPRC1 in prostate cancer models.
• Whether inhibiting cPRC1 can sensitize prostate cancer cells to AR-targeted therapy will be investigated in preclinical models. This will validate inhibition of cPRC1 as a therapeutic strategy in prostate cancer.
• Whether cPRC1 may function as a predictive biomarker for ARSI treatment in advanced prostate cancer will be investigated using samples and data from patients.
• If successful, this project will characterize the role of cPRC1 in promoting resistance to enzalutamide, provide an early rationale and data in support of therapeutic targeting of cPRC1, and validate use of cPRC1 expression as a biomarker of response to ARSIs.

What this means to patients:  ARSIs are standard therapy for advanced prostate cancer, but resistance inevitably develops; new treatments are urgently needed.  Dr. Younger and team have identified cPRC1 as a key mediator of resistance to enzalutamide. This project will characterize the biological role of cPRC1 in prostate cancer and determine its potential as a biomarker for predicting responses to ARSIs and a therapeutic target to resensitize prostate cancer cells to treatment with ARSIs. This could lead to new treatment strategies to prevent therapeutic resistance and prolong the lives of patients with advanced prostate cancer.