The PCF Young Investigator Award-Class of 2016 recipients are:
Rohit Bose, MD, PhD
Memorial Sloan Kettering Cancer Center
Mentor: Charles Sawyers, MD
Proposal Title: Epigenetic Sensitization of Enzalutamide Response
- The androgen receptor (AR) is the primary driver of prostate cancer, and targeting AR is one of the most efficacious treatments for the disease. However, resistance to AR-targeted therapies such as enzalutamide (Xtandi®) is inevitable. New methods are needed to improve AR-targeted treatment strategies.
- Dr. Rohit Bose will investigate whether epigenetic regulators, which control which genes can be expressed in a cell, affect the activity of AR.
- Epigenetic regulators function by modifying the genome to allow or prevent gene transcription. Whether the activity of epigenetic regulators and the epigenetic modifications of the genome in prostate cancer cells associate with enzalutamide resistance, will be determined.
- Finally, small molecule inhibitors of epigenetic regulators will be tested for their ability to enhance prostate cancer cell sensitivity to enzalutamide.
- If successful, this study will identify a new treatment strategy to enhance the sensitivity of prostate cancer to enzalutamide.
What this means for patients: New strategies are needed to overcome treatment resistance. Dr. Bose will investigate the interactions between epigenetic regulators and the androgen receptor to determine if co-targeting these pathways will enhance therapeutic efficacy. This approach may lead to new and more effective treatments for patients.
Ginevra Botta, PhD
Harvard: Broad Institute of MIT and Harvard
Mentor: Eliezer Van Allen, MD
Proposal Title: Drug Re-Purposing for Cancer Therapies
- Prostate cancer cells require the sustained expression and activity of the androgen receptor (AR) for their growth and survival. Androgen deprivation therapy (ADT) is the initial treatment used in advanced metastatic prostate cancer patients. However, resistance and tumor recurrence is common, ultimately resulting in the patient’s death.
- Dr. Ginevra Botta is studying mechanisms of ADT-resistance. She has performed preliminary studies that identified genes that regulate sensitivity to ADT, including INPP5A which functions to prevent calcium accumulation within cells.
- Loss of INPP5A was found to confer ADT resistance while also leading to high levels of calcium in cells. Whether high calcium levels promote ADT-resistance will be investigated in experimental cell models. In addition, the role of calcium-activated pathways such as CaMKII, in driving ADT-resistance and cell proliferation will be determined.
- Several additional genes that confer ADT-resistance without requiring AR were identified. The mechanisms by which these genes activate ADT-resistance will be investigated. In addition, whether these genes can be targeted to prevent ADT-resistance will be tested.
- If successful, this project will identify novel genes that play a key role in ADT-resistance and determine their potential as therapeutic targets.
What this means for patients: New treatment strategies are needed to prevent the development of ADT-resistance by prostate tumors. Dr. Botta will characterize ADT-resistance mechanisms and identify novel targets for treatment to prevent progression to lethal disease.
Albert Chang, MD, PhD
University of California, San Francisco
Mentors: Lawrence Fong, MD, Felix Feng, MD
Proposal Title: Investigating the Immune Profile in Patients with Oligometastatic Prostate Cancer Receiving Intermittent Androgen Deprivation Therapy, Radiation Therapy, and Anti-PD-1 Antibody With or Without Intratumoral Injection of a TLR9 agonist
- Therapies that activate the immune system against a patient’s cancer can be curative in a variety of tumor types, but have not yet demonstrated significant efficacy in prostate cancer. New methods are needed to harness this powerful system in prostate cancer patients.
- Dr. Albert Chang will evaluate the responses of patients with oligometastatic (≤3 bone metastases) hormone-sensitive prostate cancer enrolled in a phase II clinical trial testing a novel immunotherapy regimen. Patients will receive the immune cell-activating therapy anti-PD1 (Pembrolizumab) with radiation therapy, and with or without another immune-stimulating adjuvant-like agent, SD-101.
- Dr. Chang will evaluate immune system responses for associations with clinical response to therapy. Immune system features that will be evaluated include the frequencies of various tumor-killing and tumor-protecting immune cell populations, and the production of immune-regulating molecules called cytokines.
- T cells are the major tumor-killing immune cell type. To indicate whether the immune-modulating therapies enhance the frequencies of anti-tumor T cells, the diversity and stability of T cell clones will be determined over the course of therapy.
- If successful, this project will result in a new immunotherapy for the treatment of prostate cancer and identify predictive biomarkers that enable selection of patients most likely to benefit from these treatments.
What this means for patients: More effective and personalized treatment regimens involving immunotherapy will improve the clinical outcomes of prostate cancer patients. Dr. Chang will evaluate a new immunotherapy regimen and develop biomarkers to identify patients who are most likely to respond.
Alastair Davies, PhD
University of British Columbia
Mentor: Amina Zoubeidi, PhD
Proposal Title: Targeting and Mechanistic Insights into EZH2-Driven Plasticity in Advanced Prostate Cancer
- Prostate cancers which have developed resistance to androgen deprivation therapy (ADT), often continue to be driven by the androgen receptor (AR). These tumors can be treated with the second generation AR-pathway inhibitors abiraterone and enzalutamide, but it is only a short time before therapeutic resistance and disease progression ensue.
- One AR-therapy resistance mechanism involves conversion of prostate cancer cells into a neuroendocrine prostate cancer (NEPC) phenotype, which does not rely on AR for survival. Understanding the transition to NEPC will guide highly specific targeting of this lethal form of prostate cancer.
- Dr. Alistair Davies will explore whether re-activation of a dormant stem-cell program in AR-targeted therapy-resistant prostate cancer is responsible for the transition to NEPC.
- The role of EZH2, an enzyme that regulates the structure of DNA and controls cell stemness, will be determined in NEPC tumors from patients and in experimental NEPC models. Factors that control the activity of EZH2 will also be examined.
- In addition, the potential therapeutic efficacy of an experimental drug (GSK126) that targets both EZH2 and AR will be examined in pre-clinical models of NEPC.
- If successful, this project will lead to a new understanding of the biology of NEPC and a new treatment for this highly aggressive form of prostate cancer.
What this means for patients: Neuroendocrine prostate cancer (NEPC) is an aggressive form of hormone therapy-refractive prostate cancer, for which no effective therapy exists. Dr. Davies will identify drivers of NEPC biology and develop a new treatment for this lethal form of prostate cancer.
Renée de Leeuw, PhD
Thomas Jefferson University
Mentors: Karen Knudsen, PhD, William Kelly, DO, Maha Hussain, MD
Proposal Title: Altered Kinome States and Implications of CDK4/6 Inhibitor Resistance in Prostate Cancer
- Targeting regulators of cell division, such as the CDK4 and CDK6 enzymes, may be an effective therapeutic strategy in some patients with prostate cancer. Understanding what regulates sensitivity and resistance to CDK4/6-inhibitors is critical for optimizing the use of these therapies.
- The retinoblastoma (RB) protein, a tumor suppressor gene that controls cell division, is commonly lost in advanced prostate cancer. Loss of RB has been shown to induce resistance to CDK4/6-inhibitors. However, CDK4/6-inhibitor resistance has been observed in some RB-positive tumors.
- Dr. Renée de Leeuw is investigating the mechanisms of resistance to CDK4/6-inhibitors in RB-positive prostate cancer.
- Prostate cancer cell lines that are resistant to the CDK4/6-inhibitor Palbociclib will be developed. The expression and activity of RB in these cell lines will be determined. These cell lines will then be profiled for genomic mutations, gene expression, and the activity of kinase signaling proteins, in order to identify mechanisms of resistance and biomarkers of response to CDK4/6-inhibitors.
- A phase II clinical trial is being conducted to test the efficacy of treatment with the AR antagonist enzalutamide alone or in combination with the CDK4/6-inhibitor Ribociclib. Tumor tissues from patients enrolled in this study will be interrogated for CDK4/6 activity as a measure of CDK4/6-inhibitor activity.
- Patient tumor specimens will also be cultured in the laboratory, studied for drug responsiveness, and molecularly profiled in order to identify biomarkers of response and potential alternative therapies for CDK4/6-inhibitor resistant prostate cancer.
- If successful, this project will develop biomarkers that predict whether patients are likely to benefit from CDK4/6-inhibitors or should receive alternative therapies.
What this means for patients: Therapies that target cell division may have promise for the treatment of prostate cancer. Dr. de Leeuw will study the biology of resistance and response to CDK4/6-inhibitors and identify biomarkers that will predict response to these and alternative therapies. This will enhance precision medicine for prostate cancer patients.
Eleonora Dondossola, PhD
The University of Texas MD Anderson Cancer Center
Mentors: Peter Friedl, MD, PhD, Christopher Logothetis, MD
Proposal Title: Preclinical Targeting of Early-Stage and Established Prostate Cancer Lesions in Bone by Radium-223: Impact on Tumor Cells, Stroma and Markers of Response
- Bone metastases are a major complication in patients with advanced prostate cancer, but have limited treatment options. Radium-223, a radioactive calcium analog that targets the bone environment, has recently been approved for the treatment of patients with metastatic castrate-resistant prostate cancer (CRPC). However, how Radium-223 impacts tumor growth to prolong patient lives is unclear.
- Dr. Eleonora Dondossola is exploring the mechanisms by which Radium-223 acts to prevent the growth of prostate tumor bone metastases.
- A novel preclinical model that allows the visualization of prostate tumors grown within a bone scaffold will be used to examine the effect of treatment with Radium-223 on the numbers and organization of tumor and stromal cells (bone cells, blood vessels, and infiltrating immune cell types) over time. This will allow determination of how Radium-223 impacts tumor cell growth and death, and whether any other cells types are killed by the treatment.
- Gene expression in tumor cells and stromal cells will be assayed to determine the mechanisms by which Radium-223 exerts anti-tumor effects.
- Radium-223 targets areas of increased bone turnover, implying that tumors must be larger and tissue-damaging for Radium-223 to be taken up by the surrounding bone tissue and act on the tumor. Whether Radium-223 can also act to prevent the growth of micro-metastatic bone lesions will be investigated.
- Finally, biomarkers of Radium-223 responses will be identified in preclinical models and validated using tumor samples from patients who were treated with Radium-223.
- If successful, this project will identify mechanisms by which Radium-223 prevents the growth of prostate cancer bone metastases, determine how early in the disease course this therapy can be effective, and identify biomarkers that predict treatment responses.
What this means for patients: Radium-223 has been shown to extend the lives of prostate cancer patients, yet how this therapy exerts its effects is unclear. Dr. Dondossola will determine the mechanisms of Radium-223 activity and identify biomarkers that predict patient responses to this therapy. This will result in optimized use of Radium-223 in patients.
Christopher Kloss, PhD
University of Pennsylvania
Mentor: Carl June, MD
Proposal Title: Overcoming Immunosuppressive Barriers in Chimeric Antigen Receptor Mediated T Cell Immunotherapy for the Eradication of Metastatic Prostate Cancer
- If appropriately harnessed, the immune system has the potential to eradicate cancer. Chimeric Antigen Receptor (CAR) T cell immunotherapy consists of T cells genetically engineered to seek out and kill tumor cells. CAR T cells have shown efficacy in many cancer types but further research is needed to create CAR T cells that are active against prostate cancer.
- Dr. Christopher Kloss will generate CAR T cells that can target the prostate cancer cell-specific protein, PSMA. In addition, these CAR T cells will be engineered to be resistant to the negative immune regulatory molecule, TGFβ.
- These anti-PSMA, TGFβ-resistant CAR T cells will be profiled for their activity in preclinical models. In addition, the effects of rendering these cells resistant to TGFβ will be determined.
- As a second approach, Dr. Kloss will investigate whether avoiding inhibitory signals from the negative-regulatory proteins PD-1, CD96 and TIGIT can enhance CAR T cell responses. This will be accomplished by knocking out the expression of these genes alone or in combination in CAR T cells and surveying their anti-tumor activities.
- If successful, this project will generate highly active CAR T cell immunotherapies for prostate cancer.
What this means for patients: Chimeric Antigen Receptor (CAR) T cell immunotherapy for prostate cancer is a promising but yet unproven approach for eradicating prostate cancer. Dr. Kloss will generate CAR T cells that are refractory to inhibitory signals and have strong efficacy against prostate cancer. These studies will lead to a new immunotherapy for prostate cancer.
Christos Kyriakopoulos, MD
University of Wisconsin
Mentors: Douglas McNeel, MD, PhD, Glenn Liu, MD
Proposal Title: Pilot Trial of Neoadjuvant Combination Immunotherapy Targeting the Androgen Receptor in Patients with Prostate Cancer
- Androgen deprivation therapy (ADT) is the mainstay of treatment for metastatic prostate cancer, but has limited benefit if given as a neoadjuvant treatment prior to prostatectomy. ADT has been demonstrated to elicit effects on the immune system, indicating that combining ADT with immunotherapy may have improved results in prostate cancer.
- Dr. Christos Kyriakopoulos is testing the effects of a treatment strategy combining ADT with a prostate cancer vaccine and a “checkpoint” immunotherapy prior to prostatectomy.
- A clinical trial will be initiated to compare the safety and efficacy of ADT alone, ADT plus a vaccine that targets the androgen receptor (pTVG-AR), and ADT plus pTVG-AR plus the checkpoint immunotherapy anti-PD-1 (Nivolumab), in patients with newly diagnosed prostate cancer. These treatments will be followed by radical prostatectomy.
- The effects of each treatment on T cell activity will be determined in prostate tissues obtained the time of radical prostatectomy as compared to baseline T cell activity in prostate biopsy specimens obtained at the time of diagnosis. These studies will indicate whether these treatments induce T cells to enter tumors and attack tumor cells.
- In addition, whether or not the pTVG-AR vaccine elicits anti-AR T cells and whether treatment with anti-PD-1 can increase the magnitude of the anti-AR immune response will be determined.
- If successful, this project will lead to the development of a novel and highly-effective therapy for prostate cancer patients.
What this means for patients: Androgen deprivation therapy (ADT) may have immune-modulating effects that can be harnessed to improve the outcomes of prostate cancer patients. Dr. Kyriakopoulos will test the efficacy of a new ADT plus dual-immunotherapy treatment combination. This may lead to a new treatment that can be used earlier in the course of disease to improve patient outcomes.
David Labbé, PhD
Harvard: Dana-Farber Cancer Institute
Mentors: Myles Brown, MD, Anthony D’Amico, MD, PhD
Proposal Title: Characterization of the Epigenome as a Critical Mediator of Prostate Cancer Lethality Driven by Diet-Induced Obesity
- A high-fat diet and obesity are risk factors for lethal prostate cancer, however the mechanisms by which these are linked is unknown.
- Epigenetics controls the gene expression programs of cells by changing the structure of DNA in a way that allows or prevents access to various genes. Epigenetics is important in cancer by allowing the expression of growth-promoting genes instead of adhering to the controlled-growth program of normal cells.
- Dr. David Labbé is studying how a fatty diet modulates the epigenetic program to promote prostate cancer.
- Diet-induced obesity has been found to alter the epigenetic program of premalignant prostate lesions. Whether this new obesity-induced epigenetic program is maintained or continues to change as tumors progress will be determined.
- The role of factors likely to participate in this process, including “pioneer factor” gene-regulating proteins and reconfigurations of large “super-enhancer” DNA regions, will be investigated.
- In addition, whether diet-induced obesity plays a role in generating genomic instability by altering DNA repair mechanisms will be explored.
- If successful, this project will define the biology underlying the effects of a high-fat diet and obesity on prostate cancer and may uncover novel therapeutic targets.
What this means for patients: Lifestyle factors such as obesity and a high-fat diet significantly increase the risk of lethal prostate cancer. Dr. David Labbé will identify the mechanisms by which a high fat diet and obesity promote prostate cancer, which will lead to new therapeutic targets and will encourage lifestyle modifications by prostate cancer patients.
Benjamin Larman, PhD
Johns Hopkins University
Mentor: Charles Drake, MD, PhD
Proposal Title: Defining the Antigenic Determinants of Response to Cancer Immunotherapy
- The immune system has the power to effectively recognize and eliminate cancer, when conditions are optimal. This occurs when immune cells are able to recognize and kill tumor cells that express specific proteins. B-cells can also become involved in anti-tumor immune responses by producing antibodies that target tumor proteins. Identifying the tumor-associated proteins targeted by immune cells and antibodies will inform the development of novel cancer vaccines.
- Benjamin Larman is working to identify tumor proteins targeted by anti-tumor antibodies.
- A novel high throughput platform will be used to identify tumor-targeting antibodies from pancreatic cancer, colorectal cancer, and melanoma patients undergoing treatment with immunotherapy in clinical trials. The tumor-associated proteins targeted by the antibodies will be identified and correlated with objective responses and/or autoimmune side effects.
- Bioinformatics and machine learning methods will be employed to discover relationships between anti-tumor immune responses and clinical outcomes in order to use antibody profiles to predict clinical responses to immunotherapy.
- If successful, this project will answer fundamental questions in tumor immunology, identify novel tumor vaccine targets, and develop antibody profiles as biomarkers to help clinicians monitor patient responses to immunotherapy.
What this means for patients: Proteins uniquely expressed by tumor cells can be the targets of anti-tumor immune responses. Identification of these proteins is critical for developing new immunotherapeutic strategies. Dr. Larman is conducting a study to identify the proteins targeted by anti-tumor antibodies and determine their association with clinical outcomes. This project will result in the development of biomarkers for patient responses to immunotherapy and identify potential targets for novel tumor vaccines.
Stacy Loeb, MD
New York University
Mentor: Herbert Lepor, MD
Proposal Title: #ProstateCancer: Quantitative and qualitative evaluation of digital media and other communications to improve prostate cancer advocacy, research and management
- Digital media are increasingly being used for communication, education and scientific exchange about health issues. Properly applied, digital media can be effectively used to interact with and educate prostate cancer patients, families, advocates, and the general public, all around the globe.
- Dr. Loeb will characterize current social media use in prostate cancer and identify how social media is being used for knowledge sharing, advocacy, and dissemination of new research findings. This will be achieved by reviewing published literature on social media use in prostate cancer and assessing analytics of prostate cancer-related hashtags in Twitter.
- In addition, Dr. Loeb will conduct focus groups with prostate cancer patients and their families to explore their informational needs, and identify gaps in knowledge and existing resources. The focus groups will concentrate on active surveillance, precision medicine and clinical trials.
- Dr. Loeb will use these information to design new digital strategies and content for PCF.org and PCF social media platforms to enhance prostate cancer advocacy, knowledge sharing, and dissemination of new research opportunities and findings to a range of audiences. In addition, strategies will be implemented to use social media to enhance professional scientific exchange and education.
- If successful, this project will result in a new social media strategy that can be used by PCF and others to reach a global audience and significantly increase knowledge, awareness and advocacy for prostate cancer research.
What this means for patients: Digital media has the potential to be an effective platform to reach and educate billions of people on topics surrounding prostate cancer. Dr. Loeb will investigate the use of social media for advocacy about prostate cancer, dissemination of information to the public, and advancing prostate cancer research within the scientific community. Dr. Loeb will then create new content and social media strategies that can implemented by PCF to reach patients and their families around the globe.
Reem Malek, PhD
Johns Hopkins University
Mentors: Phuoc Tran, MD, PhD, Kenneth Pienta, MD
Proposal Title: Synthetic DNA Repair Deficiency and Sensitization to PARP Inhibition of Prostate Cancer by Co-Targeting of Twist1-Hoxa9
- PARP-inhibitors are a new class of agents that have demonstrated efficacy in a subset of prostate cancers that harbor mutations in DNA repair genes. Other factors that control sensitivity and resistance to PARP-inhibitors in prostate cancer are unknown.
- TWIST1 and HOXA9 are genes with a role in metastasis that confer resistance to PARP-inhibitors in leukemia patients.
- Dr. Reem Malek is exploring whether TWIST1 and HOXA9 play a role in mediating resistance to PARP-inhibitors in prostate cancer patients.
- The expression of TWIST1, HOXA9, and two other related factors, WDR5 and MLL2, will be modulated in prostate cancer cell lines to determine how these proteins affect the expression of DNA repair genes and resistance to PARP-inhibitors. Whether these factors are important for the repair of damaged DNA will also be investigated.
- Whether increased expression of TWIST1 or HOXA9 associate with increased expression of DNA repair genes in prostate cancer patient samples will be examined.
- Finally, whether treatment with inhibitors of TWIST1 or HOXA9 can sensitize prostate cancer cells to PARP-inhibitors will be tested in preclinical models. This will indicate that tumors that have high levels of TWIST1 or HOXA9 can be sensitized to PARP-inhibitors by the addition of therapies targeting these genes.
- If successful, this project will lead to the identification of a new subset of prostate cancer patients who may benefit from treatment with a combination of PARP-inhibitors and TWIST1/HOXA9-inhibitors.
What this means for patients: PARP-inhibitors are a new, highly-effective class of therapies which primarily have efficacy against tumors with mutations in in DNA repair proteins. Dr. Malek will identify new therapeutic targets that will induce PARP-inhibitor-sensitivity in another subset of prostate cancer patients. This may lead to a new precision medicine treatment for prostate cancer.
Mark Markowski, MD, PhD
Johns Hopkins University
Mentor: Angelo De Marzo, MD, PhD
Proposal Title: Identification of AR-Independent Mechanisms of Action and Resistance of BETi in a Novel Murine Model of Prostate Cancer
- BET-inhibitors are a new class of therapeutics that inhibit the androgen receptor (AR) by blocking a critical interplay between AR and BET proteins. These therapies have demonstrated promising efficacy in preclinical prostate cancer models. However, BET-inhibitors can have efficacy even in AR-negative prostate cancer cells, due to unknown mechanisms.
- Dr. Mark Markowski is studying the mechanisms of response and resistance to BET-inhibitors in AR-negative prostate cancer.
- BET-inhibitors also target the cancer-causing gene c-MYC, which can drive prostate cancer in the absence of AR.
- The role of c-MYC in driving BET-inhibitor resistance in the absence of AR will be examined in experimental models.
- c-MYC-regulated genes will be studied to identify those that may play a role in therapeutic resistance. Whether targeting any of the putative resistance genes can rescue sensitivity to BET-inhibitors will then be tested by co-treating prostate cancer cells with BET-inhibitors and therapies that block the resistance gene.
- Loss of the tumor suppressor gene PTEN leads to hyperactivity of the oncogenic PI3K pathway, while co-targeting of PI3K and BET is synergistic. This indicates that PTEN-loss may lead to BET-inhibitor resistance in AR-negative prostate cancer. The effects of PTEN on BET-inhibitor sensitivity will be studied in prostate cancer models.
- Finally, the efficacy of a triple therapy targeting AR, BET, and PI3K will be tested in preclinical models.
- If successful, this project will optimize the use of several promising new therapies in prostate cancer and credential these for advancement to clinical trials.
What this means for patients: Resistance to therapies often involves the modulation of alternative pathways that affect tumor growth. Dr. Markowski will identify resistance mechanisms to BET-inhibitor therapy and optimize drug combinations, which will lead to new treatment strategies for patients.
Joaquin Mateo, MD, PhD
Institute of Cancer Research, UK
Mentor: Johann de Bono, MD, PhD
Proposal Title: Defining the Landscape and Clinical Relevance of ATM Defects in Lethal Prostate Cancer
- Defects in DNA repair genes including ATM are present in 20-30% of castration-resistant prostate cancer (CRPC). Prostate tumors harboring these mutations are sensitive to treatment with the PARP-inhibitor Olaparib, and may also be sensitive to other DNA-damage therapies such as platinum chemotherapy.
- Dr. Joaquin Mateo is studying the landscape of ATM mutations in CRPC and their impact on responsiveness to PARP-inhibitors and other treatments.
- The landscape of ATM aberrations in CRPC tumors, including gene mutations, gene silencing, alterations in gene splicing (how the gene is arranged for expression into a protein), and whether mutations were hereditary, will be determined in CRPC tumors from patients in an ongoing Olaparib clinical trial (TOPARP).
- To determine if ATM aberrations confer sensitivity to various therapies, ATM will be knocked down or mutated in cell lines to study the effects on DNA repair activities and drug sensitivity.
- In addition, patients with ATM mutations will be prospectively enrolled onto phase II clinical trials testing Olaparib or platinum chemotherapy (Carboplatin), and followed for treatment outcomes.
- In patients that progress, tumor and blood samples will be collected and examined for mutations and gene expression changes to identify therapeutic resistance mechanisms.
- Once the spectrum of clinically important ATM mutations have been identified, a targeted sequencing test will be developed to identify these mutations in patient samples.
- If successful, this project will lead to the identification of gene mutations that confer sensitivity to specific therapies, enabling precision medicine treatments for these patients.
What this means for patients: DNA repair gene mutations confer sensitivity to PARP-inhibitors and other DNA-damaging therapies. Dr. Mateo is examining the spectrum of mutations in the ATM gene and their functional relevance in patients with advanced prostate cancer. This project will lead to tests and strategies advancing precision medicine for prostate cancer patients.
Sean McBride, MD
Memorial Sloan Kettering Cancer Center
Mentor: Michael Zelefsky, MD
Proposal Title: Biologic Predictors of Outcome in Very High Risk Prostate Cancer Patients Treated with SBRT, ARN-509, and Abiraterone on a Phase 2 Trial
- Patients with high-risk prostate cancer often receive treatment with the combination of radiotherapy and androgen deprivation therapy (ADT). However, most patients still experience recurrences, and there is substantial toxicity associated with this treatment approach. New approaches are needed to improve patient outcomes and reduce treatment-associated toxicities.
- Dr. Sean McBride is evaluating whether stereotactic, hypofractionated radiotherapy delivered with 6 months of ARN-509, abiraterone, and leuprolide will result in improved outcomes compared to conventional radiation therapy and long-term ADT in patients with high-risk prostate cancer.
- Genomic testing will be performed on patient tumor samples and on tumor DNA found circulating in the bloodstream to identify mutations that predict treatment responses. Mutations that arose during therapy will also be evaluated to identify mechanisms of resistance.
- The androgen receptor (AR) gene, which is the primary driver of prostate cancer and target of ARN-509, abiraterone, and leuprolide, will be specifically evaluated for mutations that confer treatment resistance.
- Circulating tumor cells (CTCs) are shed from tumors into the circulation and can be enumerated as an indication of tumor burden. CTC numbers will be evaluated in patients prior to and at several time points following therapy to determine if they may serve as predictive biomarkers of recurrence.
- If successful, this project will identify predictive biomarkers and resistance mechanisms associated with radiotherapy treatment in combination with a more complete androgen suppression therapy.
What this means for patients: New treatment strategies are needed to prevent recurrence and disease progression in patients with high-risk localized disease. Dr. McBride will evaluate treatment response and resistance mechanisms and identify predictive biomarkers associated with a novel treatment scheme, which will enable better prediction of recurrences and earlier salvage interventions.
David Miyamoto, MD, PhD
Harvard: Massachusetts General Hospital
Mentors: Daniel Haber, MD, PhD, Matthew Smith, MD, PhD
Proposal Title: Molecular Analysis of Circulating Tumor Cells to Study Mechanisms of Treatment Resistance in Prostate Cancer
- Circulating tumor cells (CTCs) are cancer cells shed from primary and metastatic tumors into the peripheral blood, and can be repeatedly and non-invasively obtained by blood draws to study tumor characteristics.
- Dr. David Miyamoto is studying CTCs from prostate cancer patients who develop resistance to anti-androgen therapy in order to identify treatment resistance mechanisms.
- The androgen receptor (AR) is the primary driver of prostate cancer and a major therapeutic target. CTCs will be isolated from patients prospectively enrolled in a clinical trial and analyzed for alterations in the AR gene that may contribute to AR-targeted therapy resistance. These studies will enable understanding of the full range of clinically relevant AR alterations and will provide blood-based predictive biomarkers.
- WNT and glucocorticoid receptor (GR) pathways are two alternative mechanisms that prostate cancer cells may use to survive when AR is suppressed. CTCs will be assessed for the activities of these pathways and their association with anti-androgen therapy resistance in a prospective patient cohort.
- Finally, complete genomic characterizations will be performed on single CTCs to identify any other mechanisms of anti-androgen therapy resistance. CTCs from patients will also be grown in the laboratory and used to validate and model the effects of potential resistance mechanisms.
- If successful, this project will lead to a comprehensive characterization of clinically relevant AR abnormalities and identify critical pathways associated with resistance to anti-androgen therapies.
What this means for patients: Identifying mechanisms of treatment resistance is critical for optimizing treatment strategies for patients. Dr. Miyamoto will utilize circulating tumor cells to identify anti-androgen therapy resistance mechanisms. This will lead to the development of non-invasive biomarkers that predict response to therapy and the identification of new potential therapeutic targets.
Hao Nguyen, MD, PhD
University of California, San Francisco
Mentors: Davide Ruggero, MD, Peter Carroll, MD, MPH
Proposal Title: Targeting the UPR (Unfolded Protein Response) Pathway in Neuroendocrine and Metastatic Castrate Resistant Prostate Cancer
- Because of the unregulated growth of cancer cells, protein synthesis is often deregulated, resulting in an accumulation of unfolded or misfolded proteins. This activates the “unfolded protein response,” (UPR) which slows down protein synthesis to allow time for the cell to process any misfolded or unfolded proteins, to avoid excess cell stress and cell death.
- Dr. Hao Nguyen is studying the role of the UPR in prostate cancer and whether this pathway represents a viable therapeutic target.
- To determine whether the UPR has a role in prostate cancer initiation, maintenance, or disease progression, the effect of inhibiting the UPR pathway will be studied in preclinical models of prostate cancer driven by overexpression of the cancer-driver gene MYC, and loss of the tumor suppressor gene PTEN.
- How oncogenic stress activates the UPR will be investigated by profiling the changes in protein synthesis in prostate cancer cells. Whether any of these genes can be targeted to alter UPR activation will be explored. This may lead to a potential prognostic indicator for UPR activity.
- Finally, whether targeting the UPR may be efficacious against castrate resistant prostate cancer (CRPC) or neuroendocrine CRPC phenotypes will be explored in preclinical models.
- If successful, this project will lead to an entirely novel approach to targeting prostate cancer.
What this means for patients: The overproduction of proteins can activate cell stress pathways in cancer cells. Dr. Nguyen is exploring how pathways that allow prostate cancer cells to adapt to the accumulation of malfunctioning proteins can be exploited for cancer therapeutics and may lead to a new treatment approach.
Russell Pachynski, MD
Mentor: Robert Schreiber, PhD
Proposal Title: Profiling Immune Cell Trafficking Within the Prostate Tumor Microenvironment
- The immune system has the powerful potential to eliminate cancer, but many factors hamper optimal immune activity and reduce the efficacy of immunotherapy. The balance of anti-tumor and tumor-supportive immune cell types and signaling molecules within the tumor is critical in directing outcomes of treatment with immunotherapies.
- Chemokines are immune signaling molecules that function to control immune cell entry into various tissues. Chemokines play a role in bringing immune cells into tumors and may affect patient outcomes.
- Dr. Russell Pachynski will perform a comprehensive analysis of the immune cell types and chemokines present in prostate tumors in order to ascertain avenues for immunotherapeutic intervention.
- Levels of chemokines and immune cell types will be correlated to identify any chemokines that may affect the entry of specific immune cell populations into tumors.
- Finally, the effects of targeting candidate chemokines for immunotherapy will be evaluated in preclinical models of prostate cancer.
- Dr. Pachynski has found that expression of the chemokine chemerin/RARRES2 is turned off in prostate tumors and affects trafficking of tumor-killing immune cells into the tumor. Overexpression of chemerin/RARRES2 will be tested as one potential immunotherapeutic strategy.
- If successful, this project will identify factors that can be altered to improve immunotherapy for prostate cancer patients.
What this means for patients: Immunotherapies are often unsuccessful because tumor-killing immune cells are unable to enter tumors. Dr. Pachynski will identify molecules that control prostate tumor infiltration by immune cells and test the therapeutic effects of targeting these molecules. This may lead to new strategies to improve prostate cancer immunotherapy.
Loredana Puca, PhD
Weill Cornell Medical College
Mentors: Himisha Beltran, MD, Mark Rubin, MD
Proposal Title: Epigenetic Therapy to Target Castration Resistant Neuroendocrine Prostate Cancer
- A subset of prostate tumors that develop resistance to androgen receptor (AR)-targeted therapies lose their dependence on AR for growth and survival and instead adopt features characteristic of neuroendocrine cells. This neuroendocrine phenotype is highly aggressive, for which new understandings and treatments are urgently needed.
- Dr. Loredana Puca is studying the genomic characteristics of neuroendocrine prostate cancer in order to develop novel treatment strategies.
- The EZH2 gene is a critical regulator of the epigenetic program of cells, which is the DNA structure that controls access to various genes for expression. EZH2 has been implicated in previous studies as a driver of the neuroendocrine phenotype.
- To better understand the mechanisms by which EZH2 modulates AR signaling and the neuroendocrine phenotype, prostate tumors with neuroendocrine features will be profiled for EZH2-regulated genes and alterations in the epigenetic program, and compared with AR therapy-resistant prostate tumors without neuroendocrine features.
- The efficacy of targeting EZH2 will be tested in preclinical models of neuroendocrine prostate cancer. In addition, the effect of co-treatment with EZH2-inhibitors and other therapies will be tested.
- If successful, this project will identify a novel therapeutic strategy for neuroendocrine prostate cancer.
What this means for patients: Prostate tumors with neuroendocrine features are highly aggressive and refractory to androgen receptor (AR)-targeted therapies. Dr. Puca will elucidate the mechanisms that control development and maintenance of this phenotype and test a novel treatment strategy that has the potential to extend the lives of patients.
Steven Rowe, MD, PhD
Johns Hopkins University
Mentors: Kenneth Pienta, MD, Martin Pomper, MD, PhD
Proposal Title: Impact of PSMA-Targeted 18F-DCFPyL PET/CT on Patients with Prostate Cancer
- Accurate risk-prediction and staging of patients is critical for developing optimal treatment plans. These important clinical questions could be answered by improved methods of tumor imaging that have increased sensitivity and specificity in identifying tumor burden and aggressiveness.
- Dr. Steven Rowe is studying the application of a novel positron emission tomography (PET) imaging agent 18F-DCFPyL, which targets PSMA, a molecule highly expressed on prostate cancer cells.
- 18F-DCFPyL-PET/CT scans will be used to image prostate cancer patients in a variety of clinical contexts who are undergoing treatment at John’s Hopkins University.
- Whether the 18F-DCFPyL scan impacts the treating clinician’s decisions on the patient’s treatment plan will be determined by surveying clinicians for their patient management decisions before and after patients undergo 18F-DCFPyL PET/CT examinations.
- Finally, whether the 18F-DCFPyL scan impacts patient outcomes will be determined by monitoring treatment outcomes in all imaged patients.
- If successful, this project will measure the impact of a novel PET imaging technology on the management of patient care and clinical outcomes.
What this means for patients: New imaging technologies are needed to accurately assess tumor burden and design optimal treatment plans. Dr. Rowe will determine whether a novel PET imaging technology with enhanced sensitivity and specificity for detecting prostate cancer impacts treatment plans and patient outcomes. This project will form the basis for large, prospective, multi-center trials that will validate this imaging agent for informing patient management in prostate cancer.
Simpa Salami, MD, MPH
University of Michigan
Mentors: Ganesh Palapattu, MD, Scott Tomlins, MD, PhD
Proposal Title: Molecular Characterization of the Biologically Dominant Nodule in Multifocal Prostate Cancer with N1 Disease
- In the prostate, multiple primary tumors can develop and progress in parallel. However, which of these tumors leads to clinically relevant and lethal disease is unclear.
- Moreover, prognostic tests performed on biopsy samples assume that the lesion that was biopsied for the test is fully representative of disease potential. Understanding how to apply and interpret these tests in patients with multifocal disease is critical.
- Dr. Simpa Salami is studying how prognostic genomic tests can be best applied in patients with multifocal primary prostate cancer.
- Several primary prostate tumor lesions from patients who developed lymph node metastases will be characterized by genomic sequencing and gene expression to identify which primary lesion gave rise to the metastasis.
- The prognostic accuracy of existing prognostic tests (Oncotype DX™, Prolaris™and Decipher™) in predicting lymph node metastasis in primary multifocal prostate cancer will be determined by comparing each of multiple primary tumor lesions with the lymph node metastasis using gene expression panels that reflect each commercial test.
- If successful, this project will guide the application of existing assays and the development of new assays that better inform patient prognosis. In addition, this study may lead to the identification of prioritized genes and/or molecular pathways that can be targeted for therapy in patients with metastatic prostate cancer.
What this means for patients: Prognostic tests that predict patient risk from primary tumor biopsies may be inaccurate in patients with multiple primary tumors. Dr. Salami will compare multiple primary lesions from metastatic prostate cancer patients in order to determine the strengths and limitations of these tests and enable development of more accurate risk stratification tests. This will improve the ability of clinicians and patients to create optimal treatment plans.
Bryan Smith, PhD
University of California, Los Angeles
Mentor: Owen Witte, MD
Proposal Title: Normal Stem Cell Surface Markers as Therapeutic Targets for Advanced Prostate Cancer
- Advanced prostate cancer often acquires characteristics of normal prostate stem cells. Whether these stem cell-like features can be targeted for treatment remains unknown.
- Dr. Bryan Smith is studying molecules on the surface of human prostate stem cells in order to identify any that may serve as targets for treating advanced prostate cancer.
- Trop2 and CD49f are two molecules whose co-expression is used to identify human prostate stem cells. Cells with the Trop2-positive CD49f-positive phenotype will be individually analyzed for gene expression patterns to determine if these cells are composed of multiple subpopulations with distinct molecular programs.
- The genes whose expression varies the most across different subpopulations will be used to identify and study discreet subpopulations of prostate cells. Each subpopulation will be evaluated for gene expression patterns, ability to act as typical stem cells, and ability to initiate prostate cancer under experimental conditions.
- Surface molecules expressed by the normal prostate stem cell populations that are enriched in advanced prostate cancer will be identified and studied for their function in cancer.
- Therapeutic antibodies will be developed that can target these surface molecules, and tested for efficacy in preclinical prostate cancer models.
- If successful, this project will lead to new understandings of prostate cancer biology and identify new therapeutic targets for advanced prostate cancer.
What this means for patients: Prostate cancers often take on stem cell features, which may be therapeutically targetable. Dr. Smith will identify molecules expressed on the surface of stem cells that are also important in prostate cancer and test the efficacy of therapeutically targeting these molecules. This may lead to novel treatments for advanced prostate cancer patients.
Jean Tien, PhD
University of Michigan
Mentor: Arul Chinnaiyan, MD, PhD
Proposal Title: Characterization of Prostate Cancer-Associated Transcript 47 as a Novel Prostate Cancer Oncogene and Therapeutic Target
- Long non-coding RNAs (lncRNAs) are RNA molecules longer than 200 nucleotides that do not generate a protein product but instead perform functions in the cell as RNA.
- Several lncRNAs have been discovered that play roles in prostate cancer and may also be used as prognostic markers and therapeutic targets.
- Dr. Jean Tien is studying the biology of the lncRNA PRCAT47, which was found to be the most highly expressed lncRNA in prostate cancer and was required for prostate cancer growth in preclinical models.
- In order to understand the role of PRCAT47 in prostate cancer, the impact of PRCAT47 on prostate cancer cell proliferation, survival, invasive capacity and gene expression will be examined in experimental models. Whether the presence or absence of androgens affects any of the functions of PRCAT47 will also be studied.
- The role of PRCAT47 on cancer development and metastasis will be examined in animal models by comparing the progression of prostate tumors with and without the PRCAT47 gene.
- Finally, whether drug targeting of PRCAT47 blocks prostate cancer development and progression will be evaluated in preclinical models, to determine whether PRCAT47 represents a promising therapeutic target.
- If successful, this project will define how PRCAT47 drives prostate cancer and determine the therapeutic effects of targeting this gene.
What this means for patients: LncRNAs are a newly studied class of RNA genes, some of which promote prostate cancer development. Dr. Tien will identify the mechanisms by which a lncRNA drives prostate cancer and credential this gene as a potential therapeutic target.
Quoc-Dien Trinh, MD
Harvard: Brigham and Women’s Hospital
Mentors: Donna Berry, PhD, Adam Kibel, MD
Proposal Title: Mobile Health App to Mitigate the Metabolic Effects of Androgen Deprivation Therapy: A Randomized Feasibility Trial in Men Newly Treated with Androgen Deprivation Therapy
- Androgen deprivation therapy (ADT), a mainstay of treatment for prostate cancer, is associated with increased risk for diabetes and certain cardiovascular diseases.
- Exercise programs can reduce or prevent adverse effects associated with long-term use of ADT. However, education alone does not directly translate into changes in routine physical activity or diet, while supervised exercise for all men on ADT is unrealistic.
- Dr. Quoc-Dien Trinh is developing a mobile health app that is specifically designed for men newly initiated on ADT.
- The app will provide exercise and dietary interventions adapted to the patients’ level of engagement with their own health care. User adherence, acceptance, and experience of the mobile health app will be evaluated.
- A pilot randomized clinical trial will be conducted in prostate cancer patients newly initiated on ADT, that will evaluate the effects of the app + usual care vs. usual care alone, on the accumulation of body fat mass.
- If successful, this project will develop an app-based intervention that promotes routine exercise by prostate cancer patients being treated with ADT and reduces the risk for ADT-associated metabolic diseases.
What this means for patients: Androgen deprivation therapy (ADT) is associated with increased body fat percentage and risk for metabolic diseases. Dr. Trinh is developing a mobile app that will encourage patients undergoing ADT to routinely exercise in order to minimize these deleterious side-effects of ADT. The utility of this app will be validated in clinical trials, which will lead to a new, cost-effective intervention that will improve the lives of patients.
Hung-Ji Tsai, PhD
Johns Hopkins University
Mentor: Rong Li, PhD
Proposal Title: Targeting Karyotype Heterogeneity in Prostate Cancer
- Aneuploidy, a phenomenon where cells gain or lose chromosomes, is a hallmark of cancer and can lead to drug resistance. Currently there are no therapeutic solutions targeting aneuploidy-driven cancer due to a poor understanding of the mechanisms by which aneuploidy impacts cell biology.
- Dr. Hung-Ji Tsai will is studying the role of aneuploidy in cancer and is developing strategies to exploit these features for effective therapeutic strategies.
- A genome-wide screen will be performed in a yeast cell system to identify genes required for the continued growth of aneuploid cells, but do not impact the growth of cells that have normal chromosome numbers (euploid).
- Whether previously known functions of these genes are important in regulating the growth of aneuploid cells will be investigated. In addition, how these genes impact the evolution of the tumor genome and heterogeneity of the tumor cell population will be determined.
- Finally, whether specific aneuploid states (gains or losses of specific chromosomes) confer resistance or sensitivity to particular drugs will be explored. For instance, cells with a gain of the chromosome 8q region are hypothesized to be more resistant to Docetaxel and may emerge in response to Docetaxel treatment, but may also be more sensitive to treatment with Topotecan. These hypotheses will be tested, as well as determining the efficacy of combining treatment with Docetaxel plus Topotecan.
- If successful, this project will identify genomic alterations that confer drug resistance and drive tumor evolution, as well as identify more effective treatment combinations.
What this means for patients: Aneuploidy, the gaining or losing of chromosomes as cancers progress, may confer selective advantages to tumor cells including drug resistance. Dr. Tsai will define the genetic pathways that various aneuploid cells rely upon for survival and growth, which may provide new targets for anticancer therapy.
Jelani Zarif, PhD
Johns Hopkins University
Mentor: Kenneth Pienta, MD
Proposal Title: Targeting M2-Tumor Associated Macrophages (M2-TAMs) in Lethal Prostate Cancer
- Tumors are composed not only of cancer cells, but a number of other cell types that infiltrate tumors, including immune cells. M2 macrophages are a type of immune cell that promote tumor growth by providing growth and metastasis-supportive factors and by suppressing the activity of anti-tumor immune cells.
- Dr. Jelani Zarif is studying methods to target M2 macrophages as a treatment for prostate cancer.
- Novel proteins that are expressed on the surface of M2 macrophages will be identified in various primary and metastatic patient tumors.
- The efficacy of targeting M2 surface proteins with antibody-drug conjugates (antibodies that target a surface protein, attached to cytotoxic drugs) will then be explored in preclinical prostate cancer models.
- If successful, this project will credential novel therapeutic targets in the prostate tumor microenvironment.
What this means for patients: The tumor microenvironment includes many non-tumor cells that support tumor growth and represent potential therapeutic targets. Dr. Zarif will identify and credential new targets on a tumor-supportive immune cell type which may lead to new treatments for prostate cancer patients.