2023 Lowell Milken – PCF Young Investigator Award
Wayne Brisbane, MD
University of California, Los Angeles
Mentors: Leonard Marks MD, Robert Reiter MD, Paul Boutrous PhD
- 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
- 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
- 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
- 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.
- 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
- 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
- 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.