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Young Investigator Award – Class of 2021

The PCF Young Investigator Award-Class of 2021 recipients are:


2021 National Institutes of Health-PCF Young Investigator Award

Mohammad Atiq, MD
Mohammad Atiq, MD

National Institutes of Health

Seeking Immunotherapeutic Synergy with Tumor-targeting Immunocytokines in Metastatic Prostate Cancer

Mentor: Ravi Madan, MD

Description:

  • Immunotherapy can be a very effective and even curative treatment for cancer, but has yet to be optimized for prostate cancer. New immunotherapy strategies are urgently needed.
  • M9241 is a novel IL-12-based immunotherapy developed at the NCI that can enhance anti-tumor immune activity. In early clinical studies, M9241 had an acceptable safety profile and resulted in PSA declines in prostate cancer patients.
  • Dr. Mohammad Atiq hypothesizes that M9241 and docetaxel may act in synergy and could be a potential new treatment for prostate cancer.
  • In this project, Dr. Atiq will be a lead investigator on a phase I/II clinical trial to test the safety, tolerability, and clinical efficacy of docetaxel in combination with NHS-IL12 in patients with metastatic prostate cancer.
  • Patient immune responses to the combination treatment will be evaluated.
  • Genomic analyses will be done to identify associations between genomic mutations and/or immune responses and clinical outcomes.
  • If successful, this project will result in a new treatment for prostate cancer and provide data on the biology and biomarkers for treatment efficacy.

What this means to patients: Dr. Atiq will test the safety and efficacy of a novel immunotherapy combination in patients with metastatic prostate cancer. This could lead to an effective new treatment for patients.


2021 Michael and Patricia Berns-PCF Young Investigator Award

George Butler, PhD
George Butler, PhD

Johns Hopkins University

Investigating the Polyaneuploid Transition as a Mechanism of Therapy Resistance in Distant Site Metastases

Mentor: Kenneth Pienta, MD

Description:

  • Polyaneuploid cancer cells (PACC) are a recently discovered cancer cell state, where giant cancer cells with either enlarged or multiple nuclei form under stress. PACCs are more resistant to cancer treatment and may be the cause of treatment resistance and cancer recurrence.
  • Dr. George Butler is investigating the biology of PACCs in prostate cancer.
  • In this project, Dr. Butler will use new genetic lineage tracing and time-lapse imaging technologies to map cancer cells as they transition through the PACC state in response to therapy. Whether non-PACC cancer cells that are derived from PACCs have a “memory” that confers therapy resistance will be investigated.
  • Molecular profiles will be obtained from PACCs throughout these transitions, and investigated to identify vulnerabilities that may be targeted by new treatments.
  • Novel therapeutic strategies that sequence standard chemotherapy followed by treatments that target PACC transition states will be tested in preclinical models.
  • If successful, this project will determine the role and biology of PACCs in treatment resistance and cancer progression, and identify targetable vulnerabilities of PACCs that can be used as new treatments to prevent the emergence of resistance to standard cancer therapies.

What this means to patients: Polyaneuploid cancer cells (PACC) are a recently discovered cancer cell state that may enable therapeutic resistance and cancer recurrence. Dr. Butler will study the biology of PACCs and determine ways to therapeutically target them, in order to prevent cancer from recurring after standard therapies.


2021 Igor Tulchinsky-PCF Young Investigator Award

Sujun Chen, PhD
Sujun Chen, PhD

UHN / Princess Margaret Cancer Centre

Investigating the Tumor Cells of Origin and Disease Progression Trajectories in Prostate Cancer

Mentors: Housheng He, PhD, Paul Boutros, PhD, MBA

Description:

  • Most studies on prostate cancer biology have been done on “bulk” tumor. Thus, how prostate cancer cells evolve over time and throughout disease history remains unclear.
  • Dr. Sujun Chen is using new single cell technologies to study cancer development and evolution on a single cell level.
  • In this project, Dr. Chen will perform single cell RNA and whole genome sequencing on primary and metastatic tumor samples from patients, in order to identify the tumor cells of origin and better understand their biology.
  • The clinical implication for different tumor cells of origin and how they contribute to disease aggressiveness will be determined.
  • The key mechanisms that regulate different prostate cancer disease trajectories will be identified, including mechanisms that regulate how prostate cancer cells interact with other cells in the tumor microenvironment.
  • If successful, this project will characterize the molecular biology of prostate cancer on the single cell level, and provide insights into the mechanisms underlying tumor evolution and heterogeneity.

What this means to patients: Studying tumors on a single cell level will enable a far better understanding of how tumors evolve and progress over time. Dr. Chen will create a much needed resource of single cell prostate cancer data that will help advance the development of biomarkers and the identification of novel therapeutic strategies for advanced prostate cancer.


2021 Michael and Lori Milken-PCF Young Investigator Award

Burcu Darst, PhD
Burcu Darst, PhD

Fred Hutchinson Cancer Research Center

Improving the Utility of Polygenic Risk Scores and Rare Genetic Variants for the Prediction of Prostate Cancer in Men from Diverse Populations

Mentors: Christopher Haiman, ScD, David Conti, PhD

Description:

  • Prostate cancer represents one of the largest health disparities in the US, with men of African ancestry having the highest incidence and mortality rates.
  • Prostate cancer is one of the most heritable types of cancer. Differences in germline genetics likely contribute in part to prostate cancer disparities.
  • A multi-ancestry polygenic risk score (PRS) has recently been developed that is highly predictive of prostate cancer risk across diverse populations. However, clinical implementation of the PRS first requires a better understanding of how best to use and interpret it in different populations.
  • Dr. Burcu Darst is studying how to improve the PRS and incorporate rare genetic variants in different ancestry populations, in order to further improve the ability to identify men who would benefit from earlier or more frequent prostate cancer screening.
  • In this project, Dr. Darst will use genetic data from over 100,000 men from over 75 distinct populations, to optimize use and interpretation of the multi-ancestry PRS in men from diverse and admixed populations.
  • In addition, the combined effect of rare, high-penetrant variants and PRS on prostate cancer risk in men from diverse populations will be quantified.
  • If successful, this project will substantially improve the ability of the PRS to appropriately identify men who would benefit from earlier or more intensive prostate cancer screening across diverse populations, particularly African ancestry men.

What this means to patients: Prostate cancer is highly heritable and the ability to identify men at highest genetic risk will greatly improve individualized prostate cancer screening strategies and reduce disparities. Dr. Darst will determine how to optimally use a multi-ancestry polygenic risk score (PRS) in combination with rare genetic variants, in different ancestral populations, ultimately reducing prostate cancer mortality rates and prostate cancer disparities.


2021 Art Kern in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

Ivan de Kouchkovsky, MD
Ivan de Kouchkovsky, MD

University of California, San Francisco

Therapeutic Implications of Low PSMA PET Uptake in Castration-Resistant Prostate Cancer

Mentor: Rahul Aggarwal, MD

Description:

  • Prostate specific membrane antigen (PSMA) is a protein present on the surface of most prostate cancer cells, and a target of new PET imaging agents and therapies. PSMA is biologically linked to AR, the target of standard prostate cancer hormonal therapies. However, some patients have low PSMA levels on their tumors, and these tumors are often more aggressive and less responsive to prostate cancer therapies.
  • Dr. Ivan de Kouchkovsky is studying the biology and clinical significance of PSMA-low prostate cancer.
  • In this project, Dr. de Kouchkovsky will compare the efficacy of AR-targeted therapy in metastatic castration resistant prostate cancer (mCRPC) patients with low versus high PSMA levels on PSMA PET imaging.
  • Metastatic tumor biopsies collected from patients before treatment will be studied to identify key molecular features that differ between PSMA-low vs. PSMA-high tumors.
  • The expression of two possible new therapeutic targets, CD46 and CDCP1, in PSMA-low tumors will be evaluated, to determine if these may represent promising new treatment targets in these tumors.
  • If successful, this project will identify clinical and molecular differences between PSMA-low vs. PSMA-high tumors and identify possible new treatment options for PSMA-low prostate cancer.

What this means to patients: PSMA-low prostate tumors are present in a subset of mCRPC patients, and are often more aggressive. Dr. de Kouchkovsky will determine if these tumors are less responsive to standard hormonal therapies and identify molecular differences that may lead to the establishment of new treatment approaches. These results will have direct implications for the management of mCRPC patients with PSMA-low PSMA tumors help guide treatment decisions in this patient population.


2021 John Black Charitable Foundation-PCF Young Investigator Award

Harveer Dev, MD, PhD
Harveer Dev, MD, PhD

University of Cambridge

Identifying and Overcoming Resistance to AR/DDR-Targeting Therapies using Orthogonal Single-Cell CRISPR and Peptide Screening Platforms

Mentors: Stephen Jackson, PhD, Charlie Massie, PhD, Ian Mills, PhD

Description:

  • Prostate cancers are driven by the Androgen Receptor (AR), and androgen deprivation therapy (ADT) together with radiotherapy is a common treatment option in patients with localized disease. AR plays a role in repair of damaged DNA, and this likely contributes to the synergy seen with the combination of ADT and radiotherapy.
  • In addition to radiotherapy, other prostate cancer treatments that work by damaging DNA include PARP inhibitors, which are now FDA-approved for patients with alterations in certain DNA damage repair (DDR) genes, and experimental treatments including ATM inhibitors.
  • Dr. Harveer Dev is studying the role of AR in DNA repair, in order to develop biomarkers to guide treatment selection and to inform the development of improved AR/DDR-targeting therapies.
  • In this project, Dr. Dev will use genome-wide screening technologies to identify and characterize regulators of AR-DDR function, and to identify AR-regulated genes that confer resistance to radiotherapy, PARP-inhibitors, and ATM-inhibitors.
  • Whether patient responses to ADT + radiotherapy can be predicted using a panel of experimentally-derived biomarkers will be investigated in African-American and overall populations.
  • ADT and ADT+DDR-targeting treatment-resistant models will be developed and used to screen for novel therapeutic targets that can overcome treatment resistance.
  • If successful, this project will improve the understanding of AR in DNA repair biology, define biomarkers that better predict the response to AR/DDR-targeting combination treatment, and identify new treatment targets which will form the basis of small molecule inhibitor development with industry partners.

What this means to patients: The development of resistance to ADT/DDR-targeting combination therapies is an increasingly important clinical challenge in prostate cancer. Dr. Dev will better define how AR functions in DDR activities, identify novel biomarkers for ADT+DDR-targeting treatments, and identify new therapeutic targets that may prevent the development of resistance to ADT+DDR-targeting treatments.


2021 Pfizer-PCF Young Investigator Award

David Einstein, MD
David Einstein, MD

Harvard: Beth Israel Deaconess Medical Center

Identifying and Targeting Immunogenic Prostate Cancer

Mentors: Steven Balk, MD, PhD, Kai Wucherpfennig, MD, PhD

Description:

  • Prostate cancer is typically considered a poorly immunogenic tumor, meaning anti-tumor immune responses that develop are weak and/or rare, which has limited the efficacy of immunotherapies.
  • Dr. Einstein and colleagues have observed a subset of primary prostate cancers which appear to be highly immunogenic, characterized by high levels of tumor-infiltrating T cells and expression of the immunotherapy target PD-L1. A clinical trial is underway to test the efficacy of anti-PD1 immunotherapy in patients whose primary tumors have these features and are experiencing a PSA recurrence after primary therapy.
  • In this project, Dr. Einstein will develop biomarkers to identify immunogenic primary prostate tumors, as these are most likely to respond to immunotherapies.
  • The team will identify at least 100 cases of immunogenic primary prostate cancer, including patients from the trial, and new cases identified from archival samples and from patients who have just undergone prostatectomy. Patients of African ancestry (AA) will enriched for, to ensure generalizability and because a particularly immunogenic phenotype has been described in association with AA.
  • Studies will be performed to comprehensively characterize the numbers, types, and functions of immune cells infiltrating these tumors.
  • Whether any specific tumor mutations are associated with immunogenic prostate cancer will be investigated. The impact of RB1, BRCA2, and CHD1 mutations on anti-tumor immune responses will be specifically evaluated, as these mutations are hypothesized to increase tumor immunogenicity.
  • If successful, this project will define immune and genomic mechanisms and biomarkers of immunogenic prostate cancer. These biomarkers can be used to select patients which may be more responsive to immunotherapies.

What this means to patients: Dr. Einstein is identifying and characterizing a subset of aggressive localized prostate cancer that generates anti-tumor immune responses. This will enable the development new immunotherapy approaches to target these tumors in neo-adjuvant and other settings.


2021 Larry Ruvo-PCF Young Investigator Award

Andrei Gafita, MD
Andrei Gafita, MD

University of California, Los Angeles

Development of Biomarker-Based Approaches to Optimize PSMA-Targeted Therapeutics for Advanced Prostate Cancer

Mentors: Johannes Czernin, MD, Jeremie Calais, MD, Matthew Rettig, MD

Description:

  • 177Lu-PSMA-targeted radionuclide therapy (LuPSMA) is a novel treatment that has shown significant survival benefit in phase 2 & 3 clinical trials for metastatic castration resistant prostate cancer (mCRPC), and is now under evaluation for FDA approval.
  • Enrollment of patients on these trials has typically required positive PSMA-PET imaging scans. However, the predictive value of PSMA PET for LuPSMA treatment response has not been established. Furthermore, whether standard imaging (bone scan + CT) or PSMA-PET scans are best for evaluating treatment responses to LuPSMA is not yet known.
  • Dr. Andrei Gafita is studying the role of various imaging modalities for selecting patients for LuPSMA and for evaluating treatment responses.
  • In this project, Dr. Gafita will establish an international database of molecular imaging and clinical data from patients treated with LuPSMA. This data will be used to determine the predictive value of PSMA-PET/CT alone or with the addition of FDG-PET for treatment responses to LuPSMA and outcomes including overall survival.
  • Standardized imaging criteria and nomograms will be developed for use in clinical practice and trial design for patient selection and stratification.
  • If successful, this project will establish standardized criteria for patient selection and response evaluation and by doing that, improve outcome of patients with advanced prostate cancer treated with LuPSMA.

What this means to patients: LuPSMA is a highly effective new treatment for advanced prostate cancer that is likely to receive FDA approval in the near future. Dr. Gafita is developing standardized imaging criteria that will guide optimal selection of patients who are most likely to respond to this therapy, predict outcomes, and be used to guide future clinical trials in this area.


2021 John Black Charitable Foundation-PCF Young Investigator Award

Emily Grist, MBBS
Emily Grist, MBBS

University College London Cancer Institute

Genomic Tracking of Advanced Prostate Cancer Leveraging Bespoke Assays

Mentor: Gerhardt Attard, MBBS, PhD

Description:

  • A number of trials have demonstrated the clinical benefit of adding chemotherapy or androgen receptor (AR)-targeted therapies to androgen deprivation therapy (ADT) in advanced hormone sensitive prostate cancer (HSPC). Additional treatments such as PARP inhibitors continue to be tested in this clinical space. With these multiple treatment options, emerges the need for biomarkers to guide treatment selection for individual patients.
  • Dr. Emily Grist is developing circulating tumor DNA-based biomarkers to aid in treatment selection and for early detection of treatment resistance.
  • In this project, Dr. Grist will develop a pipeline for using whole genome sequencing to detect circulating prostate cancer DNA from patient plasma samples, and study tumor genomic alterations and tumor burden.
  • The ability of this assay to detect minimal residual disease and emerging resistant tumor clones will be tested using samples from two large clinical trials, PARADIGM and STAMPEDE.
  • This test will then be used to prospectively detect and characterize circulating tumor DNA from the first precision therapy arm in the STAMPEDE trial, testing PARP-inhibitors in patients with a DNA damage repair (DDR) gene defect.
  • If successful, this project will result in a non-invasive test that uses patient blood samples to evaluate tumor DNA, select treatments, and monitor treatment response and resistance.

What this means to patients: Circulating tumor DNA can be obtained from patient blood samples and used to study tumor biology. Dr. Grist is developing a circulating tumor DNA test that will act as a biomarker for informing personalized treatment selection, monitoring treatment response and resistance, identifying patients that may benefit from a treatment switch or intensification, and studying tumor genomics and treatment resistance mechanisms.


2021 Rob Heyvaert and Paul Heynen-PCF Young Investigator Award

Andrew Hahn, MD
Andrew Hahn, MD

The University of Texas MD Anderson Cancer Center

The Impact of Body Composition on Resistance to Androgen Signaling Inhibition (ASI) in Men with Localized High-Risk Prostate Cancer

Mentors: Christopher Logothetis, MD, Daniel Frigo, PhD, Jennifer McQuade, MD

Description:

  • Men with localized high-risk prostate cancer have a 50% risk of recurrence, which is a major driver of deaths attributed to prostate cancer. In men with localized prostate cancer, body fat and obesity increase the risk for recurrence and lethal disease.
  • The influence of body fat on outcomes in advanced prostate cancer is less established, yet studies suggest that increased body fat may be associated with improved response to androgen receptor (AR)-targeted therapy in men with metastatic castration-resistant prostate cancer (mCRPC).
  • Considering the paradoxical association of body fat with outcomes in localized disease vs. mCRPC, it is critical to determine whether the influence of body fat on prostate cancer is driven by stage or by exposure to treatment with AR-targeted therapy.
  • Dr. Andrew Hahn will investigate the association between body fat and AR-targeted therapy in patients with localized high-risk prostate cancer who receive neoadjuvant AR-targeted therapy (prior to prostatectomy).
  • In this project, Dr. Hahn will use data and samples from several clinical trials of neoadjuvant AR-targeted therapy in localized high-risk prostate cancer patients that have tumor tissue and imaging available.
  • The phenotypes of different adipose tissue types in men with localized high-risk prostate cancer before and after AR-targeted therapy will be characterized.
  • Whether baseline or AR-targeted therapy-induced changes in adiposity and/or muscle measurements are associated with resistance to AR-targeted therapy will be investigated.
  • Biological links between body fat at baseline and after AR-targeted therapy and steroid hormone signaling in localized high-risk prostate cancer will be investigated.
  • If successful, this project will determine the biological interactions between body fat and treatment outcomes across prostate cancer disease states and identify whether body fat measurements may act as biomarkers to predict resistance to neoadjuvant AR-targeted therapy, thereby improving patient selection for this vs. alternative treatments.

What this means to patients: Obesity is associated with worse outcomes in patients with localized prostate cancer, but with improved responses to AR-targeted therapy in patients with mCRPC. Dr. Hahn will unravel this paradoxical observation by studying the impact of obesity on responses to neoadjuvant AR-targeted therapy in localized prostate cancer. This work will lead to new biomarkers to improve treatment selection and may empower patients by helping them understand how lifestyle influences prostate cancer.


2021 ASTRO-PCF Early Career Development Award to End Prostate Cancer

Julian Hong, MD
Julian Hong, MD

University of California, San Francisco

Artificial Intelligence Approaches for the Diagnosis and Treatment of Oligometastatic Prostate Cancer

Mentor: Felix Feng, MD

Description:

  • Metastatic prostate cancer has been traditionally been considered incurable. Recent advances in medical imaging have led to the identification of a subtype of metastatic prostate cancer called oligometastatic prostate cancer, where the cancer has spread to only a few other areas of the body. These patients have a better chance at survival, and radiation treatments to the prostate and areas of metastatic cancer have been found to improve long-term outcomes and offer a potential cure.
  • The FDA recently approved PSMA PET imaging, which improves the detection of oligometastatic prostate, and facilitates the delivery of appropriate treatment. However, these scans are not widely available and are expensive. This can delay treatments, potentially impacting cure rates, and increase unnecessary costs to patients.
  • The need to improve the delivery of PSMA PET to facilitate its advantages in diagnosis and treatment is an opportunity to apply computational approaches, such as artificial intelligence (AI). AI uses complex data from many sources to make predictions and has revolutionized many fields outside of medicine.
  • Dr. Julian Hong is developing AI-based approaches to combine a patient’s prior history, cancer-related information, and imaging data to identify if they are a good candidate for a PSMA PET scan and if they are likely to benefit from radiation therapy.
  • If successful, this project will result in the development of AI-based tools that will improve the delivery of PSMA PET and the identification of patients at risk of oligometastatic cancer, guiding the use of the most effective treatments for those patients.

What this means to patients: PSMA PET is a new highly sensitive imaging technology that can detect prostate cancer metastasis much earlier than conventional imaging, and can aid in the detection of patients with oligometastatic prostate cancer for whom there may still be curative treatment options. Dr. Hong will develop AI-based tools that will help clinicians to identify patients at risk for development of oligometastatic prostate cancer and who would benefit from PSMA PET imaging and metastasis-directed radiation therapy.


2021 Greg Brown in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

Price Jackson, PhD
Price Jackson, PhD

Peter MacCallum Cancer Centre

Automated Interpretation of PSMA and FDG PET Images to Improve Prognosis and Management in Advanced Prostate Cancer

Mentors: Michael Hofman, MBBS, Kai Qin, PhD

Description:

  • PSMA-PET and FDG-PET are two molecular imaging technologies that have been used to aid selection of patients who are most likely to benefit from 177Lu-PSMA-targeted radionuclide therapy (LuPSMA), a new treatment that will likely soon be FDA approved for advanced prostate cancer patients.
  • An individual’s likelihood of response to LuPSMA treatment is related to PSMA levels and disease phenotypes seen on PSMA-PET, and concordance between PSMA & FDG PET imaging. However, visual assessment of these large datasets can be time-consuming and the human eye may fail to appreciate the complex changes that occur in response to specific therapies.
  • Dr. Price Jackson is developing an artificial intelligence (AI) machine-learning based approach to evaluate PSMA & FDG PET imaging data from patients treated with LuPSMA on a number of clinical trials conducted at the Peter MacCallum Cancer Centre.
  • Computational algorithms will be developed to automatically define total tumor volume, correlate imaging biomarkers and predict treatment outcome from a variety of therapeutic regimens.
  • Additionally, a similar technological approach will be developed to use SPECT imaging to track treatment responses and calculate the radiation doses delivered to tumor and organs following treatment with LuPSMA.
  • If successful, this project will result in an automated technology that can be used to identify, stage, and refer patients for the ideal cancer therapy based on their unique pattern of disease.

What this means to patients: PSMA-PET and FDG-PET can be used to select patients for treatment with LuPSMA. Dr. Jackson is developing an AI-based method to evaluate PSMA-PET and FDG-PET imaging data and identify patients most likely to benefit from LuPSMA. This automated computational method can be freely shared and will offer a consistent level of expertise across centers, enabling clinicians to optimally identify patients who should receive this promising emerging treatment.


2021 Varian-PCF Young Investigator Award

Sophia Kamran, MD
Sophia Kamran, MD

Harvard: Massachusetts General Hospital

Dissecting Tumor-Immune Dynamics and Radiotherapy Response in Oligometastatic Prostate Cancer

Mentors: Jason Efstathiou, MD DPhil, Eliezer Van Allen, MD

Description:

  • Emerging evidence suggests that metastasis-targeted radiation therapy (RT) can extend survival in patients with oligometastatic prostate cancer, a clinical state in which a patient has fewer than 3-5 metastatic lesions. Preclinical studies suggest that this may be due to RT-mediated activation of anti-tumor immune responses. This suggests that immunotherapy may synergize with RT in the treatment of oligometastatic prostate cancer.
  • However, oligometastatic prostate cancer has not been fully characterized, with varying clinical definitions and poor understanding of the underlying biology. It has been suggested that a delicate balance of tumor-immune dynamics maintain the oligometastatic state, and disruption of these dynamics with RT may tip the scale in favor of anti-tumor immunity.
  • Dr. Sophia Kamran is studying the tumor and immune biology of the oligometastatic prostate cancer state.
  • In this project, Dr. Kamran will compare tumor genomic alterations in oligometastatic prostate cancer with localized and widely metastatic prostate cancer, in order to determine if unique genomic alterations contribute to this state.
  • Comprehensive profiles of T cells and other anti-tumor immune cells in oligometastatic prostate cancer will be determined before and after RT treatment, in order to identify immune features that correlate with long-term responses to RT.
  • If successful, this project will improve understanding of the tumor-immune biology of oligometastatic prostate cancer and identify biomarkers and mechanisms of response to RT. This will be used to inform the design of clinical trials that combine RT with immunotherapy in select oligometastatic prostate cancer patients, with the goal of further improving clinical outcomes.

What this means to patients: Oligometastatic prostate cancer represents an early and possibly biologically distinct state of prostate cancer that may be curable. Dr. Kamran will identify tumor and immune biomarkers that predict response of oligometastatic prostate cancer to RT, and may be used to inform more effective treatment strategies that combine RT with immunotherapy.


2021 National Institutes of Health-PCF Young Investigator Award

Anson Ku, PhD
Anson Ku, PhD

National Institutes of Health

Leveraging HER2 Inhibition to Sensitize High-Risk Localized “Low AR” Prostate Tumors to Neoadjuvant Intense Androgen Deprivation Therapy

Mentors: Adam Sowalsky, PhD, Eytan Ruppin, MD, PhD

Description:

  • Neoadjuvant intense androgen deprivation therapy (iADT) is an emerging clinical paradigm in which patients with localized but high-risk prostate cancer are treated with systemic agents currently approved for use in later stage disease (such as enzalutamide or abiraterone in combination with ADT), prior to radical prostatectomy.
  • Results from multiple clinical trials have shown that approximately 30-60% of men will inherently be resistant to neoadjuvant iADT, and that the volume of disease remaining after treatment is prognostic for long-term clinical outcome.
  • Dr. Anson Ku is studying the mechanisms of inherent resistance to neoadjuvant iADT.
  • Data from a recent trial analyzed by Dr. Ku and colleagues revealed greater AR activity at baseline was associated with the most durable responses, while greater activity of the EGF receptor pathway proteins HER2/HER3 were associated with increased residual disease after treatment.
  • In this project, Dr. Ku will evaluate the biological relationship between AR and the EGF receptor pathway and the role of HER2/HER3 in resistance to iADT.
  • Whether pharmacological inhibition of the EGF Receptor pathway family has potential to sensitize prostate cancer to treatment with iADT will be investigated.
  • A classifier will be developed that can identify patients who are unlikely to respond to neoadjuvant iADT, and may benefit from anti-HER2 and iADT combination therapy.
  • In addition, the source of the ligands that activate the HER2 pathway in prostate cancer will be identified.
  • If successful, this project will establish mechanisms and biomarkers for a subset of low-AR prostate tumors that respond poorly to neoadjuvant iADT. Moreover, as HER2-targeted therapies are FDA approved in other settings, this project will generate preclinical evidence to support clinical trials of HER2-targeted therapies in the neoadjuvant setting in combination with iADT.

What this means to patients: Neoadjuvant intense androgen deprivation therapy (iADT) is an experimental strategy in which patients with localized prostate cancer are treated with systemic androgen targeted therapies prior to receiving surgery or radiation therapy. Dr. Ku will determine how the EGF receptor pathway may confer resistance to iADT in a subset of patients, and identify biomarkers and promising new combination treatment strategies for these patients.


2021 Marc and Lisa Cummins-PCF Young Investigator Award

Manoj Kumar, PhD
Manoj Kumar, PhD

Stanford University

Development of Trop2-Targeted PET-Imaging Probe and Therapy for Advanced Prostate Cancer

Mentors: Tanya Stoyanova, PhD, Jianghong Rao, PhD, James Brooks, M.D.

Description:

  • Trop2 is a cell surface receptor overexpressed in about 80% of epithelial cancer. High levels of Trop2 are predictive of localized prostate cancer recurrence post radical prostatectomy. Trop2 is significantly elevated in the late-stage metastatic CRPC and NEPC. Thus, Trop2 may be a promising new diagnostic and therapeutic target in prostate cancer.
  • Dr. Manoj Kumar and colleagues have developed and characterized Trop2-targeting novel humanized antibody fragments.
  • Dr. Kumar will employ strategies to engineer these antibody fragments as a Trop2-targeted immuno-PET imaging probe and an antibody-drug conjugate (ADC).
  • Evaluation of the immuno-PET probe and targeted therapy will be performed using the preclinical models of prostate cancer.
  • The prodrug constructs of ADC will be tested for selectively releasing the cytotoxic drug to the tumor sites. The antibody-drug payload will be optimized for improved anti-tumor activity evaluating cellular processing, cytotoxicity, plasma stability, therapeutic efficacy, and safety profile.
  • If successful, this project will result in a new set of Trop2-targeted imaging and therapeutic agents ready to be tested in clinical trials.

What this means to patients: Trop2 is a promising therapeutic target present on the surface of prostate cancer cells. This non-invasive imaging approach would assess whole-body Trop2+ tumor status, predict therapy outcome, and monitor therapy response. The new Trop2 targeted therapy would expand therapeutic options for advanced prostate cancer, potentially improving clinical outcomes. The proposed research could further guide the combination imaging-based treatment strategies.


2021 Michael and Lori Milken-PCF Young Investigator Award

Rajendra Kumar, PhD
Rajendra Kumar, PhD

Johns Hopkins University

Molecular Signatures of SupraT Induced Ferroptosis and its Role in Prostate Cancer Growth Inhibition

Mentors: Sushant Kachhap, PhD, Sam Denmeade, MD

Description:

  • Bipolar androgen therapy (BAT) is a promising experimental treatment strategy for prostate cancer, in which patients are cycled monthly between extremely high (supraphysiological) and extremely low (near-castrate) levels of testosterone. This is achieved by giving patients androgen deprivation therapy (ADT) along with monthly shots of supraphysiological levels of testosterone.
  • Promising response rates to BAT have been seen, with ~25% of patients achieving a >50% decline in PSA levels, and objective responses observed in ~40% of patients.
  • However, the mechanisms by which BAT kills prostate cancer cells remains unclear, as do biomarkers for predicting which patients are most likely to benefit.
  • Dr. Rajendra Kumar and colleagues have found that exposure of prostate cancer cells to supraphysiological testosterone levels induces ferroptosis, an iron-dependent form of cell death. This form of cell death can activate the immune system, suggesting that BAT may induce anti-tumor immune responses and may have synergy with immunotherapy.
  • In this project, Dr. Kumar will investigate the mechanisms by which supraphysiological testosterone induces ferroptosis and whether this contributes to the efficacy of BAT therapy.
  • The mechanisms by which supraphysiological testosterone induces ferroptosis and inhibits the growth of prostate cancer will be determined.
  • The cellular and molecular mechanisms of ferroptosis induced immune responses will be investigated in humanized mouse models of prostate cancer and in tumor samples from patients receiving BAT
  • If successful, this project will provide insights about the role of ferroptosis in BAT responses, and will enable development of ferroptotic signatures as biomarkers for the efficacy of BAT therapy in prostate cancer patients.

What this means to patients: BAT therapy is an experimental prostate cancer treatment with promising response rates seen in clinical trials. Dr. Kumar will demonstrate whether ferroptosis contributes to the efficacy of BAT therapy, and generate biomarkers for selecting patients to receive BAT and rationale for combing BAT with immunotherapy.


2021 Amgen-PCF Young Investigator Award

Edmond Kwan, MBBS
Edmond Kwan, MBBS, PhD

Vancouver Prostate Centre

Integrated Tissue and Circulating Tumour DNA Profiling to Risk Stratify De Novo Metastatic Hormone-Sensitive Prostate Cancer Prior to Systemic Therapy

Mentors: Alexander Wyatt, DPhil, Gerhardt Attard, MBBS, PhD

Description:

  • Molecular tumor profiling has enabled profound insights into prostate cancer biology and therapy response. However, the genomic landscape of ‘de novo’ metastatic hormone-sensitive prostate cancer (mHSPC) is incompletely understood, in part due to tumor samples being underrepresented in contemporary studies.
  • A better understanding of mHSPC genomics is greatly needed, focusing on biomarkers to predict which established and emerging treatment options would be most beneficial to individual patients.
  • Dr. Edmond Kwan will use robust and proven genomic sequencing approaches to characterize the genomic landscape of de novo mHSPC in two large patient cohorts of plasma circulating tumor DNA (ctDNA) samples and matched prostate biopsy tissue.
  • In this project, Dr. Kwan will explore the relationship between patient clinical characteristics and ctDNA abundance at the time of de novo mHSPC diagnosis.
  • The effect of short-term androgen deprivation therapy on the amount of ctDNA detectable in blood will also be closely examined.
  • Finally, dynamic changes in the genomic composition of mHSPC derived from tumour tissue and pre-/on-treatment blood samples will be determined to uncover specific genomic aberrations that closely relate to features of disease aggression in de novo mHSPC.
  • If successful, this project will provide the first prospective landscape of genomic alterations in de novo mHSPC, propose new risk stratification frameworks, and identify clinical scenarios where ctDNA testing can complement tumor tissue testing to have the greatest impact on patient management.

What this means to patients: The genomic landscape of ‘de novo’ metastatic hormone-sensitive prostate cancer (mHSPC) is incompletely understood. Dr. Kwan will comprehensively profile mHSPC cases at diagnosis and following treatment with systemic therapies. This will enable development of methods for predicting de novo mHSPC outcomes, broaden understanding of molecular mechanisms of therapeutic resistance, and inform the development of clinical guidelines on genomic profiling in de novo mHSPC. Ultimately, these studies will lead to improved precision medicine and clinical trials for patients with advanced prostate cancer.


2021 Emilio Bassini in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

Andrew Laccetti, MD
Andrew Laccetti, MD

Memorial Sloan Kettering Cancer Center

Digital Activity Monitoring for Personalized Prediction of ADT-associated Fatigue

Mentors: Michael Morris, MD, Jessica Scott, PhD

Description:

  • Androgen deprivation therapy (ADT) and next-generation androgen receptor signaling inhibitors (ARSIs) are highly effective treatments for prostate cancer but are limited by side effects including fatigue. This fatigue can be severe, impacting function in up to 43% of men on long-term ADT. It represents one of the leading causes of treatment interruption or dose reduction for men on ARSIs and is associated with significantly impaired quality of life (QOL).
  • Predictors and modifiable risk factors for ADT-related fatigue remain to be established. Their discovery is critical to better guide treatment selection and identify patients best suited for preventative strategies.
  • Dr. Andrew Laccetti is studying the ability to use wearable activity monitors (WAMs) to study therapy-induced fatigue in prostate cancer patients. WAMs, like Fitbit or the Apple Watch, continuously record step count and physiological parameters like heart rate and sleep. They provide an objective measure of daily activity level in real-time.
  • In this project, Dr. Laccetti will conduct a prospective observational study in men with prostate cancer who are planned to initiate ADT alone or in combination with an ARSI (abiraterone, enzalutamide or apalutamide). Participants will be continuously monitored via a WAM to determine activity level (daily step count). Fatigue and quality of life questionnaires will be collected in addition to blood work. These measurements will be assessed for 12-months after starting treatment.
  • The relationships between pre-treatment activity level and changes in activity levels during treatment, and clinically meaningful fatigue after 12-months of ADT with/without an ARSI will be determined.
  • Whether inflammatory markers associate with clinically meaningful fatigue after 12-months of ADT with/without an ARSI will be investigated.
  • If successful, this project will establish real-time digital activity monitoring via a WAM as a means for clinicians to assess risk for the development of clinically meaningful ADT-related fatigue, which will better guide treatment selection. This work will also facilitate the identification of patients best suited to and support further research of mitigating strategies for treatment related fatigue
  • What this means to patients: Fatigue is a common and deleterious side effect of ADT and next-generation androgen receptor signaling inhibitors used for the treatment of prostate cancer. Dr. Laccetti will determine whether wearable activity monitors, like Fitbit or the Apple Watch, can be used to monitor patients for therapy-induced fatigue, and thus identify patients who require fatigue-mitigating strategies and interventions to improve their quality of life.


    2021 Art Kern in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

    Haolong Li, PhD
    Haolong Li, PhD

    University of California, San Francisco

    Investigating PTGES3 as a Novel Therapeutic Target in Advanced Prostate Cancer

    Mentors: Felix Feng, MD, Luke Gilbert, PhD, Kevan Shokat, PhD

    Description:

    • The androgen receptor (AR) is the central therapeutic target for advanced prostate cancer. While treatments that directly target AR prolong patient survival, aggressive prostate cancers invariably find a way to evade these therapies, most commonly by restoring AR activity via a variety of clinically validated mechanisms. Comprehensively understanding the protein regulation machinery of AR and identifying alternative therapeutic targets are crucial for effective treatment of this disease.
    • Dr. Haolong Li and colleagues have developed a technology to identify regulators of AR that may be promising therapeutic targets. The top novel targetable hit identified was prostaglandin E synthetase (PTGES3). PTGES3 was further validated as essential for cell growth and survival in all AR-driven prostate cancer models tested.
    • In this project, Dr. Li is validating PTGES3 as a new biomarker and therapeutic target in prostate cancer.
    • The mechanisms by which PTGES3 regulates AR will be determined, including how PTGES3 regulates AR protein levels and AR-mediated gene expression.
    • Data from three ongoing clinical trials will be used to prospectively validate PTGES3 overexpression as a biomarker of resistance to AR-directed therapies.
    • Novel lead compounds for PTGES3 inhibition have been developed, and their efficacy will be tested in preclinical prostate cancer models.
    • If successful, this project will inform on the biology of PTGES3 in prostate cancer and validate it as a promising new biomarker and treatment target. The preclinical drug developed from this work may eventually benefit patients with aggressive prostate cancer that is resistant to current AR-directed therapies.

    What this means to patients: PTGES3 is a promising new treatment target recently identified by Dr. Li and colleagues. This study will shed light on the biology underlying this novel AR regulator from a mechanistic, biomarker, and therapeutic approach. This will enhance our fundamental understanding of AR biology, and contribute to new therapeutic approaches towards AR in advanced prostate cancer.


    2021 Patrice and Precious Motsepe-PCF Young Investigator Award

    Catherine Marshall, MD
    Catherine Marshall, MD

    Johns Hopkins University

    PARP Inhibitors and Clonal Hematopoiesis in Men with Advanced Prostate Cancer

    Mentors: Emmanuel Antonarakis, MD, Jun Luo, PhD Lukasz Gondex, MD, PhD

    Description:

    • Clonal hematopoiesis (CH) is an age-related process by which hematopoietic cells acquire somatic mutations associated with myeloid malignancies. CH is associated with an increased risk of cardiovascular disease, hematologic malignancies, and bone marrow failure. This is important because cardiovascular disease and bone marrow failure are two of the leading causes of death in men with prostate cancer.
    • CH is prevalent in an age-dependent manner in men with advanced prostate cancer and may be associated with shorter metastasis free survival and overall survival in men with prostate cancer. Additionally, therapies used for prostate cancer may contribute to the development of CH which may in turn impact outcomes for men on these therapies.
    • Dr. Catherine Marshall is studying whether PARP inhibitors, a new precision medicine for some patients with prostate cancer, may accelerate the progression of CH, and the mechanisms by which this may occur.
    • In this project, Dr. Marshall will determine if PARP inhibitor treatment in patients with mCRPC is associated with an increase in prevalence of CH over time, compared to patients with mCRPC not on PARP inhibitor therapy.
    • Whether CH contributes to poor clinical outcomes in patients with advanced prostate cancer will be prospectively evaluated.
    • Whether patients with advanced prostate cancer and clonal hematopoiesis (CH) have different inflammatory signatures than patients without CH will be determined. This will help to inform whether poorer outcomes in men with prostate cancer and CH might be because of an increase in inflammatory cytokines.
    • If successful, this project will determine whether PARP-inhibitors increase risk for CH in prostate cancer patients, and whether this contributes to poorer outcomes, allowing identifying subsets of patients with advanced prostate cancer that may need additional or alternative therapies, either for their cancer, or supportive care while on those therapies. Furthermore, it could also identify a subset of patients who may benefit from alternative therapies, especially in early disease.

    What this means to patients: Clonal hematopoiesis (CH) is a pre-malignant hematologic condition that is associated with adverse outcomes in the general population, and may contribute to worse outcomes in prostate cancer patients. Dr. Marshall will determine whether PARP-inhibitors accelerate the development of CH compared to other prostate cancer treatments, and enable identification of patients who may benefit from mitigating therapies or alternative treatment approaches, to avoid the ill effects of CH.


    2021 Robert and Cindy Citrone-PCF VAlor Young Investigator Award

    Amy Moran, PhD
    Amy Moran, PhD

    Oregon Health & Science University

    Investigating Mechanisms of Androgen Mediated T cell Suppression in High-Risk Prostate Cancer

    Mentor: Lisa Coussens, PhD

    Description:

    • Men and women have striking differences in their risk for autoimmune diseases, susceptibility to many cancers, and response to some pathogens, such as SARS-COV2.
    • In males, testosterone is the most common androgen and is implicated in dampening immune responses, resulting in higher viral titers and increased cancer-associated mortality, yet is protective in autoimmunity.
    • Notably, prostate cancer is largely refractory to immunotherapy and tumor cells are a local source of androgens. Whether or not androgens suppress anti-tumor immunity or the efficacy of immunotherapies in prostate cancer patients is unknown.
    • Dr. Amy Moran is studying the mechanisms of immunotherapy resistance in prostate cancer patients, and how androgens or the androgen receptor (AR) contribute.
    • In a clinical trial, Dr. Moran and colleagues observed that responses to enzalutamide + anti-PD1 immunotherapy were higher in patients with lower AR activity in T cells. The team further demonstrated that AR prevents expression of T cell activation genes, and that treatment with enzalutamide + anti-PD1 synergistically activated T cells.
    • In this project, Dr. Moran will determine whether androgens within the prostate tumor microenvironment repress T cell mediated anti-tumor immunity.
    • The impact of AR inhibition on T cell function will be evaluated by comparing T cells within tumors with those adjacent to the tumor in prostate cancer biopsy samples.
    • The gene expression landscape of T cells after genetic deletion or pharmacologic inhibition of AR activity will be investigated.
    • If successful, this project will reveal how androgens and AR activity regulate human T cell function and immunotherapy resistance and may reveal novel therapeutic approaches to reduce hormone-mediated immune suppression.

    What this means to patients: Androgens have a suppressive effect on T cells and may underlie why patients with prostate cancer typically have poor responses to immunotherapy. Dr. Moran will define the biology of androgen and AR functions in T cells in prostate cancer patients, which will lead to improved therapeutic strategies combining AR-targeted therapy with immunotherapy.


    2021 J. Eustace Wolfington-PCF Young Investigator Award

    John Murad, PhD
    John P. Murad, PhD

    City of Hope

    Impact of the Microbiome on PSCA-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy for Prostate Cancer

    Mentor: Saul Priceman, PhD

    Description:

    • Chimeric antigen receptor (CAR) T cells are a type of immunotherapy where a patients’ own T cells are engineered to target and kill their cancer. CARs targeting a number of cancer antigens, including the prostate stem cell antigen (PSCA), are under development for the treatment of prostate and other cancers. A clinical trial testing the safety and efficacy of PSCA-targeted CAR T cells in prostate cancer is ongoing at The City of Hope.
    • The microbiome is the complex community of microbes that live on the skin and mucosal surfaces of the human body. The microbiome regulates many normal body functions, including immune education. Further, the composition of the microbiome has been shown to influence responses to cancer therapies, including immunotherapy.
    • Dr. John Murad is studying if the microbiome influences treatment responses to CAR T cells, in an attempt to identify strategies to improve the efficacy of CARs to target immunosuppressive solid tumors, such as prostate cancer.
    • In this project, Dr. Murad will evaluate the impact of microbiome manipulation on systemic immunity, the tumor microenvironment, and the efficacy of PSCA-CAR T cell therapy in animal models of prostate cancer.
    • The microbiome of human prostate cancer patients enrolled in the ongoing PSCA-CAR T cell clinical trial will be characterized, and whether microbiome status correlates with response and/or resistance to therapy will be determined.
    • If successful, this project will characterize the role of the microbiome in responses to PSCA-CAR T cell immunotherapy and inform the next stages of clinical development of prostate cancer targeted cell therapy.

    What this means to patients: CAR T cells are a promising class of experimental treatments for prostate cancer that are currently being tested in clinical trials. Dr. Murad is evaluating the role of the host microbiome in influencing responses to CAR T cells. This will improve our understanding of the role of microbiome in therapeutic responses, and ultimately provide avenues to improve clinical outcomes of prostate cancer patients undergoing CAR T cell immunotherapy.


    2021 Clay Hamlin–PCF Young Investigator Award

    Alexandros Papachristodoulou, PhD
    Alexandros Papachristodoulou, PhD

    Columbia University Irving Medical Center

    Interrogating mitochondrial dysfunction for precision medicine in high-risk prostate cancer

    Mentors: Cory Abate-Shen, PhD, Mark Stein, MD, James McKiernan, MD

    Description:

    • The molecular mechanisms driving disparities in prostate cancer incidence and mortality remain largely unknown.
    • Mitochondria are the powerhouses of the cell, integrating fuel metabolism to provide energy needed for function. There is increasing evidence that mitochondrial dysfunction propels prostate cancer progression, particularly in high-risk population groups.
    • NKX3.1 is a key tumor suppressor gene in prostate cancer whose reduced expression contributes to disease aggressiveness, particularly in men of African descent. Co-occurrence of NKX3.1 loss and mitochondrial genome (mtDNA) mutations are associated with poorer prognosis in prostate cancer patients; however, whether there is functional link between these in driving prostate cancer is yet unknown.
    • Dr. Alexandros Papachristodoulou is investigating the role of NKX3.1 in preserving mitochondrial function to suppress prostate cancer, and whether these mechanisms contribute to prostate cancer disparities in African American men.
    • In this project, Dr. Papachristodoulou will define mediators of mitochondrial and metabolic dysfunction in prostate cancer, using mouse models based on loss of function of NKX3.1.
    • Whether mitochondrial alterations are functionally linked with and can be a biomarker for more aggressive prostate cancer will be investigated, using data from patient cohorts including African American patients.
    • Furthermore, whether mitochondrial vulnerabilities represent a therapeutic target for suppression of prostate cancer in high-risk groups will be determined. The role for metformin as an anti-cancer agent in this setting will be investigated.
    • If successful, this project will determine the mechanisms by which mitochondrial dysfunction promotes tumor progression and uncover precision medicine strategies in men with high-risk prostate cancer. If pre-clinical data appear promising, the team anticipates setting up a clinical trial testing metformin in men undergoing active surveillance.

    What this means to patients: Mitochondrial dysfunction appears to contribute to prostate cancer progression and may contribute to prostate cancer disparities in African American patients. Dr. Papachristodoulou will define the role of mitochondrial dysfunction in driving more aggressive prostate cancer and determine whether mitochondrial-targeting agents such as metformin, may impede progression to lethal prostate cancer in high-risk groups.


    2021 J. Eustace Wolfington-PCF Young Investigator Award

    Abhijit Parolia, PhD
    Abhijit Parolia, PhD

    University of Michigan

    Targeting SWI/SNF ATPases in FOXA1-Altered Prostate Cancers

    Mentors: Arul Chinnaiyan, MD, PhD, Joshi Alumkal, MD, Marcin Cieslik, PhD

    Description:

    • FOXA1 is a tumor driver that is mutated in >35% of metastatic castration resistant prostate cancer (CRPC) cases. FOXA1 normally functions to regulate AR activity, however FOXA1 mutants found in prostate cancer have gained additional oncogenic functions.
    • Dr. Abhijit Parolia and colleagues previously found that FOXA1 mutations in prostate cancer were of 3 classes, which differ in function, when they tend to arise in disease history, and the other genomic alterations that tend to co-occur.
    • In this project, Dr. Parolia will investigate the mechanisms by which each of the three different classes of FOXA1 alterations enable prostate cancer development and/or metastasis in preclinical prostate cancer models.
    • SWI/SNF proteins have been found to interact with wild-type and mutant FOXA1 variants and inactivation of SWI/SNF can turn off oncogenic FOXA1 activities. The effect of novel SWI/SNF-degrading treatments on the FOXA1-mutant gene program and prostate cancer growth will be assessed in preclinical prostate cancer models.
    • If successful, this project will identify mechanistic underpinnings of class-specific functions of FOXA1 mutants and validate the SWI/SNF complex as a targetable vulnerability in FOXA1-driven CRPC tumors.

    What this means to patients: FOXA1 alterations are enriched in aggressive CRPC subtypes that remain incurable. Dr. Parolia will determine the mechanisms by which FOXA1 mutations drive prostate cancer, and provide rationale for testing novel SWI/SNF-degrading treatments in clinical trials that will ultimately impact over 35% of CRPC patients that harbor FOXA1 alterations.


    2021 PCF Young Investigator Award

    Anna Plym, PhD
    Anna Plym, PhD

    Harvard: Brigham and Women’s Hospital

    Investigating Whether a Healthy Lifestyle or Pharmacological Intervention can Offset the Risk of Lethal Prostate Cancer in Men at High Genetic Risk

    Mentors: Lorelei Mucci, ScD, Adam Kibel, MD

    Description:

    • Prostate cancer is the most heritable of all cancers, with genetic factors accounting for a large proportion of cases. Recently, 269 single nucleotide polymorphisms (SNPs) associated with prostate cancer were identified, accounting for a significant proportion of prostate cancer heritability. These SNPs have been combined into a polygenic risk score that is highly predictive of prostate cancer across ethnic groups, with a lifetime risk of over 50% in men at highest genetic risk.
    • Given the excess risk of prostate cancer among men with a high polygenic risk score and among carriers of rare genetic variants in DNA repair genes, there is an urgent need to provide men evidence-based recommendations on possible modifiable factors that could reduce their risk.
    • Dr. Anna Plym is studying whether a favorable lifestyle and diet or common pharmacological interventions could reduce genetic risk for prostate cancer.
    • In this project, Dr. Plym will utilize epidemiologic and genetic data from three large prospective cohort studies, including one which has a high representation of black men, to evaluate if men with a high polygenic risk score can offset their risk of lethal prostate cancer by adhering to a healthy lifestyle, including maintaining a healthy weight, engaging in regular physical activity, eating a healthy diet, and not smoking.
    • Whether prostate cancer patients with germline mutations in DNA repair genes (including BRCA1, BRCA2, and ATM) can offset their risk of lethal prostate cancer by adhering to a healthy lifestyle will also be evaluated.
    • The impact of common pharmacological treatments (including aspirin, statins, and finasteride) on lethal prostate cancer in men at high genetic risk will also be evaluated in these cohorts.
    • If successful, this project will identify modifiable risk factors to reduce lethal prostate cancer in men at high genetic risk. This will inform design of clinical trials on lifestyle interventions and evidence-based recommendations on optimal healthy lifestyle choices for men at high genetic risk and their families.

    What this means to patients: As tools for identifying men at high genetic risk for prostate cancer improve and become more widely used, it will be important to provide evidence-based recommendations on possible modifiable factors that could reduce risk. Dr. Plym will identify lifestyle, dietary, and common pharmacological treatments that can reduce genetic risk for prostate cancer, which will inform future interventional clinical trials and lifestyle recommendations for patients and their families.


    2021 Eric Vacca-PCF Young Investigator Award

    Fabio Quaglia, PhD
    Fabio Quaglia, PhD

    Thomas Jefferson University

    The αvβ3 Integrin as Therapeutic Target in Neuroendocrine Prostate Cancer

    Mentors: Lucia Languino, PhD, William Kelly, DO

    Description:

    • Neuroendocrine prostate cancer (NEPC) is an aggressive and treatment-resistant form of castration resistant prostate cancer (CRPC), which has lost features of prostate adenocarcinoma cells and gained features of neuroendocrine cells.
    • Dr. Fabio Quaglia and colleagues have identified αVβ3 integrin as a promising therapeutic target for NEPC. αVβ3 integrin is highly expressed in NEPC, while absent in prostate adenocarcinoma. In contrast, the related integrin family member αVβ6 shows an opposite pattern of expression with high levels in prostate adenocarcinoma and low levels in NEPC.
    • In this study, Dr. Quaglia will investigate the mechanisms by which αVβ3 contributes to the NEPC phenotype and validate its potential as a therapeutic target.
    • The expression of αVβ3 integrin, αVβ6 integrin, and αVβ3 integrin downstream effectors during prostate cancer progression toward the NEPC phenotype will be evaluated. Whether any features correlate with clinical outcomes will be determined.
    • To determine the potential therapeutic impact of targeting αVβ3, pharmacologic inhibition and genetic deletion of αVβ3 will be tested in preclinical prostate cancer models.
    • If successful, this project will define the biology of αVβ3 integrin in NEPC and determine its potential as a biomarker and therapeutic target.

    What this means to patients: Neuroendocrine prostate cancer (NEPC) is a highly aggressive form of advanced prostate cancer for which new treatments are urgently needed. Dr. Quaglia will determine whether αVβ3 integrin may be a promising new treatment target and biomarker for NEPC, as well as the biology by which αVβ3 integrin contributes to this phenotype.


    2021 National Cancer Institute – PCF Young Investigator Award

    Sonam Raj, PhD
    Sonam Raj, PhD

    National Cancer Institute (NCI)

    Identification and Mechanistic Analysis of RB1/TP53 Loss Dependent Transcription and Epigenetic Factors Encoding Lineage Plasticity and Growth

    Mentors: Kathleen Kelly, PhD, David Takeda, MD, PhD

    Description:

    • Castration resistant prostate cancer (CRPC) is an advanced form of prostate cancer which has become resistant to androgen receptor (AR)-targeted therapy. Neuroendocrine prostate cancer (NEPC) is an aggressive form of CRPC that has lost prostate cell phenotype and gained neuroendocrine cell phenotype.
    • Progression of CRPC to NEPC is often associated with mutations in the tumor suppressor genes RB1 and TP53. However the mechanisms by which these mutations and other factors drive NEPC development are unclear.
    • Dr. Sonam Raj is investigating the molecular features that are required for growth of CRPC and NEPC.
    • In this project, Dr. Raj will identify essential genes that cooperate with RB1 loss to drive CRPC and NEPC. The separate contributions of RB1 and TP53 loss in the development of NEPC will also be determined.
    • If successful, this project will identify novel essential transcription and epigenetic factors in CRPC that drive NEPC or adenocarcinoma, and are TP53 and/or RB1 dependent, thus increasing knowledge of NEPC and identifying possible therapeutic targets. The results of these unique screens will also serve as a resource for the community.

    What this means to patients: NEPC is an aggressive form of CRPC that arises from “transdifferentiation” – the conversion from one cell phenotype to another. Dr. Raj will identify critical drivers of the NEPC phenotype and create new experimental models for studying NEPC. This will improve understanding of NEPC and may lead to new treatments for this lethal form of prostate cancer.


    2021 John Paulson-PCF Young Investigator Award

    Praful Ravi, MD
    Praful Ravi, MD

    Harvard: Dana-Farber Cancer Institute

    Neoadjuvant Darolutamide and Abemaciclib in High-Risk Prostate Cancer

    Mentors: Mary-Ellen Taplin, MD, Heather Jacene, MD, Eliezer Van Allen, MD

    Description:

    • Patients with high-risk localized prostate cancer have a significant risk for disease recurrence after radical prostatectomy (RP). Data from recent trials have suggested that neoadjuvant intense androgen receptor (AR)-targeted therapy prior to RP may improve outcomes, with 15-30% of patients achieving pathologic complete response or minimal residual disease.
    • Dr. Praful Ravi is investigating whether inhibitors of the cell cycle regulators CDK4 and CDK6 may synergize with AR-targeted agents as neoadjuvant therapy prior to RP.
    • In this project, Dr. Ravi will conduct a phase 2 neoadjuvant trial testing the addition of the CDK4/6 inhibitor abemaciclib to intense AR-targeted therapy (darolutamide + leuprolide) in men with high-risk prostate cancer prior to RP.
    • The safety, tolerability, and recommended phase 2 dose of this combination will be determined. Pathologic response rates will be evaluated in RP samples following neoadjuvant abemaciclib, darolutamide and leuprolide versus darolutamide and leuprolide alone.
    • Whether changes in disease extent as measured by PSMA-PET, or blood- and tissue-based biomarkers correlate with pathologic responses to the neoadjuvant therapy will be evaluated.
    • If successful, this project will determine whether the addition of CDK4/6 inhibitors to neoadjuvant intense AR-targeted therapy has the potential to improve outcomes for men with high-risk disease, and identify biomarkers of response and resistance.

    What this means to patients: Neoadjuvant therapy with intense AR-targeted therapy is a promising experimental approach to improving outcomes in patients with high risk localized prostate cancer, who are otherwise at high risk for disease recurrence following radical prostatectomy. Dr. Ravi will conduct a clinical trial to test whether adding CDK4/6 inhibitors to neoadjuvant intense AR-targeted therapy has the potential to improve outcomes for men with high-risk disease. If this trial is positive, this could support further evaluation of this strategy in a larger phase 3 trial. The correlative studies embedded into the trial will improve understanding of high-risk prostate cancer and provide insights into the mechanisms of response and resistance to neoadjuvant therapy.


    2021 Neal Rodin in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

    Keyan Salari, MD, PhD
    Keyan Salari, MD, PhD

    Harvard: Massachusetts General Hospital

    Dissecting the Role of Homologous Recombination Deficiency and Immune Response in Early-Stage Prostate Cancer

    Mentors: Eliezer Van Allen, MD, Adam Feldman, MD, MPH

    Description:

    • Inherited and acquired mutations in BRCA2 and other DNA repair genes increase risk for the development of aggressive prostate cancer. However, the mechanisms by which DNA repair gene alterations drive prostate cancer development is unclear.
    • Dr. Keyan Salari is studying whether DNA repair alterations drives progression to aggressive disease by inducing an altered immune response in early disease stages.
    • The timing of DNA repair alterations in the development of early-stage prostate cancer will be defined using whole genome sequencing data from >500 prostate cancers with clinical and outcome data.
    • Whether prostate tumors with DNA repair alterations are infiltrated with distinct immune cell types and functionalities, that can distinguish clinically aggressive from indolent localized prostate cancers, will be determined.
    • The spatial relationships between tumor cells and immune cells with immunosuppressive and tumor-promoting activities will be determined in prostate tumors with DNA repair alterations.
    • If successful, this project will determine whether DNA repair alterations drive prostate cancer progression by inducing an immunosuppressive tumor microenvironment in early disease stages. This will enable discovery of new treatment targets and biomarkers that can identify tumors destined to remain indolent vs. aggressive.

    What this means to patients: More reliable and reproducible prognostic tools to identify localized prostate tumors destined to remain indolent vs. aggressive is needed. Dr. Salari will investigate whether DNA repair gene alterations drive prostate cancer progression by altering immune responses. This data will enhance the ability to reliably identify tumors with lethal potential at an early stage from indolent tumors suitable for active surveillance. This work also has the potential to identify new therapeutic strategies to harness the immune system to prevent progression of disease for patients on active surveillance.


    2021 Michael and Patricia Berns-PCF Young Investigator Award

    Martin Sjöström, MD, PhD
    Martin Sjöström, MD, PhD

    University of California, San Francisco

    Using 5-Hydroxymethylcytosine (5hmC) Sequencing to Investigate Treatment Resistance and Develop Liquid Biomarkers for Advanced Prostate Cancer

    Mentors: Felix. Feng, MD, David Quigley, PhD, Alexander Wyatt, DPhil

    Description:

    • Castration resistant prostate cancer (CRPC) is an advanced from of prostate cancer that has developed resistance to androgen receptor (AR)-targeting therapies. One mechanism of AR-therapy resistance is lineage plasticity, a phenomenon in which prostate cells lose prostate cell features and gain features of other cell types such as neuroendocrine cells.
    • Lineage plasticity is driven in part by epigenetic changes, where chemical modifications that control which genes a cell can and cannot express are altered.
    • Dr. Martin Sjöström is studying epigenetic modifications that drive lineage plasticity and treatment resistance in prostate cancer.
    • In this project, a comprehensive map of genome-wide epigenetic patterns of lineage plasticity in metastatic CRPC will be developed.
    • Epigenetics-based liquid biomarkers using cell-free DNA (cfDNA) will be developed that can predict pre-existing and acquired treatment responses or resistance to AR-targeted therapy or taxane chemotherapy.
    • If successful, this project will create a comprehensive map of epigenetic modifications that drive CRPC lineage plasticity and treatment resistance and develop liquid biopsy-based epigenetic biomarkers to predict treatment response and resistance.

    What this means to patients: Lineage plasticity is a major mechanism underlying the development of aggressive, treatment resistant prostate cancer, and is largely driven by epigenetic alterations. Dr. Sjöström will comprehensively map epigenetic alterations that promote lineage plasticity and use this information to develop blood-based biomarkers to predict treatment outcomes in patients. This may inform new treatment strategies to overcome resistance and increase the availability of precision medicine approaches for patients.


    2021 Peter and Laurie Grauer in Honor of Plum and Jonathan W. Simons, MD-PCF Young Investigator Award

    Shervin Tabrizi, MD
    Shervin Tabrizi, MD

    Harvard: Massachusetts General Hospital

    Development of High-Performance Liquid Biopsy in Prostate Cancer through Enhanced Cell-Free DNA Recovery

    Mentors: John Christopher Love, PhD, Viktor Adalsteinsson, PhD, Anthony V D’Amico, MD, PhD

    Description:

    • Precision medicine in management of prostate cancer requires biomarkers that can enable individualization of treatment, sensitive and early detection of disease recurrence, and monitoring of disease response on therapy.
    • Circulating tumor DNA (ctDNA) has enormous promise for this purpose, as it can be obtained non-invasively via a simple blood draw and be used to study tumor genomics and tumor burden. However, current ctDNA assays are limited by poor sensitivity due to the limited quantity of tumor DNA shed into the bloodstream in common clinical settings.
    • Dr. Shervin Tabrizi is developing a novel technology to increase the amount of ctDNA sampled in a blood draw to improve ctDNA liquid biopsy tests.
    • In this project, Dr. Tabrizi will engineer and synthesize novel DNA-protectors that can inhibit degradation and clearance of cell-free DNA, thereby increasing the quantity and quality of ctDNA that can be obtained from blood draws.
    • The most promising DNA-protectors identified will be tested in animal prostate cancer models to determine safety, toxicity and efficacy.
    • If successful, this project will result in development of an intravenous molecular agent that improve the recovery of ctDNA, and thereby expand the ability to use ctDNA tests in clinical settings.

    What this means to patients: Circulating tumor DNA (ctDNA) testing using blood samples from patients has the potential to enable monitoring of disease progression, treatment resistance, and selection of precision medicines. However, these tests require improvement before they can be widely used in clinical practice. Dr. Tabrizi will develop a new molecular agent that can be administered to patients that improves the sensitivity and accuracy of ctDNA testing, enabling it to be used in a broad array of prostate cancer clinical settings to inform management decisions and improve outcomes.


    2021 PCF Young Investigator Award

    Anna Trigos, PhD
    Anna Trigos, PhD

    Peter MacCallum Cancer Centre

    Understanding PSMA Expression Through a Deep Dive into the Genetic, Gene Expression and Microenvironment Profiles of mCRPC

    Mentors: Shahneen Sandhu, MBBS, Michael Hofman, MBBS, David Quigley, PhD

    Description:

    • 177Lu-PSMA-targeted radionuclide therapy (LuPSMA) is a new PSMA-targeted treatment for prostate cancer, poised to become a new standard of care.
    • However, a third of men with metastatic castration resistant prostate cancer (mCRPC) have limited responses to LuPSMA treatment, and all patients who initially respond eventually develop progressive disease.
    • Unfortunately, our understandings of the function of PSMA in prostate cancer, what governs PSMA expression, and mechanisms of resistance to LuPSMA are limited.
    • Dr. Anna Trigos is studying the molecular factors associated with various patterns of PSMA expression and LuPMSA responses in prostate cancer patients.
    • In this project, Dr. Trigos will perform comprehensive molecular profiling on tumor samples from mCRPC patients who have undergone PSMA-PET scans and/or LuPSMA treatment, to identify genetic alterations, gene expression profiles and tumor microenvironment patterns that associate with various patterns of PSMA expression, in LuPSMA-naïve and LuPSMA-resistant disease.
    • If successful, this project will identify molecular factors associated with distinct PSMA expression patterns and clinical phenotypes, and molecular changes associated with acquired resistance to LuPSMA. This will help narrow down potential combination therapies for LuPSMA and refine biomarkers for patient selection.

    What this means to patients: LuPSMA is a promising new treatment that will likely soon become approved for patients with metastatic castration resistant prostate cancer (mCRPC). However, PSMA, the target of the treatment, is not uniformly expressed on all prostate cancer cells, and it is unclear how this and other factors influence responses to LuPSMA. Dr. Trigos will create a profile of molecular features that associate with PSMA expression patterns and response and resistance to LuPSMA. This will enable identification of potential treatment approaches to improve the efficacy of LuPSMA.


    2021 Republic National Distributing Company-PCF Young Investigator Award

    Yuehui Zhao, PhD
    Yuehui Zhao, PhD

    The University of Texas MD Anderson Cancer Center

    Delineating Clonal Evolution of Resistance to Androgen Deprivation Therapy and Metastasis in Newly Diagnosed Early Metastatic Prostate Cancer

    Mentors: Nicholas Navin, PhD, Amado Zurita, MD

    Description:

    • In contrast to most solid malignancies which evolve from a single cell, primary prostate cancer can evolve from multiple independent normal cells in the prostate. The evolution of multiple tumor lineages may lead to distinct clones with diverse malignant traits and result in multi-clonal seeding events to metastatic sites.
    • A greater understanding of how multifocal prostate cancer and different prostate cancer clones contribute to therapeutic resistance and metastasis is needed to improve the outcomes of metastatic prostate cancer patients. Additionally, identifying new clinical markers is essential for stratifying patients to improve treatment strategies.
    • Dr. Yuehui Zhao is using novel genomic technologies to study tumor evolution and metastasis.
    • In this project, Dr. Zhao will use novel single cell DNA and RNA sequencing technologies combined with spatial transcriptomics, to reconstruct the tumor subclonal structure and characterize the tumor microenvironment in a primary and metastatic prostate tumor, and resolve how the tumor evolved. These data will be used to develop a machine learning-based method to investigate the spatial distribution of tumor subclones.
    • How clonal evolution may contribute to the development of resistance to androgen deprivation therapy (ADT) as well as biomarkers of response to ADT will be identified. The mechanisms by which metastatic sites can be seeded by different tumor clones will be investigated.
    • If successful, this project will provide new insights into how different tumor clones evolve, drive disease progression, adapt to the metastatic niche, and promote treatment resistance.

    What this means to patients: To better understand metastasis in prostate cancer and develop more effective new treatments, it is necessary to trace tumor evolutionary trajectories and identify genomic drivers of metastasis. Dr. Zhao will use single-cell multi-omics approaches to resolve tumor heterogeneity and evolution and identify mechanisms of metastasis and treatment resistance. These understandings will accelerate the identification of new biomarkers and treatments for prostate cancer.


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