The PCF Challenge Award Winners – Class of 2018 recipients are:
Principal Investigators: Mark Pomerantz, MD (Harvard: Dana-Farber Cancer Institute), Philip Kantoff, MD (Memorial Sloan Kettering Cancer Center)
Co-Investigators: Deborah Schrag, MD, MPH (Harvard: Dana-Farber Cancer Institute), Lorelei Mucci, ScD (Harvard TH Chan School of Public Health), Kenneth Offit, MD, MPH (Memorial Sloan Kettering Cancer Center), Vijai Joseph, PhD (Memorial Sloan Kettering Cancer Center), Wassim Abida, MD, PhD (Memorial Sloan Kettering Cancer Center), Matthew Freedman, MD (Harvard: Dana-Farber Cancer Institute)
Project Title: The Impact of DNA Damage Repair Abnormalities in Prostate Cancer
- Approximately 25-30% of metastatic prostate cancers harbor mutations in a class of genes that repair damaged DNA (DDR genes). In about half of these patients (12%), the mutations had been inherited, and likely caused the development or progression of their cancer.
- This tri-institutional team will investigate the prevalence of DDR mutations and their prognostic significance in men with high-risk, localized prostate cancer.
- To determine whether inherited alterations in DDR genes can identify a more aggressive form of disease within the high-risk localized prostate cancer population, 3,000 men diagnosed with high-risk localized prostate cancer and who have long-term clinical follow-up data, will be evaluated for inherited alterations in 40 different DDR genes.
- Whether any DDR gene alterations associate with poor clinical outcomes will be determined.
- Whether the aggregation of rare variants within genes or across genes within DNA repair pathways increase the risk of disease progression will also be evaluated.
- The team will model the effectiveness, cost-effectiveness and cost-utility ratios for DDR germline mutation screening and risk-tailored management, compared to no screening and standard management for men with high-grade/locally advanced prostate cancer.
- The impact of screening family members of germline DDR variant carriers will also be modeled.
- If successful, this project will result in the identification of inherited DDR gene alterations that likely drive more aggressive forms of high-risk localized prostate cancer, and facilitate informed decisions about whether germline DDR testing with tailored treatment holds promise as an effective strategy to reduce the morbidity and mortality of prostate cancer.
What this means to patients: Inherited DNA damage repair (DDR) gene alterations that likely caused prostate cancer are found in 12% of patients with metastatic disease, but their significance in localized prostate cancer is unclear. This tri-institutional team will determine the prevalence and prognostic significance of inherited DDR gene alterations in high-risk localized prostate cancer, and model the impact of germline screening and risk-tailored management in this population. This will lead to improved outcomes in a subset of men with high-risk localized prostate cancer who would otherwise inevitably develop more advanced and potentially lethal disease.
Principal Investigators: Julie Graff, MD (VA Portland Health Care System, Oregon Health & Science University), Amy Moran, PhD (Oregon Health & Science University), Karen Sfanos, PhD (Johns Hopkins University)
Co-Investigators: Reid Thompson, MD, PhD (VA Portland Health Care System), Lauren Peiffer, DVM (Johns Hopkins University), Tomasz Beer, MD (Knight Cancer Institute, OHSU), George Thomas, MD (Knight Cancer Institute, OHSU), Lisa Coussens, PhD (OHSU)
Project Title: Fecal Microbiota Transplant to Enhance Response to PD-1 Inhibition in Metastatic Castration Resistant Prostate Cancer
- Clinical trials have found that some men with metastatic castration resistant prostate cancer (mCRPC) whose cancer is progressing on the androgen receptor (AR) antagonist enzalutamide can have profound and durable responses to the immune checkpoint inhibitor pembrolizumab. However, no universal predictor of response or resistance has been found.
- Preclinical and clinical studies have suggested that the composition of the fecal microbiota can impact responses to checkpoint inhibitors.
- Julie Graff and team will investigate whether responses to pembrolizumab can be enhanced in advanced prostate cancer patients by fecal microbiota transplant (FMT) to increase gastrointestinal (GI) bacterial diversity and transfer anti-tumor response properties between individuals.
- A phase II clinical trial will be conducted in a Veteran’s Administration Hospital to evaluate whether the transfer of fecal microbiota from pembrolizumab responders into non-responders can enhance sensitivity to pembrolizumab re-treatment.
- The diversity of GI microbiota among mCRPC patients who responded to pembrolizumab, either on the FMT transplant trial or on a trial testing pembrolizumab in men progressing on enzalutamide, will be investigated to determine if there are differences in GI microbiota that correlate with treatment response. The team will also determine how the GI microbiome complexity changes in non-responders after FMT from responders, and if these changes correlate with subsequent treatment response.
- Rigorous investigation of the activation and function of immune cells pre- and post-FMT will be performed to examine the interplay between the immune system, the tumor, and the gut microflora.The ability of bacterial species enriched in the GI tract of patients responding to pembrolizumab to activate immune responses will be evaluated. Mutated tumor antigens targeted by immune cells in patients who responded to pembrolizumab after FMT will also be identified.
- If successful, this project will identify novel mechanisms of response or resistance to checkpoint inhibitors and new treatment strategies by which to enhance anti-tumor immune responses in patients with mCRPC.
What this means to patients: Checkpoint immunotherapy can induce dramatic tumor shrinkage and even cures in many cancer types, but has not yet been optimized in prostate cancer. Dr. Graff and team will determine whether fecal microbiota transplant (FMT) from patients who previously responded to immune checkpoint inhibitors can impact anti-tumor immune responses and enhance sensitivity to pembrolizumab re-treatment in men with mCRPC. This may lead to a novel treatment strategy to successfully treat prostate cancer with immune checkpoint inhibitors.
Principal Investigators: Susan Halabi, PhD (Duke University), Christopher Sweeney, MBBS (Harvard: Dana-Farber Cancer Institute), Jayne Tierney, PhD (University College London)
Co-Investigators: Sandipan Dutta, PhD (Duke University)
Project Title: Surrogate Endpoints of Overall Survival in Men with Metastatic Hormone Sensitive Prostate Cancer
- Metastatic hormone sensitive prostate cancer (mHSPC), is a currently incurable and inevitably lethal form of prostate cancer for which new treatments are urgently needed.
- The identification of intermediate clinical trial endpoints (ICEs) that are highly predictive surrogates for overall survival (OS), but can be determined much earlier in clinical trials, will reduce the time it takes to conduct clinical trials and encourage pharmaceutical companies to develop new drugs for these patients.
- Susan Halabi and team will identify reliable ICEs for OS for mHSPC that can be used to speed clinical trials.
- Data from previously conducted phase II and III clinical trials will be pooled and evaluated for ICEs. To reflect the changing treatment landscape for mHSPC, ICEs and prognostic models will be assessed in two phases. Data from the pre-docetaxel era in the mHSPC setting (19 trials with over 6,000 men) will be used to identify ICEs, while data from mHSPC treated with docetaxel and/or abiraterone (12 trials with over 6,000 men) will be used to validate the ICEs.
- The team will evaluate whether PSA <0.2 ng/ml at 6-7 months, time to castration-resistance, and time to clinical progression, may be reliable ICEs that predict OS.
- Prognostic models of clinical outcomes that are based on clinical factors, will be developed to predict OS and the ICEs being evaluated.
- Prognostic factors of extreme treatment resistance (progression-free survival (PFS) <6 months) and durable response (OS duration >10 years) will also be evaluated.
- If successful, this project will identify ICEs that reliably predict OS in men with mHSPC, as well as clinical factors that predict outcomes. This information can be used to design clinical trials and help clinicians to tailor optimal treatments for individual patients.
What this means to patients: Intermediate clinical endpoints (ICEs) that can reliably predict overall survival (OS) can markedly speed the time it takes to know if a treatment is effective in clinical trials. Dr. Halabi and team will identify and validate ICEs for men with metastatic hormone sensitive prostate cancer (mHSPC), and develop prognostic models of clinical outcomes. This will shorten the time it takes to conduct clinical trials and improve clinical trial design for mHSPC.
Principal Investigators: Steven Patierno, PhD (Duke University), Daniel George, MD (Duke University), Jennifer Freedman, PhD (Duke University), Jiaoti Huang, MD, PhD (Duke University), Amanda Hargrove, PhD (Duke University), Muthana Al Abo, MD, PhD (Duke University)
Co-Investigators: Terry Hyslop, PhD (Duke University), Hailiang Hu, PhD (Duke University)
Project Title: Targeting RNA Splicing in Race-Related Aggressive and Lethal Prostate Cancer
- Alternative RNA splicing is a common phenomenon in which different gene segments are included or excluded from RNA, resulting in different versions of a protein being made, which can alter cell biology. Whether targeting alternative and aberrant RNA splicing has promise for the treatment of prostate cancer is unknown.
- African American men are more likely to develop and die from prostate cancer compared with Caucasian men, however the biological differences driving this disparity are unknown.
- Steven Patierno and team will investigate the role of altered RNA splicing in driving aggressive prostate cancer in African American vs. Caucasian patients, and whether targeting this biology can reverse disease progression.
- The team previously found that differential RNA splicing of the PI3K-delta gene may underlie race-related prostate cancer aggressiveness. The effects of PI3K-delta targeted therapy on prostate cancers with different expression levels of PI3K-delta variants will be tested in animal models.
- Alternative RNA splice variants of glutaminase may drive prostate cancer progression. A pilot clinical trial will be conducted to test the efficacy of a glutaminase-inhibitor (CB-839) for the treatment of prostate cancer. Preclinical studies will also be conducted to test the potential for combining glutaminase-inhibitors with enzalutamide.
- The team has identified and prioritized five pathways in which RNA splicing is dysregulated in prostate cancer in a race-related manner, for which readily available inhibitors exist (DNA-PK, FGFR, MET, NF-kB and WEE1). Whether race-related differential RNA splicing of these genes correlates with sensitivity or resistance to corresponding pathway inhibitors, will be determined.
- The team is developing novel therapeutic splice-switching oligonucleotides (SSOs) and RNA-targeted small molecules to specifically modulate RNA splicing. Therapeutics that target AR-V7, a constantly activated version of the androgen receptor (AR), as well as other genes for which RNA splicing is dysregulated in prostate cancer in a race-related manner (PI3K-delta, GLS1, FASN, RHOU and LMO7) will be developed and tested in preclinical models.
- If successful, this team will validate alternative RNA splice variants that drive race-related prostate cancer aggressiveness and develop novel treatments that target these variants.
What this means to patients: Alternative RNA splicing, in which cells make different versions of proteins with altered functions, is a major driver of prostate cancer progression and treatment resistance. Dr. Patierno and team are identifying genes for which RNA splicing is dysregulated in prostate cancer in a race-related manner, and developing novel treatments to target these genes.
Principal Investigators: Claire Fletcher, PhD (Imperial College London), Charlotte Bevan, PhD (Imperial College London)
Co-Investigators: Karen Knudsen, PhD (Thomas Jefferson University), Johann de Bono, MD, PhD (Institute of Cancer Research), Ian Mills, PhD (University of Oxford)
Project Title: Long Non-Coding RNA, NORAD, and its Targeting MicroRNAs as Treatment Stratifiers and Modulators of DNA Damage and Immune Response in Advanced Metastatic Prostate Cancer
- Advanced prostate cancers commonly gain defects in DNA damage-repair (DDR) genes, which can sensitize tumors to drugs targeting DNA repair pathways and immunotherapy.
- NORAD is a long non-coding RNA (lncRNA) that functions to maintain chromosomal stability, cell division and DNA damage repair activities. Targeting NORAD may be an effective means of sensitizing cancer cells to drugs targeting DNA repair pathways and immunotherapy.
- Claire Fletcher and team are studying the role of NORAD as a biomarker of DDR deficiency and treatment responses, and as a therapeutic target in prostate cancer.
- NORAD expression is controlled by a class of small regulatory RNAs called microRNAs, particularly miR-346. Based on this knowledge, the team has generated a microRNA signature that acts as a surrogate for both NORAD levels and DDR activity.
- In this project, the team will use clinical samples to determine whether the NORAD-surrogate microRNA signature, NORAD levels, and/or miR-346 levels may function as biomarkers to predict patient responses to PARP-inhibitors, taxane chemotherapy, and immunotherapy.
- Refined microRNA/NORAD signatures will be developed and validated for each drug.
- The role of NORAD and miR-346 in prostate cancer cell growth and survival will be determined.
- Whether miR-346 delivery can reduce NORAD levels and sensitize tumor cells to DNA-damaging drugs will be investigated.
- The effects of miR-346 and NORAD on anti-tumor immune responses will be determined in prostate cancer animal models.
- If successful, this project will determine whether NORAD signatures can act as biomarkers to predict treatment responses, and provide rationale for targeting NORAD as a novel therapeutic strategy in prostate cancer.
What this means to patients: Novel therapeutic strategies are urgently needed for advanced prostate cancer. Dr. Fletcher and team are studying the role of the genome-protecting RNA NORAD as a biomarker to predict whether a patient is likely to respond to DNA damage-targeting treatments or immunotherapy, and the potential for targeting NORAD as a novel strategy to improve treatment responses.
Principal Investigators: Thomas Hope, MD (University of California, San Francisco), Matthew Rettig, MD (University of California, Los Angeles), Michael Morris, MD (Memorial Sloan Kettering Cancer Cancer), Matthias Eiber, MD (Technical University of Munich)
Co-Investigators: Shuang George Zhao, MD (University of Michigan), Felix Feng, MD (University of California, San Francisco), Lisa Bodei, MD (Memorial Sloan Kettering Cancer Center), Johannes Czernin, MD (University of California, Los Angeles)
Project Title: Mechanisms of Resistance to PSMA Radioligand Therapy: Radiation Resistance Versus Dose
- Prostate-Specific Membrane Antigen (PSMA) is a protein that is highly expressed on the surface of most prostate cancer cells, and is a promising therapeutic target.
- PSMA-targeted radioligand therapies are a new type of treatment composed of PSMA-targeted molecules attached to radioactive isotypes, which deliver radiation directly to prostate cancer cells.
- Thomas Hope and team are testing the efficacy of the PSMA-targeted radionuclide therapy 177Lu-PSMA-617 in clinical trials for advanced prostate cancer.
- In this project, studies will be performed in conjunction with a phase III 177Lu-PSMA-617 trial to determine the contributions of inherent tumor radiation-sensitivity and the dose of radiation delivered to the tumor, to response to 177Lu-PSMA-617.
- Biomarkers that indicate the sensitivity of tumors to 177Lu-PSMA-617 radiation will be developed by assessing changes in tumor gene expression that correspond with response to therapy. This data will indicate the contribution of inherent tumor radiation-sensitivity to response to 177Lu-PSMA-617.
- In addition to radioactive beta particles, 177Lu-PSMA-617 also emits an amount of photons sufficient to enable visualization within the body using SPECT/CT imaging.
- SPECT/CT imaging will be performed on patients treated with 177Lu-PSMA-617 in order to determine how much radiation enters patients’ tumors and how this correlates with response to the treatment.
- Finally, gene expression and radiation dose data will be integrated to model the contribution of these factors to treatment responses and to create a novel signature to predict response to therapy.
- If successful, this project will improve understanding of the factors associated with benefit from this therapy and improve selection of patients able to benefit from it.
What this means to patients: PSMA-targeted radioligand therapies are a highly promising type of new prostate cancer treatment. Dr. Hope and team will evaluate the contributions of inherent tumor radiation-sensitivity and the dose of radiation delivered to the tumor, to response to 177Lu-PSMA-617, and develop biomarkers that will improve selection of patients most likely to benefit. This study will also inform the development of strategies to increase therapeutic responses to 177Lu-PSMA-617.
Principal Investigators: George Coukos, MD, PhD (University of Lausanne, and Ludwig Cancer Research), Mark Rubin, MD (University of Bern)
Co-Investigators: Alexandre Harari, PhD (UNIL/LICR/CHUV), Michal Bassani-Sternberg, PhD (CHUV/LICR), Urania Dafni, ScD, MSc (CHUV/UNIL), Fernanda Herrera, MD, PhD (CHUV)
Project Title: Immune-Radiation Therapy for Metastatic Castration-Resistant Prostate Cancer
- Checkpoint immunotherapy is a type of treatment that activates a patients’ own immune cells to attack their cancer, by blocking negative immune cell signals. Checkpoint immunotherapy has been highly successful in many cancer types, but has not yet been optimized in prostate cancer.
- George Coukos and team are investigating whether radiation therapy can improve responses to checkpoint immunotherapy in prostate cancer.
- The team will conduct a phase I clinical trial to test the safety and preliminary efficacy of high dose radiation to one metastatic deposit followed by low-dose irradiation delivered to the remaining tumor deposits, combined with intravenous low-dose chemotherapy (cyclophosphamide), followed by ipilimumab and nivolumab checkpoint immunotherapy in subjects with advanced, immunologically unfavorable metastatic castration resistant prostate cancer (mCRPC).
- Whether this treatment regimen is able to increase immune cell infiltration into tumors will be investigated, using tissue biopsies from patients on the trial. The activities and gene expression patterns of tumor-infiltrating immune cells will be determined.
- Whether the treatment combination induces anti-tumor immune responses will be determined. Mutated tumor proteins and prostate cell lineage proteins targeted by immune cells will be identified.
- Specific genetic and genomic characteristics of tumors for which anti-tumor immune responses cannot be generated will be determined.
- If successful, this study will result in a new effective immunotherapy strategy for prostate cancer and identify biomarkers and mechanisms of treatment response vs. resistance.
What this means to patients: Successful optimization of immunotherapy for prostate cancer may lead to long lasting tumor remission and eventually “cure” in prostate cancer patients. Dr. Coukos and team are testing a novel treatment strategy combining radiation therapy with immunotherapy in patients with mCRPC, and determining the biology and biomarkers of treatment response vs. resistance.
Principal Investigators: Michael Shen, PhD (Columbia University Irving Medical Center), Charles Drake, MD, PhD (Columbia University Medical Irving Center), Andrea Califano, PhD (Columbia University Irving Medical Center)
Co-Investigators: Cory Abate-Shen, PhD (Columbia University Irving Medical Center), Susan Bates, MD (James J. Peters Veterans Affairs Medical Center, Bronx), Antonio Tito Fojo, MD (James J. Peters Veterans Affairs Medical Center, Bronx), Massimo Loda, MD (Dana-Farber Cancer Institute), Francesco Cambuli, PhD (Columbia University Irving Medical Center)
Project Title: Master Regulators Underlying Tumor-Microenvironment Interactions in Metastatic Prostate Cancer
- The androgen receptor (AR) is the primary driver and main therapeutic target in advanced prostate cancer. However, resistance to anti-androgen therapy is inevitable, and current therapeutic options for AR-therapy resistant disease have only a limited impact on patient survival.
- Identification of master regulator (MR) proteins that drive aggressive prostate cancer, as well as drugs that can specifically target these MRs, is critical for advancing treatment and extending the lives of patients. Califano and his laboratory have developed novel algorithms to tease out MR’s using gene expression profiling data.
- Drs. Michael Shen and Cory Abate-Shen, along with the team’s young investigator Dr. Cambuli, are using single-cell analyses to investigate MR proteins specific to the immune and stromal components of the tumor microenvironment (TME), while Dr. Loda will perform state-of-the-art imaging of the MR proteins to understand their role in cancer cells. The investigators will test drugs that can specifically target these MRs as a precision oncology based approach to treatment.
- A proof-of-concept precision medicine clinical trial will be performed with mCRPC patients in the Bronx VA hospital, under the direction of Drs. Drake, Bates, and Fojo. Single-cell analysis of patient tumor biopsies will be performed to identify TME-based master regulators that can be targeted with existing drugs. Predicted treatment regimens will be prioritized based on expected impact, agent availability, and activity in parallel studies in patient-derived tumor cultures and xenografts. A final treatment regimen will be selected by the treating physician in conference with the study team.
- Master regulators that drive prostate tumor/microenvironment interactions will be identified using gene expression data from single cells isolated from tumors, and validated in preclinical models.
- The types of tumor/microenvironment cells that express master-regulators driving prostate cancer progression, their location within cells, and their effects on the tumor microenvironment, will be determined in experimental models.
- If successful, this project will identify novel prostate cancer drivers from the tumor microenvironment, and validate these as therapeutic targets in a precision medicine clinical trial.
What this means to patients: Advanced prostate cancer is currently incurable and new treatment strategies are urgently needed. This team will develop a precision medicine platform to identify and validate individualized treatments that target novel prostate cancer drivers in the tumor microenvironment.
Principal Investigators: Steven Balk, MD, PhD (Beth Israel Deaconess Medical Center/Harvard Medical School), Huihui Ye, MD (Beth Israel Deaconess Medical Center/Harvard Medical School), David Avigan, MD (Beth Israel Deaconess Medical Center/Harvard Medical School), Gordon Freeman, PhD (Dana-Farber Cancer Institute)
Co-Investigators: Jacalyn Rosenblatt, MD (Beth Israel Deaconess Medical Center/Harvard Medical School), Manoj Bhasin, PhD (Beth Israel Deaconess Medical Center/Harvard Medical School), Catherine Wu, MD (Dana-Farber Cancer Institute), Lillian Werner, MSc (Dana-Farber Cancer Institute), David Einstein, MD (Beth Israel Deaconess Medical Center/Harvard Medical School), Kathleen Mahoney, MD, PhD (Dana-Farber Cancer Institute), Dina Stroopinsky, PhD (Beth Israel Deaconess Medical Center/Harvard Medical School), Xiao Wei, MD (Dana-Farber Cancer Institute)
Project Title: Identifying and Targeting Immunogenic Prostate Cancer at High Risk for Lethal Metastatic Progression
- The immune system is naturally able to recognize and kill tumor cells. However, for cancer to progress, tumors prevent immune cell activity through mechanisms such as expression of immune-suppressive “checkpoint” signals, like PD-L1.
- Checkpoint immunotherapy is a type of treatment that blocks negative immune checkpoint signals and reactivates anti-tumor immune responses. Anti-PD-L1/PD1 checkpoint immunotherapy has been highly effective, and even curative, in many types of cancer. In prostate cancer however, responses have been seen only in select patients.
- Optimizing immunotherapy for prostate cancer would vastly improve outcomes for patients.
- Steven Balk and team are studying methods to improve immunotherapy in prostate cancer patients and developing biomarkers to identify the patients who will benefit from these treatments.
- Expression of PD-L1 in tumors is considered a potential biomarker to identify patients who may benefit from anti-PD-L1/PD1 checkpoint immunotherapy. Genomic and immune features that are associated with T cell infiltration and PD-L1 expression will be investigated in prostate cancer samples. Whether high PD-L1 expression is associated with genomic instability or with an exhausted T cell phenotype, will be determined.
- Dr. David Einstein is leading a phase 2 clinical trial to test the PD-1 inhibitor nivolumab in patients experiencing biochemical recurrence after primary treatment for prostate cancer, who have a rapid PSA doubling time indicative of high risk for progression to lethal, metastatic disease, and who do versus don’t exhibit PD-L1 expression in tumors. Immune and genomic features that correlate with response or resistance to treatment will be determined.
- Finally, T cells that are able to recognize and target tumors will be obtained from patients responding to treatment with anti-PD1 or with radiation therapy. Mutated tumor proteins recognized by anti-tumor T cells will be identified and investigated for potential as tumor vaccine targets.
- If successful, this project will identify biomarkers that can predict responsiveness to checkpoint immunotherapy, and identify possible avenues for improving immunotherapy for prostate cancer patients.
- This project will synergize with the Cancer Center at Beth Israel Deaconess Medical Center’s Immunotherapy Institute, which integrates basic science, clinical research and patient care to mobilize the immune system in the fight against cancer through the study of personalized cancer vaccines, checkpoint blockade inhibitors, CAR T-Cell therapy and bone marrow transplantation.
What this means to patients: Checkpoint immunotherapy holds vast promise for improving patient outcomes but remains to be optimized in prostate cancer. Dr. Balk and team will conduct experimental studies and clinical trials to identify and validate biomarkers that classify prostate cancer patients most likely to respond to checkpoint immunotherapy. In addition, mutated tumor proteins that are targeted by T cells during treatment with immunotherapy or radiation therapy will be identified and tested as potential cancer vaccine targets.
Principal Investigators: Nima Sharifi, MD, (Cleveland Clinic)
Co-Investigators: Jianneng Li, PhD (Cleveland Clinic), Eric Klein, MD (Cleveland Clinic), Mohammad Alyamani, PhD (Cleveland Clinic), Jorge Garcia, MD (Cleveland Clinic), Cristina Magi-Galluzzi, MD, PhD (Cleveland Clinic), Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute), Shaun Stauffer, PhD (Cleveland Clinic)
Project Title: Therapeutic Reversal of a Metabolic Mechanism that Drives Prostate Cancer Resistance to AR Antagonists
- Prostate cancer cells are dependent on the androgen receptor (AR) as a primary fuel source, and AR is therefore the primary treatment target in this disease. However, resistance to AR-targeted therapy commonly develops and cancers can continue to progress. Understanding the mechanisms underlying treatment resistance is critical for improving treatment strategies.
- Nima Sharifi and team have found that some prostate cancers can develop resistance to AR-targeted therapy by switching to dependency on the glucocorticoid receptor (GR), which can drive expression of similar genes as AR. The team is investigating the mechanisms by which this occurs.
- Whether and how enzalutamide and apalutamide treatment alter glucocorticoid or androgen metabolism will be determined.
- Whether resistance to the AR-targeted therapies enzalutamide and apalutamide can be driven by glucocorticoid metabolism pathway alterations, including loss of the GR-inhibiting enzyme 11βHSD2, or increase in GR-promoting enzymes, will be investigated in preclinical models.
- Samples from a clinical trial testing neoadjuvant apalutamide plus androgen deprivation therapy (ADT) in patients with intermediate- or high-risk localized prostate cancer who are undergoing radical prostatectomy, will be used to determine whether treatment responses are associated with levels of metabolic enzymes that regulate the GR and AR pathways.
- Whether targeting of GR-promoting enzymes may be effective for preventing resistance to AR-targeted therapies will be investigated in preclinical cell line and animal models.
- Finally, the team will develop a potent inhibitors of GR-promoting enzymes for testing in clinical trials.
- If successful, this project will detail mechanisms by which a switch to GR-dependency can occur and drive resistance to the AR-targeted therapies, and develop new treatments to prevent this from happening.
What this means to patients: Resistance to AR-targeted therapies and development of castration resistant prostate cancer (CRPC) can be caused by turning on the GR pathway. Dr. Sharifi and team are investigating the mechanisms by which this occurs and are developing novel treatments to target the GR pathway. Targeting both AR and GR may prevent the development of CRPC in some patients.