The PCF Young Investigator Award-Class of 2022 recipients are:
2022 Todd Boehly – PCF Young Investigator Award
Vipul Bhatia, PhD
Fred Hutchinson Research Center
Mentors: John K. Lee, MD, PhD, Peter Nelson, MD
STEAP1 Directed Next-Generation Chimeric Antigen Receptor T Cell Therapies for Metastatic Castration Resistant Prostate Cancer (mCRPC)
Description:
- Cancer immunotherapies that have been highly effective in other cancer types are rarely effective in prostate cancer. New strategies to optimize immunotherapy in prostate cancer are needed.
- Chimeric antigen receptor (CAR) T cells are a type of personalized immunotherapy in which a patient’s own T cells are engineered to recognize and target their cancer. CAR T cells are highly effective in leukemias and lymphomas and are under development for other cancer types.
- In this project, Dr. Vipul Bhatia and team are developing CAR T cells that may be more effective in prostate cancer, by targeting two prostate cancer proteins instead of one.
- Dr. Bhatia will screen for potential alternate surface antigen, which is expressed upon STEAP1 antigen loss, and develop CAR T cells that target two proteins highly expressed on most prostate cancer cells but not normal cells and will test their efficacy in preclinical models.
- Genome wide CRISPR screen would be performed to identify gene elements that make STEAP1 CAR T cells less fatigued and more likely to continue attacking prostate cancer.
- If successful, this project will develop more effective next generation CAR T cells for prostate cancer and may lead to new clinical trials testing these treatments in patients.
What this means to patients: Dr. Bhatia and team are identifying new mechanism that governs resistance to existing CAR T cells and developing new CAR T cell immunotherapy for prostate cancer, that targets two prostate cancer proteins instead of one. This approach may be more effective as prostate cancer cells will be less able to evade this treatment. These preclinical studies may result in new agents that can be tested in trials and may ultimately improve outcomes in patients with prostate cancer.
2022 CRIS Cancer Foundation, Eustace Wolfington and Larry Leeds – PCF Young Investigator Award
Dimitrios Doultsinos , PhD
University of Oxford
Mentors: Claire Fletcher, PhD, Ian Mills, PhD
Exploring Synthetic Lethality of Targeting miR346-Unfolded Protein Response Dependent DNA Damage Response Mechanisms in Treatment-Resistant Prostate Cancer
Description:
- Cancer cells exhibit rapid proliferation, which is supported by altered metabolism and demand for greater rates of protein and nucleic acid synthesis. However, as expected for a production line, faster rates of protein generation may lead to greater numbers of mistakes in the “end product” protein structure. Accumulation of such erroneous proteins trigger stress signals that if not resolved may lead to cell death. To avoid death, cancer cells employ altered stress detection and response pathways.
- The unfolded protein response is one such pathway that senses stress caused by high levels of mis-folded proteins and reduces the rates of protein synthesis by governing processes like ERAD (protein clearance), metabolic rate and mRNA/miRNA cleavage.
- Dr. Dimitrios Doultsinos is investigating the biology of the unfolded protein response in prostate cancer, focusing on the roles of pathway regulators IRE1 and XBP1 as well as miR-346, a miRNA that has been shown to have clinical significance in prostate cancer as well as biological links to the unfolded protein response.
- In this project, Dr. Doultsinos will evaluate the biologic mechanisms by which IRE1, XBP1, and miR-346 synergize to coordinate stress responses to DNA damage.
- Whether targeting these factors may have therapeutic potential alone or in combination with other prostate cancer treatments will be evaluated in preclinical prostate cancer models.
- If successful, this project will uncover a new biology of prostate cancer and may lead to the development of new biomarkers and treatments that may be particularly relevant for patients with alterations in DNA damage repair pathways.
What this means to patients: Altered stress response pathways are a hallmark of cancer which allows tumor cells to rapidly grow and avoid normal death signals; however, these alterations may also create sensitivities that can be therapeutically targeted. Dr. Doultsinos will determine the biology of the unfolded protein response in prostate cancer and determine whether these alterations may act as biomarkers for sensitivity to certain treatments, or may be promising therapeutic targets themselves.
2022 Michael & Lori Milken – PCF Young Investigator Award
Renu Eapen, MBBS, FRACS (Urology)
Peter MacCallum Cancer Center
Mentors: Michael Hofman, MBBS, Declan Murphy, MC BCh BaO, FRCS Urol, FRACS, Paul Neeson, PhD
The Clinical and Immune Landscape Changes in Response to Upfront Lutetium PSMA Therapy in Patients with High-Risk Localized Prostate Cancer
Description:
- Lutetium PSMA (LuPSMA) is a new treatment consisting of a radioactive isotope attached to a prostate cancer-targeting molecule, which brings radiation directly to tumors anywhere in the body. LuPSMA was recently FDA-approved for metastatic castration-resistant prostate cancer and extends survival in these patients. The efficacy of LuPSMA in earlier disease states is currently being evaluated in clinical trials.
- LuPSMA is hypothesized to activate anti-cancer immune responses, by killing tumor cells in a way that alerts the immune system. However, the effects of LuPSMA on tumor immunity, and whether these immune effects contribute to its efficacy, are unclear.
- A clinical trial, LuTectomy, is underway at the Peter MacCallum Cancer Center to evaluate the efficacy and toxicity of up-front LuPSMA in patients with high-risk localized prostate cancer before undergoing radical prostatectomy.
- In this project, Dr Renu Eapen will use samples from patients enrolled into the LuTectomy trial to study changes in tumor-immune biology in response to LuPSMA treatment.
- How and what changes LuPSMA treatment causes in tumor immune cell types and whether the immune system responses to LuPSMA treatment are associated with patient outcomes of the clinical trial will be investigated.
- If successful, this project will improve understanding of how LuPSMA works on the immune microenvironment of prostate cancer and may potentially change management of high-risk prostate cancer.
- The LuTectomy data will inform future studies on upfront or early use of LuPSMA therapy alone or in combination with other treatments to improve outcomes and long-term survival in patients with high-risk localized prostate cancer.
What this means for patients: Dr. Eapen and her team are investigating the efficacy and immune mechanisms of action of LuPSMA as a new treatment strategy in patients with high grade prostate cancer. LuPSMA could represent a new treatment option to cure selected patients with localized prostate cancer. The LuTectomy data will be pivotal in designing the next potentially practice-changing clinical trial.
2022 Foundation Medicine – PCF Young Investigator Award
Nicolette Fonseca, PhD
University of British Columbia (UBC)
Mentors: Alexander Wyatt, D. Phil and Kim Chi, MD
Developing a Novel ctDNA-Based Approach to Patient Risk Stratification and Treatment Selection in mCRPC: A Large Population-Based Cohort Study
- Prostate cancer that has spread to other organs is incurable but new treatments have improved life expectancy. However, this disease is heterogeneous and can manifest with aggressive spread in some patients but remain slow growing in others. Refining treatment selection relies on tumor biomarkers that relay information about an individual’s unique tumor biology.
- Sampling tumor material requires invasive biopsies which are difficult to perform on patients with metastatic disease. Dr. Nicolette Fonseca is studying tumor DNA (ctDNA) released into the circulation as a non-invasive biomarker (i.e., liquid biopsy) in prostate cancer patients to inform outcomes and optimize treatment selection.
- Previous studies show that ctDNA in blood is closely linked to disease aggression, and that the quantity of ctDNA can be used to identify favorable and unfavorable prognostic subgroups.
- Dr. Fonseca will prospectively validate in >1000 samples whether ctDNA is a strong and independent biomarker of aggressive disease in patients with metastatic castration resistant prostate cancer (mCRPC) across different treatment contexts.
- Dr. Fonseca will build a user-friendly computational model that incorporates ctDNA together with clinical and radiographic risk factors to predict individualized life expectancy. This public and free model will be adaptable to different treatment scenarios and be able to use results from different blood ctDNA tests.
- If successful, this project will result in the development of practical online tools that can improve physician decision making about treatment selection and intensification, patient monitoring and clinical trial enrolment.
What this means to patients: Dr. Fonseca is developing low-cost, non-invasive, blood-based biomarker tests that evaluate circulating tumor DNA levels to predict outcomes and identify optimal treatment strategies for patients. This project will greatly accelerate precision medicine and improve outcomes for patients with prostate cancer.
2022 ZERO, John & Amy Phelan, and Alec & Kelly Gores – PCF VAlor Young Investigator Award
Jun Gong, MD
Cedars-Sinai Medical Center
Mentors: Stephen Freedland, MD, Edwin Posadas, MD
A Nationwide VA Study on Systemic Treatment Patterns in Black Patients with Metastatic Castration-Resistant Prostate Cancer
Description:
- Prostate cancer racial disparities remain a significant problem, with Black patients more than twice as likely to die from prostate cancer compared with White patients.
- Meanwhile, several clinical trials in metastatic castration resistant prostate cancer (mCRPC) have found that Black patients do as well or better than White patients. These clinical trials, however, have been limited by inclusion of small numbers of Black patients.
- Dr. Jun Gong is investigating treatment patterns and disparities in a nationwide Veterans Affairs (VA) cohort.
- In this study, Dr Gong and colleagues will use data from over 10 million Veterans in the VA to generate the largest known cohort of Black patients with mCRPC to assess non-biological factors of race that can drive disparities in systemic therapy outcomes between Black and White patients.
- The frequency of use of standard mCRPC drugs and differences in time to initiation of first-line therapy in mCRPC will be compared by race.
- How differences in treatment patterns impact survival outcomes between Black and White patients with mCRPC will be investigated.
- If successful, this project will determine how differences in treatment patterns contribute to racial disparities in systemic therapy outcomes using the largest nationwide VA cohort of Black and White patients with mCRPC to date.
What this means to patients: Disparities in prostate cancer mortality are a major problem. The contributors to these disparities are multifactorial and complex but include unequal access to health care. Dr. Gong and team will use a large VA data cohort to investigate how differences in treatment patterns and time to treatment initiation contribute to prostate cancer disparities. These findings will support strategies to improve access to standard and novel prostate cancer treatments while ensuring timely initiation of such treatments in Black patients, to reduce prostate cancer disparities.
2022 Todd Boehly – PCF Young Investigator Award
Roni Haas, PhD
University of California, Los Angeles (UCLA)
Mentor: Paul Boutros, PhD, MBA
Associating Germline Variants with Prostate Tumour Evolution and Lethality
Description:
- Prostate cancer is one of the most heritable cancer types, with ~57% of the risk of developing prostate cancer defined by inherited genetic variants. These variants differ dramatically across populations and are associated with clinical and therapeutic outcomes in ways that are difficult to predict. Uncovering the precise contributions of inherited genetic variants to prostate cancer development is critical for advancing patient management.
- Dr. Roni Haas is studying how genetic variants contribute to prostate cancer biology.
- A novel bioinformatic framework will be developed to map genetic variants to hallmark biological functions in cancer development and progression. This framework will include methods to predict the genetic component of pathway activities and link them to prostate cancer aggressiveness.
- In addition, the relationships between genetic variants and cancer DNA methylation will be investigated in advanced prostate cancer. DNA methylation is a type of epigenetic mechanism in which chemical marks on the DNA regulate gene expression. These chemical marks determine whether genes in a given region can be expressed or not by changing the ability of proteins to interact with the DNA, and controlling how condensed vs. open a DNA region is.
- If successful, this study will result in novel prognostic biomarkers for early detection and prediction of patient outcomes, and potential new targets for therapy. These will advance personalized clinical management in patients with prostate cancer.
What this means to patients: Prostate cancer is highly heritable, yet it remains unclear how genetic variants contribute to prostate cancer development and progression. Dr. Haas and team will link genetic variants to their role in disease development and progression, including how they contribute to hallmark cancer biology pathways and impact the cancer epigenome.
2022 Ronald & Victoria Simms – PCF Young Investigator Award
Ashley E. Holly, PhD, MBA
Cleveland Clinic
Mentors: Nima Sharifi, MD, Matthew Vander Heiden, MD, PhD
Elucidating Metabolic Health for Prostate Cancer Patients through Dietary Intervention (DINE Study)
Description:
- Active surveillance (AS) is often a preferred choice for patients with localized prostate cancer due to improved quality of life (QoL) compared to cancer therapies after diagnosis; however, for many patients, local or systemic treatment is necessary, which can adversely impact their metabolic health.
- There exists a pressing unmet need to identify lifestyle changes patients can make to improve their metabolic health prior to and during cancer therapies.
- Studies have suggested that diet can impact prostate cancer progression, however, more robust and conclusive studies are needed.
- Dr. Ashley E. Holly will conduct a two-part clinical trial to evaluate the impact of two dietary interventions, low fat and lower carbohydrate, on metabolism in (1) patients with a high suspicion of prostate cancer and (2) patients diagnosed with localized prostate cancer who are placed on active surveillance.
- The impact of these dietary interventions on patient and tumor metabolism, biomarkers of inflammation and metabolic disorders (such as diabetes), and on the composition of the gut microbiome will be evaluated. Patient dietary behavior, safety, and compliance will also be evaluated.
- If successful, this project will determine whether and how dietary interventions impact biology in patients and will provide a foundation for testing the impacts of dietary interventions on outcomes and quality of life in patients undergoing ADT or other treatments.
What this means to patients: Dr. Holly and team are conducting a controlled diet study to evaluate the impact of low fat or lower carbohydrate diets on the metabolic state of patients. This will provide knowledge of lifestyle changes patients can make to improve their outcomes when on active surveillance or undergoing treatment for prostate cancer.
2022 James Coulter – PCF Young Investigator Award
Tamara Jamaspishvili, MD, PhD
State University of New York (SUNY) Upstate Medical University
Mentors: Jeremy Squire, PhD, Alina Basnet, MD
Single-Center Retrospective Clinical Study of Artificial Intelligence (AI)-Based Protein Assessment of Three Tumor Suppressor Genes (“Triple-TSG”) for Improved Risk Stratification and Treatment Management of Advanced Prostate Cancer
Description:
- Hormonal therapy or androgen deprivation therapy (ADT), with or without radiation, is a mainstay of treatment for advanced prostate cancer. Unfortunately, treatment failure and development of hormone-insensitive or castrate-resistant prostate cancer (CRPC) is very common and alternative treatment options are limited or less effective. Therefore, it is crucial to timely and accurately stratify the patients who will likely respond to ADT and progress to lethal metastatic (mCRPC) or non-metastatic (nmCRPC) castrate-resistant prostate cancer.
- Dr Jamaspishvili’s research focuses on developing artificial intelligence (AI)-based tissue biomarker assessment to better risk stratify the diseases and identify patients at risk of disease progression, metastasis or treatment resistance.
- Improvement in biomarker research is urgently needed to advance precision medicine. Developing bias-free, objective, quantitative approaches in pathology practices is a prerequisite for precision medicine and biomarker-guided clinical trials.
- In this project, Tamara Jamaspishvili aims to clinically validate PTEN (tumor suppressor gene) loss assessment AI-based workflow that she and her colleagues at NCI have developed to predict prostate cancer recurrence and metastasis.
- Along with PTEN loss assessment, Dr Jamaspishvili and her multi-disciplinary team will assess two crucial tumor suppressor genes, p53 and Rb1, which are known to identify patients with more aggressive diseases and who are unlikely to respond to hormonal therapy. They will examine immunohistochemically stained scanned prostate cancer tissue images to unravel complex cellular and molecular relationships predicting disease progression, duration and response to hormonal treatment, and the development of hormone-resistant prostate cancer.
- Improving prostate cancer risk stratification and management will positively impact the quality of life of cancer patients by timely avoiding unnecessary side effects and finding effective treatment options early in the disease process.
- Dr Jamaspishvili and her team believe their cost-efficient, bias-free AI-based biomarker approach will be an excellent alternative to expensive genomic testing in low-to-middle income countries.
- If successful, this project will develop a new cost-efficient tissue test using prostate cancer tissue images to identify patients at risk for aggressive disease and poor outcomes and guide treatment management in such patients.
What this means to patients: In this project, Dr. Jamaspishvili and team will create an AI-based “triple-tumor suppressor gene” protein status assessment that uses pathology slides to improve risk stratification and help guide physicians in the treatment management of patients with high-risk, advanced prostate cancer. This could also serve as a cost-efficient screening method in low-to-middle income countries where genomic testing is still expensive and challenging.
2022 Michael & Lori Milken – PCF Young Investigator Award
Mayuko Kanayama, MD, PhD
Johns Hopkins University
Mentors: Jun Luo, PhD, Tamara Lotan, MD, William Isaacs, PhD
Functional and Treatment Implications of a Rare Germline HOXB13 Variant Affecting Risk of Lethal Prostate Cancer in Patients of African Ancestry
Description:
- Prostate cancer incidence and mortality is disproportionately high in patients of African descent. Many factors likely contribute to this disparity, including genetics, modifiable risk factors (e.g., diet, lifestyle), and unequal heath care access.
- Certain inherited variants in the HOXB13 gene are known to increase risk for prostate cancer. Dr. Mayuko Kanayama and others have recently identified and characterized a HOXB13 gene variant found specifically in patients of African ancestry that is associated with increased risk for aggressive prostate cancer and earlier age at diagnosis.
- In this project, Dr. Kanayama will define the functions of this HOXB13 variant in prostate cancer and determine whether it impacts response to various prostate cancer treatments, compared with a variant specific to European ancestry, and to “wild type” HOXB13.
- If successful, this project will establish rationale for screening patients of African ancestry for this variant and will identify effective treatment strategies for prostate cancer patients carrying this variant.
What this means to patients: Patients of African ancestry have a disproportionately high rate of prostate cancer incidence and mortality, the causes of which are multifactorial and unclear. Dr. Kanayama is investigating the contributions of a newly discovered variant in a prostate cancer risk gene that is found in people of African ancestry, and will determine how this variant impacts prostate cancer development and treatment responses, in order to develop new screening and treatment strategies for patients.
2022 Wild Dunes MGA – PCF Young Investigator Award
Dong-Woo Kang, PhD
Harvard: Dana-Farber Cancer Institute (DFCI)
Mentors: Christina Dieli-Conwright, PhD, MPH, Alicia Morgans, MD, MPH, Timothy Rebbeck, PhD
Exercise for Tumor Suppressive Impact in Black Patients with Prostate Cancer on Active Surveillance: The RE-MOVE Trial
Description:
- Active surveillance is a preferred management strategy for patients with early-stage prostate cancer, in which patients are closely monitored but treatments are withheld unless the disease becomes clinically significant. However, Black patients with low-risk prostate cancer have a higher risk of developing more aggressive disease and experiencing disease progression than White men, leading to concerns that active surveillance might not be an appropriate option for many.
- Emerging evidence from animal and human studies suggests that exercise has a great potential to benefit patients with prostate cancer undergoing active surveillance. Black patients have been markedly underrepresented in clinical exercise trials among cancer populations, and no exercise trials to date have been conducted in Black men with prostate cancer undergoing active surveillance.
- In the RE-MOVE Trial, Dr. Dong-Woo Kang is leading a randomized phase 2 clinical trial to test the effects of a 16-week aerobic and resistance training program vs. usual care on cancer progression (e.g., rise in PSA levels and growth of prostate cancer cell line) in Black patients with low-risk prostate cancer undergoing active surveillance.
- The effects of exercise on tumor-related biomarkers, physical fitness, psychosocial outcomes, and clinical events will also be investigated.
- If successful, this project will be a critical foundation for a larger phase 3 clinical trial to determine whether an exercise intervention can reduce or prevent prostate cancer progression in Black men with prostate cancer on active surveillance.
What this means to patients: Preclinical and epidemiologic studies have suggested that exercise can reduce prostate cancer progression, however few clinical trials have evaluated this. Dr. Kang’s project will determine whether aerobic and resistance training can reduce the risk of PSA progression in Black patients with low-risk prostate cancer undergoing active surveillance. This could lead to a new exercise-based intervention that will improve cancer outcomes, physical fitness, and psychological distress in this underrepresented group of cancer patients, which will contribute to reducing prostate cancer disparities.
2022 Henry M. Jackson Foundation for the Advancement of Military Medicine – PCF Young Investigator Award
Indu Kohaar, PhD
Center for Prostate Disease Research, Uniformed Services University of the Health Sciences; Henry M. Jackson Foundation for the Advancement of Military Medicine
Mentors: Gyorgy Petrovics, PhD, William Douglas Figg Sr., PharmD
Genetic Determinants of Aggressive Prostate Cancer in African American Patients
Description:
- African Americans have 1.7-fold higher incidence, and 2.1-fold higher mortality rates for prostate cancer than Caucasian Americans. Also, African Americans are generally younger at diagnosis, tend to present with more aggressive disease features, and are at a greater risk for metastasis.
- Inequities in socio-economic status and access to healthcare are large contributors to prostate cancer disparities. However, even after adjusting for the effects of socio-economic factors, racial disparities in prostate cancer incidence and mortality rates remain significant, suggesting a contribution from genetic factors.
- Dr. Indu Kohaar is using data from a cohort of African American and Caucasian American patients with prostate cancer who have equal access to healthcare and long-term clinical follow-up after initial treatment, to investigate genetic factors that may contribute to prostate cancer racial disparities.
- Pathogenic and likely pathogenic germline (inherited) variants in known prostate cancer risk genes, as well as a polygenic risk score, will be profiled in the patients in this cohort, to identify any associations with race, age or grade/clinical stage at diagnosis, and patient outcomes.
- The landscape of tumor mutations in lethal prostate cancer, especially African American patients, will be profiled. Whether there are any associations between germline genetic variants and mutations acquired by tumor cells, and whether such associations impact patients’ disease course or clinical outcomes, will be investigated.
- If successful, this project will lead to the identification of mutational signatures in aggressive prostate cancer genomes, with an emphasis on racial disparities.
What this means to patients: Understanding the factors that contribute to prostate cancer racial disparities will help to identify solutions to this significant problem. Dr. Kohaar and team will determine how inherited genetic variants may contribute to prostate cancer disparities and impact prostate tumor development and progression. This may enable the development of genetic and genomic biomarker tests to identify individuals at high risk for aggressive prostate cancer, that can be used to guide earlier screening and intervention and improve treatment strategies.
2022 Tony & Sage Robbins – PCF Young Investigator Award
Weiping Li, PhD
Columbia University Medical Center
Mentors: Michael Shen, PhD, Christopher Barbieri, MD, PhD Alberto Ciccia, PhD
Investigating the Role of Androgen Signaling in Promoting Genomic Instability in Prostate Cancer
Description:
- PARP-inhibitors are a precision medicine that have recently been approved for patients with metastatic castration resistant prostate cancer (mCRPC) who have mutations in certain genes that function in repairing damaged DNA. Currently ~20% of patients with mCRPC have these gene alterations and are eligible for this treatment.
- Whether PARP-inhibitors or other DNA-damaging treatments will also be effective in patients with genomic instability caused by other types of genomic alterations is not clear.
- Mutations in SPOP, which occur in ~10% of prostate cancer cases, result in hyperactivation of the androgen receptor (AR), which may promote genomic instability and affect the response to DNA-damaging therapeutic agents. Dr. Weiping Li is investigating this hypothesis.
- In this project, Dr. Li and team will investigate the mechanisms by which AR gene amplification or AR hyperactivation caused by SPOP gene mutations leads to DNA replication errors and impacts genomic stability, and whether these alterations alter prostate cancer cell responses to PARP-inhibitors or other DNA damaging treatments.
- If successful, this project may provide rationale for clinical trials testing PARP-inhibitors in advanced prostate cancer patients with AR hyperactivation caused by AR gene amplification or SPOP mutations.
What this means to patients: Dr. Li and team will investigate whether AR hyperactivation promotes prostate cancer genomic instability and increases responses to DNA-damaging therapeutic agents, including PARP-inhibitors. The findings from this project will help provide a molecular basis for future clinical trials that select prostate cancer patients with AR hyperactivation caused by AR amplification or SPOP mutations, for PARP-inhibitor treatment.
2022 Ronald & Victoria Simms – PCF VAlor Young Investigator Award
Neil Lin, PhD
University of California, Los Angeles (UCLA)
Mentors: Andrew Goldstein, PhD, Matthew Rettig, MD, Isla Garraway, MD, PhD
Using a Novel 3D Platform to Develop Metabolism-based Prostate Cancer Therapies
Description:
- Cancers often prefer to consume different metabolites than normal cells. Understanding what these are may enable the development of new therapeutic strategies to impair tumor progression.
- Tumor metabolism has been difficult to study in humans and in current experimental models. It remains unclear what fuels prostate cancer survival and growth at different stages of tumor progression, and how these preferences are influenced by tumor phenotype and progression to the castration-resistant disease state.
- Dr. Neil Lin has developed a novel 3D bioengineering platform that enables study of the exchange of nutrients between prostate cancer cells and their environment.
- In this project, Dr. Lin will use this system to determine how nutrients fuel prostate cancer cells vs. normal tissues and identify disease stage and castration-resistance influence patterns of nutrient consumption.
- Whether targeting nutrient metabolism can impair prostate cancer survival and growth will be investigated. Specifically, the impacts of dietary restriction and small molecules that target proteins involved in nutrient uptake and metabolism, will be evaluated in preclinical prostate cancer models.
- If successful, this project will define patterns of nutrient consumption in prostate cancer and identify targeted therapeutic strategies to specifically starve tumor cells.
What this means to patients: Cancer cells have a unique metabolism to support their constant and rapid growth. Dr. Lin and team will use a new 3D system to better understand prostate cancer metabolism and will test strategies to kill tumor cells by targeting tumor metabolism. These studies may ultimately lead to new treatments for patients.
2022 Eustace Wolfingon – PCF Young Investigator Award
Jacob Orme, MD, PhD
Mayo Clinic
Mentors: Alan Bryce, MD, Sean Park, MD, PhD, Haojie Huang, PhD
Overcoming NRG-1-mediated resistance in CRPC
Description:
- The identification of new therapeutic targets and treatments for advanced prostate cancer remains critical, as current treatment options will nearly always eventually fail.
- Dr. Jacob Orme and colleagues identified NRG-1 as a driver in the development of resistance to hormonal therapies in prostate cancer and as a promising biomarker and therapeutic target. They also found that mesenchymal cells, a type of non-cancer cell within tumors, are the main source of NRG-1 production.
- These findings served as rationale for initiating a phase 2 clinical trial testing enzalutamide in combination with pertuzumab and trastuzumab, which block the NRG-1 signaling partners HER2 and HER3, in patients with castration resistant prostate cancer (CRPC) with elevated NRG-1.
- In this project, Dr. Orme and team will determine the safety and efficacy of this combination treatment approach in patients with CRPC.
- The PARP pathway appears to drive NRG-1 production in mesenchymal cells. These mechanisms and whether PARP-inhibitors can prevent NRG-1 production, will be investigated using patient-derived prostate tumor models.
- If successful, this project will identify new treatment paradigms for preventing and reversing the progression of prostate cancer to the treatment-resistant CRPC state.
What this means to patients: Hormonal therapy is the backbone of treatment for aggressive and advanced prostate cancer, however treatment resistance inevitably occurs and patients progress to the CRPC state. Dr. Orme and team are conducting a clinical trial to test whether targeting NRG-1 may be effective in patients with CRPC, identifying the mechanisms, and investigating alternate therapeutic strategies for targeting this tumor driver.
2022 Robert Kraft, Adam Cohn, and Igor Tulchinsky – PCF Young Investigator Award
Ryan Park, MD
Harvard: Massachusetts General Hospital (MGH)
Mentors: Nir Hacohen, PhD, Anthony D’Amico, MD, PhD
Modulating T cell State to Prevent Radiation-Induced Lymphopenia and Enhance Anti-Tumor Immunity
Description:
- Radiation therapy (RT) is a standard therapy for localized prostate cancer. However, definitive RT can result in high rates of lymphopenia, a disorder of low numbers of lymphocytes (a major component of the immune system). Radiation-induced lymphopenia often persists over years and may permanently impact lymphocyte quality.
- Lymphopenia and poor lymphocyte quality can enable tumor recurrence and progression and are associated with poorer responses to both RT and immunotherapies.
- Understanding, predicting, and preventing radiation-induced lymphopenia is critical for improving and extending the lives of patients.
- Dr. Ryan Park is studying the mechanisms and consequences of radiation-induced lymphopenia.
- In this project, the radiation sensitivities of different types of T cells that are known to influence anti-tumor immunity will be defined. The genes that regulate radiation resistance vs sensitivity in T cells within tumor and lymph nodes will be determined.
- In addition, studies will be performed to identify small molecules that promote T cell but not tumor radiation resistance.
- If successful, this project will identify mechanisms of radiation-induced lymphopenia and identify new treatments that can be tested in clinical trials to limit radiation-induced lymphopenia.
What this means to patients: Radiation therapy is a standard treatment for prostate cancer but can deplete immune cells. Dr. Park and team will define the mechanisms that underlie the radiation sensitivity of various types of T cells and identify new treatments to prevent radiation-induced lymphopenia. This could lead to new treatments for patients that improve patient outcomes and responses to treatments including RT and immunotherapy.
2022 Joel Holsinger – PCF Young Investigator Award
Sagar Patel, MD
Emory University
Mentors: Martin Sanda, MD, Ashesh Jani, MD, Arthur Stillman, MD, PhD
Biomarker-Based Approaches to Understand and Predict Cardiovascular Toxicity from Androgen Deprivation Therapy in Patients with Prostate Cancer
Description:
- Cardiovascular (CV) mortality is a leading cause of death in patients with prostate cancer.
- Androgen deprivation therapy (ADT), a mainstay treatment for prostate cancer, is associated with increased CV disease risk, and some patients are susceptible to adverse cardiac events within months of initiating ADT. However, the mechanisms by which ADT drives heart disease remains unclear.
- Multiple studies suggest that CV risk is highest with gonadotropin releasing hormone agonists (e.g. Lupron, one of the most common forms of ADT in the United States), compared with other forms of ADT.
- Dr. Patel is conducting a randomized clinical trial of prostate cancer patients receiving ADT, to investigate how different forms of androgen-targeting therapies impact inflammation and cardiovascular biology.
- Cardiac imaging and genomic/immune-based biomarkers associated with CV risk will be evaluated to identify those that can predict which patients are at risk for CV toxicity from ADT.
- If successful, this project will identify mechanisms underlying CV toxicity from ADT and discover predictive biomarkers that can identify patients at highest risk for CV disease, which can be used to guide treatment and risk-reduction strategies.
What this means to patients: ADT is the primary therapy for advanced and aggressive prostate cancer but may increase risk for CV disease. Dr. Patel and team will investigate how Lupron versus other forms of ADT impact cardiovascular biology and identify biomarkers of CV disease risk. This project will support the development of a precision-based framework to predict CV toxicity from ADT and to inform personalized treatment decisions, such as use of alternative CV risk-reducing androgen-signaling inhibitors or early implementation of survivorship care.
2022 John Miller – PCF Young Investigator Award
Songhua Quan, PhD
Northwestern University
Mentors: Sarki Abdulkadir, MD, PhD, Navdeep Chandel, PhD
Targeting Metabolic Adaptation to Treat TP53-mutated Lethal Prostate Cancer
Description:
- Mutations in the TP53 gene are one of the most common drivers of cancer, including prostate cancer, making it an attractive therapeutic target. However, to date there are no effective treatments that specifically target tumors with TP53 mutations. Thus, identifying and targeting the Achilles heel of these cancers remain urgently needed.
- Dr. Songhua Quan has found that TP53-mutated castration-resistant prostate cancer (CRPC) exhibit high levels of asparagine production, and are sensitive to treatments that limit asparagine bioavailability.
- In this project, Dr. Quan will investigate the mechanisms by which different types of TP53 mutations control asparagine biosynthesis and how this alters prostate cancer cell metabolism.
- The role of asparagine metabolism in the development of resistance to hormonal therapy and progression to the CRPC state will be determined.
- Strategies to target asparagine production as a potential treatment option will be investigated in preclinical CRPC models.
- If successful, this project will provide insight into the functions of mutant TP53 and asparagine-mediated metabolic reprogramming in the development of CRPC, offering rationale for targeting this pathway as a new avenue to treat lethal prostate cancers with mutant TP53.
What this means to patients: New strategies are needed to prevent and treat CRPC. Dr. Quan’s project will determine the mechanisms by which TP53 mutations increase asparagine levels and alter tumor metabolism to drive CRPC, and provide preclinical rationale for therapeutically targeting these altered metabolic pathways. As the safety and clinical efficacy of drugs targeting asparagine metabolism are currently being tested in clinical trials, these studies may accelerate clinical testing of such treatments in patients with CRPC.
2022 National Cancer Institute – PCF Young Investigator Award
Michael Rothberg, MD
National Cancer Institute (NCI)
Mentors: Peter Pinto, MD, Adam Sowalsky, PhD
Identifying Tumor Microenvironmental Factors Associated with Oncologic Response to Irreversible Electroporation Focal Therapy for Prostate Cancer
Description:
- Contemporary options for management of primary prostate cancer involve either active surveillance, surgical removal, or radiation therapy delivered to the entire prostate gland.
- Focal therapy is an evolving treatment approach for select patients whereby specific portions of the prostate proven to contain cancer on biopsy are selectively treated sparing the involved prostate. Focal therapy typically has less side effects than current treatments directed towards the entire gland. However, focal therapies have been associated with rates of in-field recurrence between 16 to 50%, thus improved ways to select patients for this treatment are needed.
- Dr. Michael Rothberg is investigating the effects of the irreversible electroporation (IRE) focal therapy approach in prostate cancer to understand whether and how tumor microenvironmental (TME) factors may mediate resistance to IRE. IRE ablates tumor cells using a non-thermal mechanism that allows for better preservation of the surrounding tissues.
- In this project, Dr. Rothberg will use samples from patients undergoing IRE to characterize molecular changes during treatment and identify factors that influence the response to IRE. This data will be used to develop biomarkers to predict outcomes from IRE and to identify which patients have a higher likelihood of good outcomes with IRE.
- If successful, this project will result in the development of biomarkers that can aid in selecting patients for whom IRE may be appropriate as well as improve understanding of mechanisms of resistance to IRE focal therapy.
What this means to patients: Focal therapies have the potential to improve patient outcomes by reducing side effects from treating primary prostate cancer, however it is unclear which patients for whom this treatment approach is appropriate. Dr. Rothberg and team will define the biology of tumor responses and treatment failure to IRE focal therapy and develop biomarkers to identify patients who are likely to benefit from this approach.
2022 John Black Charitable Foundation – PCF Young Investigator Award
Ashwin Sachdeva, MBBS, PhD
University of Manchester
Mentors: Noel Clarke, ChM, Nicholas James, PhD, MBBS, Gerhardt Attard, PhD, MBBS
Mitigating Toxicity of Novel AR-Targeted Therapies in Advanced Prostate Cancer
Description:
- The use of newer, more intense androgen receptor (AR)-targeted therapies, such as abiraterone and enzalutamide, have dramatically improved survival in patients with advanced prostate cancer.
- However, these treatments can also increase risk of toxicities such as osteoporosis and sarcopenic obesity, contributing to increased risk of falls and fractures, which detrimentally impact quality of life.
- Metformin is an anti-diabetic drug that is being tested for its impact on survival in combination with ADT, in patients with advanced prostate cancer in the large multi-armed STAMPEDE clinical trial.
- Dr. Ashwin Sachdeva is investigating whether metformin, which can reduce the risk of metabolic syndrome and bone degeneration, may also mitigate ADT-related toxicities.
- In this project, Dr. Sachdeva and team will use CT and bone scan imaging data from ~3,000 patients on the STAMPEDE trial undergoing treatment with metformin + standard of care (ADT, +/- radiation therapy to prostate, +/- docetaxel or abiraterone) vs. standard of care alone, to measure changes in tumor burden, adipose tissue, skeletal muscle components, and bone architecture during treatment, to estimate changes in bone health and sarcopenia (loss of skeletal muscle mass and strength).
- If successful, this project will determine whether metformin can improve bone and/or metabolic health in patients with advanced prostate cancer undergoing ADT, and validate imaging methods as a means to assess bone and metabolic health.
What this means to patients: Hormone therapies are standard life-prolonging treatments for patients with advanced prostate cancer, but are associated with side effects that are detrimental to quality of life, including negative effects on bone and metabolic health. Dr. Sachdeva’s project will determine whether metformin can reduce risk of ADT-associated side effects including bone and metabolic disorders. This will ultimately help to minimize ADT-toxicity and reduce the risk of falls and fractures, which would improve quality of life of patients with advanced prostate cancer.
2022 Steve & Andrea Wynn – PCF Young Investigator Award
David Sanin, PhD
Johns Hopkins University
Mentors: Samuel Denmeade, MD, Edward Pearce, PhD
Effect of Androgen Receptor Modulation on Myeloid Cell Differentiation in Patients with Advanced Prostate Cancer
Description:
- Bipolar Androgen therapy (BAT) is an experimental treatment that cycles testosterone between extremely high and extremely low levels and has been demonstrated to be clinically effective against castration-resistant prostate cancer (CRPC). However, understanding how BAT works and how to improve its efficacy remains unclear.
- Increased inflammatory responses have been associated with clinical benefit, suggesting the immune system may drive responses to BAT.
- Dr. David Sanin’s project will determine immune changes in patients treated with BAT, including how modulating androgen receptor impacts the differentiation of myeloid cells.
- The effects of androgen receptor modulation will be explored in patient biopsies and in preclinical models.
- If successful, this project will provide an understanding of how BAT reprograms tumor immunity and determine whether treatments targeting myeloid cell function may improve the efficacy of BAT.
What this means to patients: BAT is a promising therapy for prostate cancer, yet more optimization is needed to improve efficacy and broaden patient benefit. Dr. Sanin and team will determine how BAT impacts tumor immunity, particularly myeloid cells, thus providing rationale for complementing BAT with immune-centric approaches in future clinical trials.
2022 Igor Tulchinsky, Robert Taubman and Richard Sandler – PCF VAlor Young Investigator Award
Martin Schoen, MD, MPH
Saint Louis Veterans Affairs Medical Center
Mentors: Kristen Sanfilippo, MD, MPH, Bruce Montgomery, MD, Ruth Etzioni, PhD
Outcomes of Metastatic Hormone Sensitive Prostate Cancer in Veterans: Facilitating Personalized Medicine
Description:
- Multiple standard-of-care treatment options are available for patients with metastatic hormone sensitive prostate cancer (mHSPC), such as such as androgen deprivation therapy (ADT) alone, ADT + androgen receptor (AR)-targeted therapies, and ADT + docetaxel. However, which treatment is best for each patient remains unclear, particularly among patients with comorbidities and patient groups that have been underrepresented in clinical trials.
- In this project, Dr. Martin Schoen will use data from the large, nation-wide Veterans Health Administration database to study Veterans with mHSPC and identify associations between treatment choices and patient outcomes.
- These data will be used to build a model of metastatic prostate cancer progression and survival with different treatments that accounts for both features of the cancer and patient characteristics.
- The differences in treatment outcomes will be evaluated in understudied and vulnerable populations including African Americans, veterans with cardiovascular disease/diabetes, patients over the age of 75, and those with high-volume prostate cancer.
- If successful, this project will result in biomarkers that can guide clinicians in selection of personalized regimens that are most appropriate for newly diagnosed mHSPC patients.
What this means to patients: Accurate prediction of outcomes in patients treated for mHSPC is necessary to select optimal therapies for individuals based on their tumor and patient characteristics. Dr. Schoen’s project will create a new predictive model of mHSPC treatment and outcomes in veterans with prostate cancer, which will accelerate personalized medicine for mHSPC.
2022 Michael & Tricia Berns – PCF Young Investigator Award
Laura Sena, MD, PhD
Johns Hopkins University
Mentors: Samuel Denmeade, MD, Erika Pearce, PhD
Understanding Metabolic Differentiation of Prostate Cancer by Bipolar Androgen Therapy
Description:
- The cyclical administration of high dose testosterone, termed bipolar androgen therapy (BAT), is a promising treatment strategy for patients with advanced prostate cancer, but is not curative.
- Dr. Laura Sena will investigate whether BAT induces cancer cell metabolic reprogramming that promotes therapy resistance.
- She will investigate whether disruption of this metabolic reprogramming will enhance the efficacy of BAT in preclinical models.
- If successful, this project will provide rationale for a clinical trial testing the combination of BAT and metabolism-targeted therapy in patients with advanced prostate cancer.
What this means to patients: Bipolar androgen therapy is a promising treatment, however more optimization is needed to improve its efficacy. Dr. Sena and team will determine whether alterations in tumor metabolism influence the response to BAT and whether the efficacy of BAT can be improved with the addition of treatments that target tumor metabolism. This may lead to clinical trials testing new treatment approaches for patients with advanced prostate cancer.
2022 Point Biopharma – PCF Young VAlor Investigator Award
Marina Sharifi, MD, PhD
University of Wisconsin
Mentors: Joshua Lang, MD, Shuang Zhao, MD, MSc, Brett Carver, MD
Elucidating Molecular Correlates of PSMA Expression in Prostate Cancer Liquid Biopsies to Identify Biomarkers of Response and Resistance to PSMA-Targeted Therapies
Description:
- The PI3K pathway is the most commonly mutated tumor-driving pathway in prostate cancer, with mutations occurring in more than 50% of mCRPC. However, clinical efficacy of PI3K pathway inhibitors has been modest, even in patients with PI3K pathway-mutated prostate cancer.
- Early data suggest the newly approved treatment LuPSMA may synergize with PI3K pathway-targeting treatments. LuPSMA is a molecular radiotherapy that targets the prostate cancer-associated protein PSMA.
- Dr. Sharifi’s project will define the mechanisms by which synergy between LuPSMA or PI3K pathway inhibitors may occur.
- Whether and how PI3K pathway mutations affect PI3K pathway activity and PSMA levels will be investigated.
- Circulating tumor cells from patients on clinical trials will be studied to determine whether they may be useful liquid biopsy biomarkers for determining PI3K pathway status in patients.
- If successful, this project will define the biology of how the PI3K and PSMA pathways intersect, and provide rationale for a precision medicine clinical trial testing the combination of PI3K-inhibitors and LuPSMA.
What this means to patients: LuPSMA is a promising new treatment for mCRPC, yet patients eventually experience disease recurrence and progression, thus additional optimization is needed. Dr. Sharifi and colleagues will investigate mechanisms of synergy between LuPSMA and PI3K pathway inhibitors and develop liquid biopsy tests that can be used as biomarkers for selecting patients who may benefit from this combination treatment. This may lead to new clinical trials testing this approach in patients.
2022 Todd Boehly – PCF Young Investigator Award
Raunak Shrestha, PhD
University of California, San Francisco (UCSF)
Mentors: Felix Feng, MD, David Quigley, PhD
Investigating Chromatin Reprogramming to Overcome Treatment Resistance in Advanced Prostate Cancer
Description:
- The development of resistance to second generation AR-signaling inhibitors (ARSIs) and progression to metastatic castrate-resistant prostate cancer (mCRPC) represents a huge obstacle to the improvement of patients’ clinical outcomes.
- A common mechanism that drives development of mCRPC are epigenetic alterations – changes in the physical structure of DNA and its accessibility that control which genes can and can’t be expressed.
- In this project, Dr. Raunak Shrestha will characterize epigenetic changes in different molecular subtypes of mCRPC that have developed resistance to ARSI, compared with mCRPC that have not been treated with ARSI.
- Molecular regulators of ARSI resistance will be identified.
- The role of known mCRPC drivers, such as AR and FOXA1, in epigenetic changes during ARSI resistance will be defined.
- If successful, this project will create the largest integrated analysis of how epigenetic alterations contribute to mCRPC lineage plasticity and ARSI treatment resistance and identify transcriptional regulators of these changes.
What this means to patients: The development of mCRPC and resistance to ARSI is a major clinical problem in prostate cancer. Dr. Shrestha and team will comprehensively define the epigenetic alterations and molecular drivers that underlie these features, which will potentially help nominate candidate therapeutic targets and new strategies to counter ARSI resistance as well as identify potential biomarkers of ARSI resistance.
2022 John Tyson – PCF Young Investigator Award
Bilal A. Siddiqui, MD
The University of Texas MD Anderson Cancer Center
Mentors: Christopher Logothethis, MD, Sumit Subudhi, MD, PhD
Bispecific Immunotherapy Strategies to Overcome the Immunosuppressive Prostate Tumor Microenvironment
Description:
- Prostate cancer has a highly immunosuppressive tumor microenvironment, which has contributed to poor responses to immunotherapies. This appears particularly true with checkpoint immunotherapy treatment in patients with bone-predominant metastatic disease, the most common site of metastasis in prostate cancer.
- Bispecific immunotherapies simultaneously bind to tumor and immune cells, to bring immune cells directly into contact with tumor cells and kill them. Studies suggest that bispecifics may be able to better promote immune cell infiltration into the prostate bone tumor microenvironment, compared with checkpoint immunotherapies.
- Dr. Bilal Siddiqui is investigating the mechanisms of response and resistance to bispecific immunotherapies in prostate cancer.
- In this project, Dr. Siddiqui and team will determine immune cell types and locations within the tumor microenvironment that are associated with response to bispecifics versus checkpoint immunotherapies in patients with advanced prostate cancer.
- Mechanisms of resistance to treatment with bispecifics versus checkpoint immunotherapies in patients with advanced prostate cancer will be identified.
- Co-clinical studies will be performed to validate mechanisms of resistance in bone vs. soft tissue sites of prostate cancer metastases and identify possible new treatment combinations that can overcome immunotherapy resistance.
- If successful, this project will identify mechanisms and biomarkers of response and resistance to bispecific immunotherapies in metastatic prostate cancer and identify possible new rational treatment combinations.
What this means to patients: Immunotherapy can be a powerful form of cancer treatment but has yet to be optimized in prostate cancer. Dr. Siddiqui will identify mechanisms of response to bispecific immunotherapies in metastatic prostate cancer. This will enable the identification of rational combination approaches to improve clinical outcomes in patients with metastatic prostate cancer.
2022 Sage & Tony Minella – PCF Young Investigator Award
Woogwang Sim, PhD
University of California, San Francisco (UCSF)
Mentor: Rohit Bose, MD, PhD
PTEN/P53 Altered Prostate Cancer has Unique Role for Tumor Associated Macrophages upon Apalutamide Resistance
Description:
- A major problem in prostate cancer is the development of resistance to hormonal therapies and progression to castration resistant prostate cancer (CRPC), which can be driven by several types of molecular alterations. Understanding the biology of the various forms of CRPC is critical toward developing new treatments.
- Dr. Woogwang Sim is studying the biology of an aggressive form of CRPC driven by combined alterations in PTEN and P53, which occur in ~15% of mCRPC cases.
- Dr. Sim has previously found that PTEN/P53-mutant CRPC have a substantial increase in tumor-associated macrophages, a phenomenon which is not seen in a form of CRPC driven instead by RB1 and P53 mutations.
- In this project, Dr. Sim will determine whether tumor associated macrophages contribute to androgen receptor (AR)-targeted therapy resistance in PTEN/TP53-mutant prostate cancer.
- The molecular interactions between tumor associated macrophages and tumor cells in AR therapy-resistant PTEN/TP53-mutant prostate cancer will be investigated.
- If successful, this project will define the role of tumor associated macrophages in PTEN/TP53-mutant prostate cancers and AR therapy resistance, and may identify new ways to target interactions between tumor associated macrophages and tumor cells.
What this means to patients: PTEN/P53-mutant CRPC is a highly aggressive form of CRPC that comprises ~15% of CRPC cases. Dr. Sim and team will determine whether tumor associated macrophages are critical drivers of treatment resistance and progression in PTEN/P53 mutant CRPC, which would provide rationale for targeting tumor associated macrophages as a strategy to prevent or delay resistance to AR-targeted therapies.
2022 Nelson & Claudia Peltz – PCF Young Investigator Award
Udit Singhal, MD
University of Michigan
Mentors: Todd Morgan, MD, Felix Feng, MD, Daniel Lin, MD
Leveraging Artificial Intelligence for Optimization of Active Surveillance and Genetic Testing in Patients with Localized Prostate Cancer
Description:
- Active surveillance is an established management strategy for patients with low-risk prostate cancer. However, no reliable biomarkers exist to predict progression on active surveillance with high fidelity.
- There also remains a critical need to develop a strategy for improved detection of inherited mutations in patients with localized prostate cancer.
- Dr. Udit Singhal is developing and validating novel artificial intelligence (AI) biomarkers using digital pathology images for prediction of progression on active surveillance and for detection of heritable germline prostate cancer risk alterations.
- In this project, Dr. Singhal will develop an AI algorithm that can evaluate digital pathology slides and predict risk of progression for patients on active surveillance for prostate cancer.
- An AI biomarker to identify patients with localized prostate cancer likely to harbor underlying germline mutations in DNA damage repair genes will be developed and validated.
- If successful, this project will lead to the development of automated, AI biomarkers for predicting progression on active surveillance and detecting germline pathogenic variations from digital pathology in patients with localized prostate cancer.
What this means to patients: The integration of population-wide, AI-based biomarkers into the routine clinical care of patients with localized prostate cancer will improve risk stratification and predict therapy responses. Dr. Singhal and team will develop AI-based digital pathology methods to predict progression on active surveillance and to detect germline pathogenic variations in patients with localized prostate cancer. These findings will help facilitate prostate cancer prognostication and guide treatment decisions based on germline mutational status, to ultimately improve patient outcomes.
2022 John & Daria Barry – PCF VAlor Young Investigator Award
Alexandra Sokolova, MD
Oregon Health & Science University (OHSU)
Mentors: Bruce Montgomery, MD, Heather Cheng, MD, PhD
Cascade Genetic Testing in Prostate Cancer: Evaluating and Overcoming Barriers
Description:
- Approximately 12% of patients with metastatic prostate cancer have inherited mutations in DNA damage repair genes that likely contributed to the development of their cancer. This has significant implications not only for treatment decisions but for cancer prevention and early detection strategies in the families of these patients.
- If a patient has inherited a mutation, there is a one-in-two (50%) risk that their children or siblings inherited the same mutation and have a higher risk for developing certain types of cancers. Therefore, there are recommendations for increased cancer screening and possibly risk-reduction surgery for people with some inherited mutations.
- “Cascade genetic testing” is recommended for relatives of patients that carry heritable cancer risk mutations. However, the current paradigm in which patients who carry these genes are encouraged to advise their relatives to undergo cascade genetic testing without direct assistance from genetics providers, has put the burden on the patient and may contribute to low uptake of genetic testing in family members.
- Dr. Alexandra Sokolova’s project will test a provider-initiated testing procedure for cascade genetic testing of family members of Veterans with prostate cancer who carry heritable prostate cancer risk mutations. In this paradigm, providers contact relatives for testing.
- Prostate cancer patients in the VA who carry heritable prostate cancer risk mutations will be randomized to provider-initiated vs. patient-initiated cascade genetic testing.
- Whether provider-initiated cascade genetic testing results in higher numbers of individuals who complete testing, less distress, and higher satisfaction, will be evaluated.
- The barriers to each approach will be determined, including the impact of any barriers associated with ethnicity, income, and education. The costs of each approach will also be compared.
- If successful, the provider-initiated procedure will result in a more effective and less costly cascade testing, and cause less stress to patients and their families.
What this means to patients: Approximately 12% of patients with metastatic prostate cancer carry heritable mutations that contributed to their disease. Relatives of these patients are encouraged to get genetic testing to determine their own carrier status. Dr. Sokolova and team will develop provider-initiated cascade genetic testing measures as an effort to increase the numbers of family members who get tested, which will ultimately improve cancer prevention in families with inherited cancer syndromes and improve equity and equality in access to cascade genetic testing.
2022 John Black Charitable Foundation – PCF Young Investigator Award
Vasilis Stavrinides, MD, PhD
University College London
Mentors: Mark Emberton, MD, Emek Demir, PhD
Immune Topology as a Predictor of Prostate Cancer Outcome in Imaging-Based Cohorts
Description:
- Multiparametric magnetic resonance imaging (mpMRI) is a standard imaging option that aids in the diagnosis of prostate cancer. However, inflammation can influence prostate cancer outcomes, yet is understudied in MRI-based studies.
- Dr. Vasilis Stavrinides is developing pathology-based tools that evaluate the immune features of the tumor microenviroment, as biomarkers to aid in prognostication of patients who are diagnosed by MRI.
- In this project, Dr. Stavrinides and team will create a tool that can map the locations of different types of immune cells in tumor tissue samples and use this to determine whether any immune patterns correlate with clinical tumor features or patient outcomes.
- Whether any immune patterns correlate with MRI features will also be evaluated.
- If successful, this project will result in the development of immune-based spatial pathology biomarkers that improve the detection of potentially aggressive MRI-visible prostate cancer at diagnosis and predict biochemical recurrence after surgery, which can help to inform patient management and treatment decisions.
What this means to patients: Improved methods to predict prostate cancer aggressiveness and clinical outcomes at diagnosis are needed to better select the most appropriate treatment strategies for individual patients. Dr. Stavrinides’ project will develop a pathology-based biomarker for use in concert with MRI at diagnosis, that will improve identification of those at highest risk of progression, disease recurrence, and metastatic spread, to ultimately improve patient management, treatment decisions, and outcomes.
2022 Ms. Lucy Shostak & Dr. Elliot Abramowitz-PCF Young Investigator Award
William Storck, PhD
University of Michigan Rogel Cancer Center
Mentor: Joshi Alumkal, MD
Development of a Rational Co-Targeting Approach to Block Neuroendocrine Prostate Cancer Cell Survival
Description:
- Neuroendocrine prostate cancer is a highly aggressive form of the disease that is characterized by activation of a brain or nerve-like program, rather than a glandular program typically found in prostate cancer. Unfortunately, neuroendocrine prostate cancer tumors are becoming more common because of new hormonal medicines used to treat advanced prostate cancer.
- There are currently no effective treatments for patients with neuroendocrine prostate cancer. Understanding the key proteins important for causing neuroendocrine prostate cancer is a critical step towards developing effective treatments.
- Dr. William Storck and team have determined that BET bromodomain proteins are important for turning on the brain or nerve-like program found in neuroendocrine prostate cancer tumors. Drugs that block BET bromodomain proteins have shown activity in neuroendocrine prostate cancer tumors in clinical trials led by this team. However, progression is universal.
- Dr. Storck seeks to build on results with BET bromodomain inhibition and identify rational combinations with other medicines in order to control neuroendocrine prostate cancer tumors more effectively. The efficacy of these combinations will be tested in the laboratory using mouse and patient neuroendocrine prostate cancer tumors.
- If successful, this project will provide the rationale for a new treatment strategy to control neuroendocrine prostate cancer more effectively so that we may begin clinical trials.
What this means to patients: Neuroendocrine prostate cancer is a highly aggressive form of advanced prostate cancer for which treatments are urgently needed. Dr. Storck will identify new combinations of medicines to treat neuroendocrine prostate cancer more effectively. The completion of the proposed work may set the stage for new clinical trials focused on patients with neuroendocrine prostate cancer in the near-term.
2022 CRIS Cancer Foundation and Clay Hamlin – PCF Young Investigator Award
Alexander Wurzer, PhD
Technical University of Munich
Mentor: Matthias Eiber, MD
Investigating Radiohybrid PSMA-Ligands for Targeted Alpha Therapy, with the Aim to Improve Targeted Alpha Therapy of Metastatic Castration-Resistant Prostate Cancer
Description:
- Molecular radiotherapy is a new class of treatment for prostate cancer, which include the recently FDA-approved treatment, LuPSMA. This type of treatment consists of a radioactive isotope attached to a tumor-targeting molecule, which brings radiation directly to tumors anywhere in the body. However, LuPSMA is not curative, and more optimization is needed.
- LuPSMA uses beta particle-emitting radioisotopes. Alpha particle-emitters such as 225 Actinium-PSMA are more potent, and a promising option for improving the efficacy of molecular radiotherapy. However, some severe toxicities including salivary gland toxicity, have been anecdotally reported with 225 Actinium-PSMA, and long-term outcomes and side effects have yet to be rigorously studied.
- Dr. Alexander Wurzer is studying the radioactive properties of 225Actinium-PSMA in the body.
- Dr. Wurzer will develop “radiohybrid” tool compounds, which allow PET imaging but use non-radioactive metals that chemically mimic the properties of Actinium, to predict the biodistribution of 225 Actinium-PSMA in patients.
- These radiohybrid compounds will be studied in animal models to estimate where in the body 225 Actinium-PSMA and the daughter isotopes produced during radioactive decay, may accumulate over time.
- If successful, this data will help to predict the accumulation of 225Actinium-PSMA radioactivity in sensitive organs, such as salivary glands and kidneys, and predict long term toxicities. This data can be used to guide the establishment of optimal radiation doses and treatment protocols of 225Actinium-PSMA, to minimize side effects.
What this means to patients: Alpha-particle emitting molecular radioligand therapies are experimental treatments that require further optimization to limit toxicities. Dr. Wurzer and team will investigate the radioactive properties of these compounds in animal models, in order to understand where radioactivity will accumulate over time, and what organs would be affected. This will help to optimize dosing and treatment protocols, to reduce toxicity and maximize the efficacy of these promising treatments.
2022 Silas Chou – PCF Young Investigator Award
Lanbo Xiao, PhD
University of Michigan
Mentor: Arul Chinnaiyan, MD, PhD
Targeting SWI/SNF Chromatin Remodeling Complex to Combat Castrate-Resistant Prostate Cancer
Description:
- Although androgen deprivation therapy (ADT) is the most efficient clinical regimen for advanced prostate cancer, nearly all ADT-treated individuals will eventually develop resistance and progress to the castration resistant prostate cancer (CRPC) state. Novel therapeutic strategies are urgently needed.
- SWI/SNF complex is a regulator of the 3D structure of chromatin, thereby controlling which genes can and cannot be expressed. SWI/SNF genes are mutated in ~20% of human cancers, and have been implicated in prostate cancer progression to CRPC.
- Dr. Lanbo Xiao is studying the role of the SWI/SNF complex as a driver and therapeutic target in prostate cancer.
- In this project, Dr. Xiao and team will test the efficacy of a novel “PROTAC” drug that degrades the ATPase subunits of SWI/SNF complex , SMARCA2 and SMARCA4, in preclinical models of CRPC.
- The mechanisms by which SWI/SNF complex alters anti-tumor immune cells in the tumor microenvironment will be investigated. Whether targeting SWI/SNF complex reverts immune alterations will be determined.
- The role of SWI/SNF in the development of neuroendocrine prostate cancer (NEPC), a highly aggressive form of CRPC will also be studied.
- If successful, this project will deepen our knowledge of the function of the SWI/SNF complex in prostate cancer biology and shed light on future applications for SWI/SNF-targeting therapeutics in advanced prostate cancer.
What this means to patients: New treatments are urgently needed for patients with advanced prostate cancer. Dr. Xiao’s project will provide preclinical rationale for a new SWI/SNF-targeting treatment in CRPC, setting the stage for clinical trials. This project will also define the role of SWI/SNF in altering anti-tumor immunity and in the development of NEPC, a highly lethal form of prostate cancer.
2022 Dr. Elliot and Nan Abramowitz – PCF Young Investigator Award
Xiaolin Zhu, MD, PhD
University of California, San Francisco (UCSF)
Mentors: Felix Feng, MD, Rahul Aggarwal, MD, David Quigley, PhD
Investigating SSTR1 as a Novel Therapeutic Target for Acquired Resistance to Androgen Receptor Signaling Inhibitors in Advanced Prostate Cancer
Description:
- Androgen receptor (AR)-targeted therapies, including abiraterone and enzalutamide, are widely used to treat advanced prostate cancer and have significantly improved patient outcomes. Unfortunately, resistance to these treatments inevitably develops, and the duration of response is particularly short in most patients with metastatic castration-resistant prostate cancer (mCRPC). Understanding and overcoming resistance to AR-targeted therapies is an important area of prostate cancer research.
- Dr. Xiaolin Zhu is studying the molecular mechanisms of resistance to AR-targeted therapies in mCRPC, and previously identified downregulation of SSTR1 as a possible mechanism.
- In this project, Dr. Zhu and colleagues will investigate the role of SSTR1 in resistance to AR-targeted therapies in preclinical models of mCRPC.
- Whether agents that activate SSTR1 can reduce tumor drug resistance to AR-targeted therapies will be investigated in preclinical models.
- In addition, the mechanisms by which SSTR1 is downregulated in mCRPC will be studied using samples from patients with mCRPC.
- If successful, this project will determine the role of SSTR1 in resistance to AR-targeted therapies and establish its potential as a new therapeutic target.
What this means to patients: The development of resistance to AR-targeted therapies is a critical problem in the treatment of mCRPC. Dr. Zhu’s project will determine whether and how downregulation of SSTR1 plays a role in this process, and whether targeting SSTR1 can prevent development or progression of mCRPC. This may provide rationale for clinical trials investigating SSTR1 agonists as a potential novel therapy for patients with mCRPC.
2022 William C. and Gina B. Carithers – PCF Young Investigator Award
Nicholas Zorko, MD, PhD
University of Minnesota / Masonic Cancer Center
Mentors: Jeffrey Miller, MD, Emmanuel Antonarakis, MD, Martin Felices, PhD
Multiplex Engineered CAR iNK Cells Targeting B7-H3 to Treat Metastatic Castration Resistant Prostate Cancers
Description:
- Immunotherapies have provided significant clinical benefit to patients with many types of metastatic cancers, but have yet to be optimized in prostate cancer. This is because prostate cancer is typically immunologically “cold,” due to an immune-suppressive tumor microenvironment (TME).
- NK cells are immune cells with potent tumor cell-killing capabilities. Engineered NK cells (iNK) that recognize and target tumor-associated proteins, are a new type of treatment being investigated.
- Dr. Nicholas Zorko is developing iNK cells that can target the B7-H3 protein. B7-H3 is highly expressed on CRPC but not on normal tissues, making it a promising target for immune-based therapies in patients with prostate cancer.
- In this project, Dr. Zorko and team will develop B7-H3-targeting human iNK cells and investigate their efficacy and functional mechanisms in preclinical CRPC models.
- Whether the anti-tumor efficacy of B7-H3-targeting iNK cells is enhanced when combined with PSMA or PD-L1-targeting antibodies will be investigated.
- In addition, whether the efficacy of B7-H3-targeting iNK cells is enhanced in combination with antibodies blocking the effects of the immune-suppressive protein TGF-beta, will be studied.
- If successful, this project will provide the basis for clinical trials evaluating the safety and tolerability of CAR iNK in patients with refractory metastatic CRPC, who currently have few effective options to control disease progression.
What this means to patients: New immunotherapy approaches are urgently needed for patients with prostate cancer. Dr. Zorko and team are developing a novel immunotherapy, in which NK cells are engineered to target the prostate tumor protein B7-H3. This project will determine mechanisms of action and provide preclinical rationale for testing this treatment in clinical trials.