Young Investigator Award - Class of 2022 - Prostate Cancer Foundation

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

Development of Next-Generation STEAP1 Chimeric Antigen Receptor T Cell Therapies to Combat Antigen Escape and T Cell Dysfunction

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 develop CAR T cells that target STEAP-1 and PSMA, two proteins highly expressed on most prostate cancer cells but not normal cells and will test their efficacy in preclinical models.  
Next generation STEAP1-CAR T cells – that are less likely to become fatigued and more likely to continue attacking prostate cancer, will also be developed and tested in preclinical models.
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 developing a 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...

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