Principal Investigators: Andrew Hsieh, MD (Fred Hutchinson Cancer Research Center), Yu Chen, MD, PhD (Memorial Sloan Kettering Cancer Center), Brett Carver, MD, PhD (Memorial Sloan Kettering Cancer Center)
Co-investigators: Peter Nelson, MD (Fred Hutchinson Cancer Research Center), Dana Rathkopf, MD (Memorial Sloan Kettering Cancer Center), Neal Rosen, MD, PhD (Memorial Sloan Kettering Cancer Center), Heather Cheng, MD, PhD (University of Washington)
Project Title: Pharmacogenetic Dissection of Protein Synthesis Control across the Spectrum of PI3K Pathway Mutations in Prostate Cancer
- The oncogenic phosphoinositide-3-kinase (PI3K) pathway is frequently mutated and hyper-activated in metastatic castrate-resistant prostate cancer (mCRPC). However, PI3K-targeted therapies have failed to show efficacy in clinical trials.
- In order to develop a strategy to successfully target this pathway in CRPC, Dr. Hsieh and team are studying how mutations in the PI3K pathway affect oncogenic pathway activities and tumor cell responses to PI3K pathway-targeted treatments.
- The biology of specific PI3K pathway alterations found in human tumors will be studied by generating cell lines harboring these mutations and assaying gene expression, pathway activation, and the ability to form tumors in animal models. In addition, each gene in the PI3K pathway (over 17) will be individually deleted in each of these cell lines in order to delineate the nodes that are critical for maintaining oncogenic activities in the context of specific mutations.
- To identify the most efficacious strategies for targeting tumors harboring specific mutations in the PI3K pathway, each of the PI3K pathway mutation-bearing cell lines will be treated with various PI3K pathway-inhibitors and examined for effects on cell death. Combination therapy with these inhibitors plus inhibitors that target the proteins in the pathway involved in gene expression will also be tested. Promising therapeutic combinations will be validated for efficacy in preclinical tumor models.
- Biomarkers will be developed to indicate oncogenic PI3K activity in clinical CRPC samples. The ability of these biomarkers to predict PI3K pathway mutations and clinical outcomes will be validated in phase Ib clinical trials with the PI3K-pathway inhibitor CC-115.
- If successful, this study will elucidate the biology of PI3K pathway mutations, and develop strategies for therapeutically targeting tumors harboring these mutations.
What this means for patients:
PI3K is a commonly mutated oncogenic pathway that has not yet been successfully targeted in CRPC patients. Dr. Hsieh and team will delineate the biology of various PI3K pathway mutations that occur in CRPC and develop strategies to effectively target tumors harboring these mutations. This will lead to a novel and powerful precision medicine approach for prostate cancer.
Principal Investigators: Gerhardt Attard, MD, PhD (The Institute of Cancer Research, London), Himisha Beltran, MD (Weill Cornell Medicine), Francesca Demichelis, PhD (University of Trento), Kim Chi, MD (University of British Columbia), Alexander Wyatt, PhD (University of British Columbia), Eliezer Van Allen, MD (Dana-Farber Cancer Institute), Christopher Maher, PhD (Washington University), Mark Rubin, MD (Weill Cornell Medicine and New York-Presbyterian Hospital)
Co-investigators: Andrew Armstrong, MD (Duke Cancer Institute), Alessandro Romanel, PhD (University of Trento)
Project Title: Development and Qualification of the PCF SELECT (Specific Evaluation in Liquid biopsies of Established prostate Cancer Targets) Plasma DNA Assay
- Genomic characterization of tumors is necessary for making precision medicine treatment decisions. Precision medicine requires invasive biopsies, which are difficult to perform, often painful, expensive, and not feasible for all patients. Collecting sequential samples at each treatment change is also difficult.
- New genomic sequencing technologies have enabled the detection of tumor aberrations from circulating tumor DNA (ctDNA), which is DNA shed from tumor cells into the circulation. ctDNA can be obtained from a simple blood draw, allowing serial samples to be collected from every patient.
- Dr. Attard, Dr. Beltran and a team of expert ctDNA investigators are developing a targeted genomic sequencing test (to be named PCF SELECT) that identifies tumor mutations in ctDNA from metastatic prostate cancer patients and can be used to guide selection of precision medicine treatments.
- The team has collectively generated genomic sequencing data from >1,000 mCRPC ctDNA samples using a range of sequencing technologies and test designs. These data will be interrogated to identify a panel of genomic alterations that can be assessed to predict clinical outcome or response to treatment.
- The test will undergo centralized development, in which genomic sequencing and analysis will be optimized and validated at a CLIA-certified genomics laboratory using clinical metastatic prostate cancer samples. This will result in the development of a clinical-grade ctDNA PCF SELECT test and test report.
- The PCF SELECT test will then be implemented at each team site to evaluate samples from metastatic prostate cancer patients participating in clinical trials.
- Associations between identified genomic aberrations and clinical outcomes or response to treatment will be determined. Questions that will be examined include: evaluating associations between patient outcomes and ctDNA aberrations in the androgen receptor (AR) gene and AR splice variants; identifying predictive ctDNA biomarkers of resistance to abiraterone, enzalutamide and/or taxanes; and characterization of genomic aberrations that emerge at treatment resistance.
- If successful, this project will result in the development of a clinical-grade ctDNA test that will be widely used by the clinical prostate cancer community for precision medicine applications for metastatic prostate cancer patients. An industry collaborator will be sought to commercialize the test.
What this means for patients:
To establish precision medicine as a standard of care for all prostate cancer patients, widely adoptable genomic sequencing tests need to be developed. Dr. Attard, Dr. Beltran and team are developing a clinically validated genomics sequencing test using circulating tumor DNA that can be obtained from blood draws, to identify actionable tumor mutations and make precision medicine treatment decisions.
Principal Investigators: Hongwu Chen, PhD (University of California, Davis), Christopher Evans, MD (University of California, Davis)
Co-investigators: Demin Cai, PhD, (University of California, Davis), Yong Xu, PhD, (Guangzhou Institute of Biomedicine and Health), Alexander Wyatt, PhD, (Vancouver Prostate Centre), Allen Gao, MD, PhD (University of California, Davis)
Project Title: Targeting ROR-gamma with Novel Therapeutics for Lethal Prostate Cancer
- The androgen receptor (AR) is the primary driver of prostate cancer. Targeting AR is the mainstay of treatment for this disease, but while effective at first, resistance to AR-targeted therapy inevitably occurs. New methods to treat prostate cancer and target AR are urgently needed.
- Dr. Chen and team are studying the therapeutic effects of targeting ROR-gamma, a protein that is amplified in metastatic prostate cancer and supports the activity of AR. The team has previously demonstrated that targeting ROR-gamma can potently inhibit the activity of AR and block the growth of CRPC in preclinical models.
- The lead ROR-gamma targeting compound that the team has developed and found to be efficacious will be further optimized. An integrated medicinal chemistry approach will be used to increase the compound’s anti-tumor potency and oral bioavailability. Pharmacokinetics and toxicity studies will be conducted to ready the most promising therapeutic candidates for entry into clinical trials.
- The mechanisms by which the optimized ROR-gamma inhibitors block tumor growth will be investigated by examining changes in gene expression and genomic transcriptional activity in CRPC cells treated with the inhibitors. The effects of the inhibitors on the activities of ROR-gamma and AR-mediated gene expression will be assessed. In addition, whether the inhibitors also exhibit off-target effects will be determined. ROR-gamma is also important in the function of certain inflammatory immune cells, thus any effects of the inhibitors on immune cells will be investigated.
- Finally, the team will develop gene expression and genomic assays that identify patients whose tumors express ROR-gamma and are thus likely to respond to ROR-gamma targeting therapies.
- If successful, this team will develop a novel ROR-gamma targeting therapy that will be entered into clinical trials for patients with CRPC.
What this means for patients:
New treatment strategies are urgently needed for patients with treatment-resistant CRPC. Dr. Chen and team are developing and optimizing a potent new therapy that targets ROR-gamma, a partner of the androgen receptor, and will ready this therapy for advancement into clinical trials for CRPC patients.
Principal Investigator: Kenneth Pienta, MD (Johns Hopkins University)
Co-investigators: Peter Kuhn, PhD (University of Southern California), Joshua Lang, MD (University of Wisconsin), Peter Nelson, MD (University of Washington), Colm Morrissey, PhD (University of Washington), Kenneth Valkenburg, PhD (Johns Hopkins University)
Project Title: Integrated Identification and Molecular Evaluation of Disseminated Tumor Cells and their Microenvironment
- Disseminated tumor cells (DTCs) are dormant tumor cells that can be found in the bone marrow of prostate cancer patients that may eventually reactivate and develop into metastases. Thus, DTCs represent a measure of residual disease. The ability to properly identify DTCs is critical for harnessing these cells as biomarkers that predict a high risk for cancer recurrence.
- Dr. Pienta and team will employ several single cell analysis biotechnologies to identify and characterize the true rate of DTCs with lethal potential in patients at the time of radical prostatectomy. These rates will also be compared to rates of circulating tumor cells (CTCs) that are present in the blood of patients, in order to determine the best biomarkers for identifying patients who are likely to eventually experience a recurrence.
- In order to differentiate DTCs and CTCs with true metastatic potential from cells that have been sloughed off from the primary tumor but lack the ability to grow in other tissues, genomic alterations and gene expression will be characterized in DTCs, CTCs, and primary tumor cells and correlated with disease recurrence.
- Precision medicine relies on the identification of ‘actionable’ mutations present in a patient’s tumor cells. Whether DTCs can be used to identify targetable genomic mutations representative of the entire metastatic tumor burden will be determined by comparing mutations present in DTCs with those present in metastatic tumor samples from the same patient.
- Finally, in order to understand how DTCs interact with the immune cells in the bone marrow, immune cells from peripheral blood, the bone marrow, and the primary tumor will be characterized and compared. Immune cell properties that correlate with disease recurrence will be identified in order to elucidate how DTCs are able to survive in the bone marrow microenvironment.
- If successful, this project will develop methods to identify DTCs, utilize these cells as biomarkers for identifying patients at high risk for recurrence, and credential genomic analyses of DTCs for guiding precision medicine decisions.
What this means for patients:
Disseminated tumor cells (DTCs) are dormant tumor cells residing in the bone marrow that may eventually reactivate and form lethal metastases. Dr. Pienta and team will elucidate the phenotype and biology of DTCs in order to use these cells as a biomarker for identifying patients at risk for relapse and to guide the management of men with advanced prostate cancer.
Principal Investigators: Russell Taichman, DMD, (University of Michigan), Laura Buttitta, PhD (University of Michigan), Todd Morgan, MD (University of Michigan), Kenneth Pienta, MD (Johns Hopkins University)
Co-investigators: Frank Cackowski, MD, PhD (University of Michigan)
Project Title: Mechanisms of Prostate Cancer Relapse in Marrow
- The bone is the most frequent site of prostate cancer metastasis. However, the mechanisms that allow prostate cancer cells to live and thrive in the bone marrow microenvironment are poorly understood.. This knowledge is necessary for developing strategies to target and prevent prostate cancer bone metastases.
- Dr. Taichman and team are studying the mechanisms that regulate the proliferation of disseminated tumors cells (DTCs) in the bone marrow. The team hypothesizes that genes which have been conserved throughout evolution and regulate primitive survival and proliferation pathways, are expressed by DTCs once they enter the bone marrow and are crucial for the development of bone metastases.
- Gene expression will be evaluated in DTCs collected from hormone-naïve prostate cancer patients who are experiencing a rising PSA after primary therapy, indicating the outgrowth of metastases. Candidate genes that are likely involved in DTC survival, dormancy or metastasis will be identified for further study in the emerging cancer model Drosophila melanogaster (fruitfly).
- Drosophila genes that correspond to the human DTC genes of interest will be identified and over-expressed in the developing Drosophila accessory gland, which is functionally analogous to the human prostate. Genes that alter the placement, proliferation or survival of Drosophila accessory gland cells will be identified as evolutionarily conserved genes with a high likelihood of regulating critical survival and proliferation pathways in human tumor cells.
- Human prostate cancer cell lines will be engineered to express different colored fluorescent proteins depending on where the cell is in the replication cycle. The genes identified as important in the developing Drosophila accessory gland will be turned off in these cells to determine their roles in prostate cancer cell proliferation and survival. Genes that show effects will then be analyzed in preclinical tumor models for their role in establishing prostate cancer bone marrow metastases.
- If successful, this project will identify the genes most critical to the establishment and growth of prostate cancer bone metastases, and credential these genes as promising therapeutic targets.
What this means for patients:
Identifying therapeutic targets for prohibiting the growth of prostate tumor bone metastases is critical for reducing deaths from this disease. Dr. Taichman and team will use a novel approach to identify evolutionarily conserved genes critical for the growth and survival of disseminated prostate cancer cells in bone. This will lead to the development of new therapies for advanced prostate cancer patients.
Principal Investigator: Eliezer Van Allen, MD (Harvard: Dana-Farber Cancer Institute), Alan D’Andrea, MD (Dana-Farber Cancer Institute), Peter Nelson, MD (Fred Hutchinson Cancer Research Center), Johann S de Bono, MD, PhD (The Institute of Cancer Research)
Co-Investigators: Jason Bielas, PhD (Fred Hutchinson Cancer Research Center), Colin Pritchard, MD, PhD (University of Washington), Michael Schweizer, MD (University of Washington), Joaquin Mateo, MD, PhD (Institute of Cancer Research), Suzanne Carreira, PhD (Institute of Cancer Research)
Project Title: Exploiting DNA Repair Defects in Metastatic Prostate Cancer to Promote Immunotherapeutic Responses
- Checkpoint immunotherapy is a powerful type of cancer therapy that can be curative in patients with certain tumor types. However, checkpoint immunotherapy has not demonstrated much efficacy in prostate cancer, to date.
- Checkpoint immunotherapy works by reawakening tumor-killing immune cells that had naturally developed but were turned off by tumor cells. Tumors with higher levels of mutations are more likely have developed these immune responses and thus may be more susceptible to checkpoint immunotherapy.
- Eliezer Van Allen and team are exploring whether a subset of prostate cancer patients who carry mutations in DNA repair genes will be more susceptible to anti-PD1 checkpoint immunotherapy.
- 500 metastatic castrate resistant prostate cancer (mCRPC) tumors will be genomically sequenced and evaluated for mutations in genes that play a role in repairing damaged DNA. Tumors that have such mutations are more likely to have consequentially developed many more mutations. These tumors will be evaluated for all mutated proteins that may be able to activate anti-tumor immune responses. In addition, whether tumors that have mutations in DNA repair genes are more likely to be infiltrated by immune cells will be evaluated.
- There are many types of mutations that can occur, but not all affect the function of the gene. The DNA repair gene mutations identified in these tumors will be studied to determine which mutations affect gene function and which have no effect.
- The team will conduct two clinical trials of PD-1 and PD-L1 inhibitors (pembrolizumab and durvalumab) in mCRPC patients with DNA repair defects and/or tumors that have a high mutational load to determine whether these therapies have activity in this mCRPC subtype.
- Finally, whether other prostate cancer therapies impact the levels of DNA damage, tumor mutations and infiltration of tumors by immune cells in prostate tumors with DNA damage mutations will be examined in preclinical models. This will indicate whether any other therapies can increase the sensitivity of prostate tumors to checkpoint immunotherapy.
- If successful, this project will lead to the identification of a subset of prostate cancer patients that may benefit from treatment with checkpoint immunotherapy.
What this means to patients: Dr. Van Allen and team are studying the biology of prostate tumors with mutations in DNA repair genes and determining whether these tumors exhibit sensitivity to checkpoint immunotherapy. This project will lead to a new, potentially curative precision medicine paradigm for prostate cancer patients with previously incurable disease.
Principal Investigator: Johann de Bono, MD, PhD (Institute of Cancer Research), Andrew Cato, PhD (Karlsruhe Institute of Technology), Stephen Plymate, MD, PhD (University of Washington), Myles Brown, MD (Dana-Farber Cancer Institute)
Co-Investigators: Laura Cato, PhD (Dana-Farber Cancer Institute), Bissan Al-Lazikani, PhD (The Institute of Cancer Research), Adam Sharp, MD, PhD (The Institute of Cancer Research), Paul Workman, PhD, (The Institute of Cancer Research), Julian Blagg, PhD (The Institute of Cancer Research), Rob van Montfort, PhD (The Institute of Cancer Research), Olivia Rossanese, PhD (The Institute of Cancer Research), Cynthia Sprenger, PhD (University of Washington)
Project Title: Targeting the Druggable Interaction between the NH2-Terminal Domain of the Androgen Receptor and BAG-1L, a Key Regulator of AR Function
- The androgen receptor (AR) is the primary driver of prostate cancer and therefore the primary therapeutic target. However, even when treated with highly potent AR-targeted therapies, prostate tumors eventually develop resistance and progress. Resistance to AR-therapy may involve expression of variant forms of AR (AR-Vs) that cannot be blocked by existing therapies. New strategies to inhibit AR that also block AR-Vs are sorely needed for the treatment of prostate cancer patients.
- de Bono and team are studying the impact of targeting BAG-1, a protein partner of AR and AR-Vs, for the treatment of prostate cancer.
- BAG-1 has previously been shown to be highly expressed in castrate resistant prostate cancer (CRPC) and interacts with AR and AR-Vs in a manner that promotes AR activity. Whether BAG-1 is required for prostate cancer growth will be determined in preclinical models. In addition, the effect of BAG-1 loss on AR and AR-V activities will be determined in preclinical models and in tumors derived from patients. The most critical mechanisms by which BAG-1 promotes prostate cancer growth will be identified.
- The effect of BAG-1 loss on normal physiology and normal prostate function will be determined in mouse models in order to identify any potential toxicities associated with targeting BAG-1.
- The interactions between BAG-1 and AR/AR-Vs will be quantitated in patient tumor samples to confirm the clinical relevance of these interactions. In addition, the regions of BAG-1 that interact with AR and the regions which are druggable will be identified.
- Finally, candidate small molecule inhibitors of the interaction between BAG-1 and AR will be identified and tested for effects on prostate tumor growth in preclinical models.
- If successful, this project will credential a novel therapeutic target for CRPC and identify lead compounds that will be optimized and advanced to clinical trials.
What this means to patients: Dr. de Bono and team are studying whether disrupting the interaction between AR and BAG-1, a protein partner of AR, will be effective in blocking prostate tumor growth, and are identifying novel therapeutic compounds to achieve this in patients. This project will lead to the development of a new therapeutic strategy for the treatment of CRPC patients that will be effective even in tumors resistant to second generation AR-therapies.
Principal Investigator: Russell Pachynski, MD (Washington University), Robert Schreiber, PhD (Washington University)
Co-Investigators: Jeffrey Ward, MD, PhD (Washington University), Elaine Mardis, PhD (Washington University), Vivek Arora, MD, PhD (Washington University), James Gulley, MD, PhD (National Cancer Institute), Kathy Sheehan, PhD (Washington University)
Project Title: Personalizing Combinational Prostate Cancer Immunotherapy
- Prostate cancer was the first solid tumor type for which an immunotherapy (a tumor vaccine) was FDA-approved. However, limited success has been achieved in patients with prostate cancer with checkpoint immunotherapies, which have led to cures in some patients with other cancer types. New strategies need to be implemented in prostate cancer patients in order to harness the full power of immunotherapy.
- Pachynski and team are developing strategies to optimize prostate cancer responses to immunotherapy.
- Tumor vaccines work by generating immune cells that target and kill cells which express tumor-associated proteins. However, tumors are highly immune-suppressive and shut down the activity of immune cells. Checkpoint immunotherapies work by blocking these off signals and reawakening anti-tumor immune cells. Combining these two types of immunotherapy may dramatically improve the anti-tumor immune response and achieve greater outcomes.
- Immune responses can also be produced against mutated genes (neoantigens) expressed by tumor cells. This can occur naturally or be prompted by immunotherapy. Patient-specific vaccines against tumor neoantigens may be more effective than vaccines which target unmutated tumor-associated proteins.
- The team will conduct a randomized phase II clinical trial testing a two-stage immunotherapy regimen. In the first treatment stage, patients with hormone-sensitive metastatic prostate cancer who have recently completed treatment with docetaxel will receive either a prostate tumor vaccine (Prostvac) alone or Prostvac combined with the checkpoint immunotherapy, anti-PD1.
- The tumors and immune cells from these patients will be evaluated to determine if the treatment resulted in the production of tumor neoantigens that can be targeted by immune cells.
- Patients for whom tumor neoantigens are identified will undergo a second treatment phase in which they will receive anti-PD1 combined with a patient-specific vaccine targeting up to 20 neoantigens. Patient outcomes and immune responses will be evaluated to determine the efficacy of this therapeutic strategy.
- If successful, this project will result in a novel immunotherapy for prostate cancer patients.
What this means to patients: Dr. Pachynski and team will conduct a clinical trial testing a new immunotherapy strategy that includes the development of patient-specific tumor vaccines. This two-stage regimen will optimize the production of anti-tumor immune responses in order to harness the curative potential of immunotherapy for prostate cancer patients.
Principal Investigators: David Karow, MD, PhD (University of California, San Diego), Christopher Kane, MD (University of California, San Diego), Donna Hansel, MD, PhD (University of California, San Diego)
Co-investigators: Sandip Patel, MD (University of California, San Diego), Nathan White, PhD (University of California, San Diego), Anders Dale, PhD (University of California, San Diego), Peter Kuhn, PhD (University of Southern California), Michael Hahn, MD, PhD (University of Southern California)
Project Title: Evaluation of Whole Body RSI-MRI as a Biomarker for Detection, Characterization and Therapy Response of Metastatic Prostate Cancer
- Patients with 5 or fewer metastatic lesions (“oligometastatic”) are potentially treatable with localized forms of treatment. However, the ability to detect disease at the early metastatic stage is limited by the sensitivity and specificity of clinical imaging technologies. New imaging techniques are needed to inform the staging and treatment of patients.
- Dr. Karow and team are developing a novel molecular imaging technology, Restriction Spectrum Imaging-Magnetic Response Imaging (RSI-MRI), for detecting metastatic prostate tumors. RSI-MRI is a radiation-free method that detects tumors based on tissue structure characteristics.
- The detection accuracy of RSI-MRI will be compared with current imaging gold standards (PET/CT and CT/bone scan) in 200 patients with known metastatic disease or who are at high risk for metastatic disease. Inconclusive lesions will be biopsied to assess factors that contribute to inaccuracies. In addition, patients with advanced metastatic disease will be consented for autopsy studies to correlate RSI-MRI-detected lesions with total disease burden.
- Whether RSI-MRI can quantitatively measure tumor responses to anti-androgen therapies and taxane chemotherapy will be assessed and compared to other measures of disease burden including PSA levels, conventional imaging, and circulating tumor cell (CTC) counts.
- Additionally, the use of RSI-MRI versus conventional imaging will be compared in a phase 1 clinical trial of the PARP-inhibitor olaparib combined with the checkpoint immunotherapy durvalumab (anti-PD-L1) in metastatic CRPC patients with DNA repair defects.
- If successful, this project will credential a new highly sensitive imaging technology for detecting metastatic tumors that will lead to improved staging of patients and evaluation of treatment responses.
What this means for patients:
Dr. Karow and team are optimizing and validating the utility of the novel molecular imaging technology, RSI-MRI, for the sensitive detection of metastatic prostate cancer and for assessment of response to treatment. This will lead to improved and earlier detection of metastases, and enhance the ability to treat and prolong the survival of patients with potentially lethal disease.
Principal Investigator: Lawrence Fong, MD (University of California, San Francisco), Felix Feng, MD (University of California, San Francisco)
Co-Investigators: Alan Ashworth, PhD (University of California, San Francisco), John Kurhanewicz, PhD (University of California, San Francisco), Albert Chang, MD, PhD (University of California, San Francisco), Thomas Hope, MD (University of California, San Francisco), David Quigley, PhD (University of California, San Francisco)
Project Title: Combination Radio-Immunotherapy for Oligometastatic Prostate Cancer
- The success of immunotherapies have been limited in prostate cancer. Improving immunotherapy for prostate cancer will likely require combinations with other treatments that amplify immune responses. Both radiation therapy and androgen deprivation therapy (ADT) have been shown to stimulate immune activity, and are options for such combinations.
- Fong and team are conducting a phase II clinical trial testing the efficacy of combining ablative radiotherapy with high-dose rate brachytherapy, the checkpoint immunotherapeutic pembrolizumab (anti-PD1), and intermittent ADT, with or without direct tumor injection of the immune adjuvant SD-101 (a toll-like receptor-9 agonist) in patients with oligometastatic (≤3 bone metastases) hormone-sensitive prostate cancer.
- The team will investigate the effects of the therapy on activities of immune cells and the T cell repertoire in the blood and within the tumor.
- Primary and metastatic tumor samples from patients will be genomically sequenced, and examined for neoantigens, which are mutations that have T cell-activating capacity. The expression of immune-activating and immune-suppressive proteins by tumor cells will also be examined.
- Activities that correspond with therapeutic responses will be identified and used to create an integrated prognostic biomarker for selecting patients that may benefit from this therapeutic regimen. In addition, changes in tumor or immune cell activities that correspond with therapeutic resistance will also be studied.
- The team will examine whether the experimental molecular imaging technology, PSMA-PET/MRI is able to track clinical responses with higher sensitivity than conventional bone or CT scans.
- Finally, the team will explore whether the novel PET agent, [18F]F-AraG, which is preferentially taken up by activated T cells, will enable tracking of immune responses in these patients.
- If successful, this project will lead to a novel and highly effective therapy for patients with advanced prostate cancer, as well as biomarkers and imaging technologies to predict and follow therapeutic responses.
What this means for patients: Achieving responses to checkpoint immunotherapy in prostate cancer patients may require combinations with other treatments. This team will develop a novel treatment strategy combining ADT and radiation therapy with immunotherapy in order to harness the power of the immune system to eliminate prostate cancer.
Principal Investigator: Akash Patnaik, MD, PhD (University of Chicago), Walter Stadler, MD (University of Chicago), Thomas Gajewski, MD, PhD (University of Chicago)
Co-Investigators: Brian Olson, PhD (Wisconsin Institute for Medical Research), Jason Luke, MD (University of Chicago), Randy Sweis, MD (University of Chicago)
Project Title: Combinatorial Immunotherapy Strategies to Reverse Immunosuppression within PTEN-deficient Advanced Prostate Cancers
- While immunotherapies have produced profound responses in some patients with melanoma and other solid tumors, clinical responses have been only rarely been observed in prostate cancer.
- Patnaik and team have found that loss of the tumor suppressor gene PTEN, is correlated with decreased immune cell activity in tumors. PTEN-loss occurs in over 75% of castrate resistant prostate cancer (CRPC), and leads to activation of the cancer-promoting PI3K pathway.
- To investigate the hypothesis that PTEN-loss leads to immune suppression, the team will profile immune cell populations and activities in PTEN-positive versus PTEN-negative metastatic CRPC.
- The effects of PTEN loss and PI3K inhibition on immune cell activities will be investigated in preclinical mouse models. Whether targeting the PI3K pathway will enhance responses to checkpoint immunotherapy (anti-PD1 and anti-CTLA4) in PTEN-deficient CRPC will then be tested in these models.
- A phase 1b clinical trial will be conducted to test the safety and efficacy of a PI3K inhibitor (GSK2636771) in combination with anti-PD1 (nivolumab) in patients with PTEN-deficient metastatic CRPC. The effects of this treatment on immune cell activities and the T cell repertoire will be studied.
- If successful, this project will result in a new precision immunotherapy regimen for patients with PTEN-deficient CRPC.
What this means for patients: Certain genomic alterations that occur in tumors can suppress immune responses and reduce the efficacy of immunotherapy. This team will establish a new precision immunotherapy regimen that combines immunotherapy with a treatment targeting a mutation common in advanced prostate cancer.
Principal Investigator: Ramon Parsons, MD, PhD (Icahn School of Medicine at Mount Sinai)
Co-Investigators: Sait Ozturk, PhD (Icahn School of Medicine At Mount Sinai), Mark Rubin, MD (Weill Cornell Medical College), William Oh, MD (Icahn School of Medicine at Mount Sinai), Ashutosh Tewari, MD (Icahn School of Medicine at Mount Sinai), Stuart Aaronson, MD (Icahn School of Medicine at Mount Sinai)
Project Title: Tumor Suppressor Signaling Approaches for the Treatment of Metastatic Prostate Cancer
- Genomic alterations that occur in tumors may cause sensitivities and weaknesses that can be exploited for therapeutic benefit. Mutations in the PTEN and p53 tumor suppressor genes are highly prevalent in advanced disease and represent potentially important targets for the treatment of metastatic, lethal prostate cancer.
- Parsons and team are studying the biology and therapeutic effects of targeting p53 and PTEN mutations in advanced prostate cancer.
- Loss of PTEN promotes tumor cell progression by unleashing the tumor-promoting PI3K pathway. The team will study the role of PTEN-loss in prostate cancer by measuring the activity of PTEN and the PI3K pathway in normal prostate, primary prostate cancer, and metastatic prostate cancer samples from patients.
- The effects of PTEN-loss on the metabolism and proliferative abilities of prostate cells will be investigated. The team will then explore whether inhibitors of PI3K, mTOR, or RAC are able to restore normal metabolism in cells that have lost PTEN.
- Mutations in p53 can lead to altered functions that promote tumor growth instead of tumor suppression. The team will identify mutations in p53 that promote prostate tumor progression and investigate the underlying mechanisms.
- ETS gene fusions commonly co-occur with PTEN-loss in advanced prostate cancer. In order to understand the biology and impact of these genetic events, the team will investigate the effects of ETS fusions combined with PTEN-loss on prostate cancer cell growth, gene expression, metabolism, metastatic activities, and sensitivity to androgen receptor (AR) targeted therapy.
- In addition, the activity of several novel therapeutic compounds that have indicated promise in the treatment of p53 and PTEN-deficient prostate cancer will be tested alone and in combinations in preclinical tumor models. These include inhibitors of tankyrase, PI3K, BRD4, EZH2, AR, glutaminase and enzymes involved in de novo pyrimidine synthesis.
- If successful, this project will result in identification of novel therapeutic strategies for the treatment of patients with p53 and/or PTEN-deficient prostate tumors.
What this means for patients: Genomic alterations that occur in tumors may cause sensitivities and weaknesses that can be exploited for therapeutic benefit. This team will develop new precision medicine treatment strategies for prostate tumors harboring mutations in the tumor suppressor genes p53 and PTEN.
Principal Investigator: Karen Sfanos, PhD (Johns Hopkins University)
Co-Investigators: Cynthia Sears, MD (Johns Hopkins University), Ashley Ross, MD, PhD (Johns Hopkins University), Corrine Joshu, PhD, MPH (Johns Hopkins University), Emmanuel Antonarakis, MD (Johns Hopkins University), Phuoc Tran, MD, PhD (Johns Hopkins University), Brian Simons, DVM, PhD (Johns Hopkins University), Adam Dicker, MD, PhD (Thomas Jefferson University), Kenneth Pienta, MD (Johns Hopkins University), Samuel Denmeade, MD (Johns Hopkins University)
Project Title: The Microbiome and Metastatic, Lethal Prostate Cancer: Establishment of an International Resource for the Prostate Cancer Research Community
- The community of microbes, i.e. microbiome, residing in the gut have been found to influence numerous aspects of human biology, including tumor development and progression and responses to various cancer treatments. However, whether the gut microbiome exerts any effects in prostate cancer has not been studied.
- Sfanos and team will establish a gut microbiome specimen biorepository and database for >1,000 men undergoing various treatments for advanced prostate cancer as an international resource for the prostate cancer research community.
- Each specimen in the repository will be subjected to DNA and RNA sequencing in order to generate microbiome profiles that include bacteria, viruses, fungi, and protozoa. These data will be linked to clinical data for each patient.
- The database will be made public, enabling first-in-field clinical studies on the associations between gut flora and prostate cancer treatment responses and toxicities.
- In addition, whether gut flora are affected by androgen deprivation therapy (ADT) and whether the gut microbiome influences responses to immunotherapy will be determined by examining gut microbiome profiles from patients enrolled in clinical trials.
- Finally, preclinical mouse models will be studied to determine how ADT and/or immunotherapy modulates the gut microbiome, and how the gut microbiome modulates the efficacy of immunotherapy.
- If successful, this project will produce a novel resource for the prostate cancer research community and determine whether the gut microbiome has a role in therapeutic responses in prostate cancer patients, opening up an entirely new field of study in prostate cancer.
What this means for patients: The community of microbes (microbiome) residing in the gut have been found to influence tumor biology and treatment responses. This team will develop a gut microbiome biobank as an international scientific resource and will determine whether the gut microbiome affects responses to various prostate cancer treatments.
Principal Investigator: Arul Chinnaiyan, MD, PhD (University of Michigan)
Co-Investigators: Elisabeth Heath, MD (Karmanos Cancer Center), Yuanyuan Qiao, PhD (University of Michigan)
Project Title: Development of an Autophagy Inducing Multi-Tyrosine Kinase Inhibitor ESK981 in the Treatment of Castration Resistant Prostate Cancer
- Therapies targeting the androgen receptor (AR) are the mainstay for the treatment of metastatic castration resistant prostate cancer (mCRPC). However, these treatments are generally not curative and patients inevitably relapse. Novel approaches to treat advanced prostate cancer are needed.
- Arul Chinnaiyan and team have identified a novel multi-tyrosine inhibitor, ESK981, with potent preclinical activity in the treatment of mCRPC.
- ESK981 appears to induce prostate cancer cell death by activating autophagy, the cell’s molecular recycling system. To explore how ESK981 affects prostate cancer cells, and whether autophagy plays a central role, the team will systematically examine the autophagy pathway and other important cellular processes such as cell death, proliferation, cell division, and metastatic activities in prostate cancer cells treated with ESK981.
- The team will conduct kinase screening studies to identify the kinase targets of ESK981. Additionally, kinase-inhibitor screens and genome-wide knockout screens will be conducted to identify genes that regulate autophagy and may be the targets of ESK981.
- The efficacy of ESK981 as a monotherapy and in combination with enzalutamide will be investigated in preclinical models of CRPC. Gene expression analyses will be conducted in these models to identify biomarkers of sensitivity and responsiveness to ESK981.
- ESK981 has cleared human phase I safety and tolerability studies. The team will initiate a phase II study of ESK981 in men with treatment naïve CRPC and in men with CRPC who have progressed on enzalutamide and/or abiraterone acetate.
- If successful, this team will elucidate the biology of a novel prostate cancer therapy, and advance this agent through clinical trials.
What this means for patients: New therapies are of critical need for the treatment of patients with castration resistant prostate cancer (CRPC). This team will conduct preclinical and clinical studies to re-position the novel multi-tyrosine inhibitor ESK981 as a treatment for metastatic CRPC.