Challenge Awards-Class of 2017

2017 Movember Foundation – Distinguished Gentleman’s Ride – PCF Challenge Award ($1 Million)

Principal Investigators: Douglas McNeel, MD, PhD (University of Wisconsin)

Co-Investigators: Glenn Liu, MD (University of Wisconsin), Robert Jeraj, PhD (University of Wisconsin), Christos Kyriakopoulos, MD (University of Wisconsin)

Project Title: Broadening T-Cell Activation with PD-1 Blockade to Treat Advanced, Metastatic Prostate Cancer

Description:

• The immune system has the ability to identify and eliminate cancer cells, if properly activated. Checkpoint immunotherapy has had major successes in some cancers, but responses have been more limited in prostate cancer, while cancer vaccines have had a modest benefit. Studies are needed to identify immunotherapeutic strategies that are more effective in prostate cancer.
• McNeel and team are developing prostate cancer vaccines and testing them in combination with checkpoint immunotherapy for the treatment of prostate cancer. The hypothesis is that checkpoint immunotherapy, which works by blocking the off-signals on T cells, will boost anti-tumor responses elicited by vaccines.
• The team has developed two prostate cancer vaccines, which activate the immune system against two prostate cancer associated proteins — the androgen receptor (AR), and prostatic acid phosphatase (PAP). Both vaccines are being tested in phase I and phase II clinical trials.
• This project will determine whether two prostate cancer vaccines is more effective than one, in combination with checkpoint immunotherapy. The team will conduct a randomized phase II clinical trial in prostate cancer patients testing the PAP vaccine + the anti-PD1 checkpoint inhibitor pembrolizumab, versus the PAP vaccine + the AR vaccine + pembrolizumab.
• Patients will be evaluated for safety, clinical responses, immune system responses against the vaccine antigens (PAP and AR), as well as immune system changes that correlate with clinical responses.
• If successful, this project will result in an effective new immune-based treatment for prostate cancer patients.

What this means to patients:  Treatment strategies that effectively activate the immune system to target cancer will provide a promising new therapeutic opportunity for men with prostate cancer.  Dr. McNeel and team will conduct a clinical trial testing the combination of two therapeutic prostate cancer vaccines plus the checkpoint immunotherapy anti-PD1, which may result in an effective new therapy for prostate cancer patients.

2017 Movember Foundation – PCF Challenge Award ($1 Million)

 Principal Investigators: Felix Feng, MD (University of California, San Francisco), Alan Ashworth, PhD (University of California, San Francisco), Charles Ryan, MD (University of California, San Francisco), Alexander Wyatt, PhD (University of British Columbia)

Co-Investigators: David Quigley, PhD (University of California, San Francisco), Li Zhang, PhD (University of California, San Francisco), Wassim Abida, MD, PhD (Memorial Sloan Kettering Cancer Center), Luke Gilbert, PhD (University of California, San Francisco)

Project Title: Identifying and Overcoming PARP Inhibitor Resistance in Patients with Metastatic Prostate Cancer

Description:

• Recent studies have found that PARP-inhibitors may be an effective treatment option for up to a third of men with metastatic prostate cancer. However, treatment resistance occurs, necessitating studies that will lead to new therapeutic strategies for these patients.
• Feng and team are studying the mechanisms of resistance to PARP-inhibitors and are developing strategies to identify and treat these patients.
• Sensitivity to PARP-inhibitors requires tumors to have mutations that disable effective repair of damaged DNA. Most commonly, such mutations are in the BRCA2 gene.
• Feng’s team have discovered that some prostate cancers become resistant to PARP-inhibitors by gaining mutations that overwrite the original BRCA2 mutation and restore the activity of the BRCA2 protein.
• In this project, the team will study patients being treated with PARP-inhibitors in clinical trials to comprehensively characterize mutations that cause tumors to be sensitive to PARP-inhibitors, and the mutations that lead to acquired PARP-inhibitor resistance.
• The patients in these trials who develop PARP-inhibitor resistance will go on to receive other treatments. These studies will determine which clinically available therapies are effective against tumors that have gained resistance to PARP-inhibitors.
• The team will also identify and test the efficacy of novel therapies against PARP-inhibitor resistant prostate cancer in preclinical models.
• If successful, these studies will define tumor mutations that confer sensitivity and resistance to PARP-inhibitors and identify treatments that may be used in patients who have progressed on PARP-inhibitors.

What this means to patients:  PARP-inhibitors are a precision medicine that will likely gain FDA-approval for the treatment of advanced prostate cancer in the next few years.  Dr. Feng and team will conduct studies that will optimize the use of these agents in patients, by identifying patients who are likely to benefit, uncovering mechanisms of PARP-inhibitor resistance, and discovering new treatments for patients who have progressed on PARP-inhibitors.

2017 Movember Foundation – PCF Challenge Award ($1 Million)

Principal Investigators: Joshua Lang, MD (University of Wisconsin), Howard Scher, MD (Memorial Sloan Kettering Cancer Center), Scott Dehm, PhD (Masonic Cancer Center, University of Minnesota), Scott Tagawa, MD (Weill Cornell Medicine and New York-Presbyterian)

Co-Investigators: Kimberly Ku, MD (University of Wisconsin)

Project Title: Therapeutic Targeting of AR Variant Prostate Cancer with a Novel Antibody Drug Conjugate

Description:

• There are currently no curative treatments for men with advanced prostate cancer. Patients currently try a series of different treatments that may prolong life and reduce symptoms, but will inevitably fail.   New therapeutic strategies for advanced prostate cancer are desperately needed.
• Lang and team have identified a novel protein, TROP-2, that is expressed on many forms of advanced prostate cancer. The team is studying whether targeting TROP-2 will be an effective treatment strategy for patients with advanced disease.
• The team will validate TROP-2 as a therapeutic target in various clinical states of prostate cancer by evaluating TROP-2 expression in patient samples. Tumor samples will also be comprehensively evaluated for mutations and genes expressed in order to identify molecular pathways associated with TROP-2 expression and various clinical disease states.
• Circulating tumor cells (CTCs) are tumor cells that can be found in the blood of patients, and represent a non-invasive alternative to tumor biopsies for evaluating tumor biology. The team will validate whether CTCs can be used to identify patients whose tumors express TROP-2 and may be candidates for TROP-2-targeted therapy.
• A phase I clinical trial has been initiated to test IMMU-132, a TROP-2-specific antibody conjugated to a chemotherapeutic drug, in patients with metastatic castrate-resistant prostate cancer (mCRPC). A phase II trial is also planned to open in late 2017.
• CTCs and tumor biopsies will be periodically collected from patients on these trials and evaluated for mutations and expression of genes including TROP-2, to identify biomarkers of response and resistance to IMMU-132.
• If successful, this project will validate whether targeting TROP-2 with IMMU-132 is promising in patients and identify biomarkers that can be used to select patients who will benefit from this treatment.

What this means to patients:  New treatments are critically needed for patients with advanced prostate cancer. Dr. Lang and team will conduct a clinical trial to test whether targeting TROP-2 with a drug-carrying antibody has promise for the treatment of prostate cancer patients and develop biomarkers that can be used to select patients who will benefit from this treatment.

2017 Movember Foundation – PCF Challenge Award ($1 Million)

Principal Investigators: Chad Mirkin, PhD (Northwestern University)

Co-Investigators: Bin Zhang, MD, PhD (Northwestern University), Timothy Kuzel, MD (Northwestern University), William Catalona, MD (Northwestern University), Andrew Lee, PhD (Northwestern University)

Project Title: Spherical Nucleic Acids as Therapeutic Vaccines for the Treatment of Prostate Cancer

Description:

• The immune system has the capacity to seek and eliminate cancer cells wherever they exist in the body. Efforts to improve immunotherapy are needed to harness this powerful cancer-fighting system for patients with prostate cancer.
• Mirkin and team are developing a novel “spherical nucleic acid” (SNA) prostate cancer vaccine composed of nanoparticles carrying the tumor-associated antigens and co-stimulatory signals necessary to activate effective anti-tumor immune responses.
• The team will design and synthesize various formulations of SNAs that vaccinate against PSMA, a protein that is highly and specifically expressed by prostate cancer cells.
• PSMA-SNA vaccine formulations will be compared in preclinical models for their ability to activate anti-PSMA-specific T-cell responses and prohibit tumor growth.
• SNAs will be tested in combination with other immunotherapies such as checkpoint inhibitors to identify strategies to improve prostate cancer immunotherapy.
• If successful, this project will qualify a novel prostate cancer immunotherapy for testing in clinical trials.

What this means to patients:  Therapies that effectively stimulate a person’s immune system to attack and kill tumor cells are highly promising but still underdeveloped in prostate cancer. Dr. Mirkin and team will develop and test a novel nanoparticle-based therapeutic prostate cancer vaccine in preclinical models, which may lead to a new immunotherapy for prostate cancer.

2017 Movember Foundation – PCF Challenge Award ($1 Million)

Principal Investigators: Ana Aparicio, MD (The University of Texas MD Anderson Cancer Center), Nicholas Navin, PhD (The University of Texas MD Anderson Cancer Center),  Theocharis Panaretakis, PhD (The University of Texas MD Anderson Cancer Center), Peter Kuhn, PhD (University of Southern California)

Co-Investigators: Brian Chapin, MD (The University of Texas MD Anderson Cancer Center), James Hicks, PhD (University of Southern California), Patricia Troncoso, MD (The University of Texas MD Anderson Cancer Center)

Project Title: Impact of Local Therapy on Outcomes of Men with De Novo Metastatic Prostate Cancer within Molecularly Defined Subsets

Description:

• Currently, hormonal therapy (sometimes combined with abiraterone or chemotherapy) is the standard of care for men who have metastatic prostate cancer at the time of diagnosis. However, some men may benefit from the addition of definitive treatment of the primary tumor (prostatectomy or radiation). More studies are needed to validate this hypothesis and better understand which patients this treatment strategy will work for.
• Ana Aparicio and team are enacting studies to identify which men who present with metastatic prostate cancer will benefit from treatment of the primary tumor in addition to current standard of care hormonal therapy.
• Prostate cancer is a highly variable disease, and responses to different treatments can depend on the unique biology of an individual’s cancer.
• Aparicio and team will investigate whether previously described molecular signatures that predict responses to hormone therapy are also predictive of responses to hormone therapy and/or the addition of local therapy in men who have metastatic prostate cancer at diagnosis.
• The team will also investigate the value and accuracy of circulating tumor DNA and circulating tumor cells obtained from patient blood draws, as biomarkers for molecularly characterizing tumors and predicting clinical outcomes.
• If successful, this study will validate molecular signatures that identify patients with metastatic prostate cancer at diagnosis who will benefit from the addition of local therapy to hormonal therapy. These data will be used to guide the design of a planned phase III clinical trial testing the addition of definitive local therapy in this patient population.

What this means to patients:  Some men who have metastatic prostate cancer at the time of diagnosis may benefit from treatment of the primary tumor in addition to standard systemic therapy. Dr. Aparicio and team will develop biomarkers that can be used to identify which of these patients will benefit from treatment of the primary prostate tumor.  These data will be used to guide planned phase III clinical trials and may lead to a new standard of care for these patients.

2017 Movember Foundation – PCF Challenge Award ($1 Million)

Principal Investigators: Nupam Mahajan, PhD (Washington University), Felix Feng, MD (University of California, San Francisco)

Co-Investigators: Jonathan Chou, MD (University of California, San Francisco), Kiran Mahajan, PhD (H. Lee Moffitt Cancer Center), Rajdeep Das, MBBS, PhD (University of California, San Francisco), Eric Small, MD (University of California, San Francisco), Amrita Basu, PhD (H. Lee Moffitt Cancer Center)

Project Title: Targeting Androgen Receptor and ACK1 Signaling with Novel Epigenetic Therapeutics in Castration-Resistant Prostate Cancer.

Description:

• The androgen receptor (AR) is the primary driver of prostate cancer and the primary treatment target. However, resistance to current AR-targeted therapies are common, necessitating the development of improved approaches to target this pathway.
• Nupam Mahajan and team have identified ACK1 as a regulator of the AR pathway. Their studies have suggested that targeting ACK1 will disable some of the major mechanisms that tumors use to evade current AR-targeted therapies.
• In this project, the team will perform preclinical pharmacokinetic, metabolic and toxicological studies on a novel ACK1 inhibitor, (R)-9bMS, and its derivatives.
• The team will examine the potential of ACK1 status, as reflected by gene amplification, expression levels, or activity, as a biomarker of treatment resistance to current androgen-directed therapies.
• In addition, the team will conduct preclinical studies in animal models of prostate cancer necessary to credential testing of the ACK1-inhibitor in prostate cancer clinical trials.
• If successful, this project will lead to the initiation of a clinical trial testing a promising new treatment in advanced prostate cancer.

What this means to patients:  New treatment strategies are needed for patients with hormone therapy-resistant prostate cancer.  Dr. Mahajan and team will develop and optimize novel inhibitors of ACK1, a molecular pathway that regulates the androgen receptor, in preclinical studies.  This may lead to a new prostate cancer treatment that is able to overcome resistance to AR-targeted therapies.

2017 PCF Challenge Award ($1 Million)

Award Donor: Janssen Pharmaceuticals

Principal Investigators: Howard Scher, MD (Memorial Sloan Kettering Cancer Center), Mary-Ellen Taplin, MD (Harvard: Dana-Farber Cancer Institute)

Co-Investigators: Wassim Abida, MD, PhD (Memorial Sloan Kettering Cancer Center), Anuradha Gopalan, MD (Memorial Sloan Kettering Cancer Center), Glenn Heller, PhD (Memorial Sloan Kettering Cancer Center), Maika Mitchell, PhD (Memorial Sloan Kettering Cancer Center), Nikolaus Schultz, PhD (Memorial Sloan Kettering Cancer Center), Steven Balk, MD, PhD (Harvard: Beth Israel Deaconess Medical Center), Atish Choudhury, MD, PhD (Harvard: Dana-Farber Cancer Institute), Eliezer Van Allen, MD (Harvard: Dana-Farber Cancer Institute), Adam Kibel, MD (Harvard: Brigham and Women’s Hospital), Huihui Ye, MD, MSc (Harvard: Beth Israel Deaconess Medical Center), Rosina Lis, MD (Harvard: Dana-Farber Cancer Institute), Wai Yi Tsui, MD, PhD (Memorial Sloan Kettering Cancer Center), Michaela Bowden, PhD (Harvard: Dana-Farber Cancer Institute), Min Yuen Teo, MD (Memorial Sloan Kettering Cancer Center)

Project Title: Curing Lethal Non-Castrate Prostate Cancer: Integrative Molecular Analysis for Mechanisms of Exceptional Response, Resistance and Recurrence

Description:

• The use of aggressive, multimodality therapy in patients with localized high-risk or early metastatic prostate cancer may be able to significantly prolong cancer-free remission and survival.
• Scher and team will conduct a clinical trial to test whether intense androgen suppression therapy and radiation to visible metastases, followed by prostatectomy, can eliminate prostate cancer in patients with high risk localized disease likely to relapse after local therapy and patients with early metastatic tumors that are incurable with any single treatment.
• Tumor samples collected from patients prior to initiating the treatment course will be profiled for mutations and expressed genes in order to identify biomarkers that can be used to identify the patients most likely to benefit from this treatment strategy.
• The team will also molecularly characterize tumor samples collected at the time of prostatectomy (after androgen suppression therapy) in order to study the biology of tumor cells that are able to resist intense androgen suppression therapy.
• Finally, after treatment is completed, patients will be evaluated for whether there is any tumor DNA in their blood, which is produced by residual cancer cells. Tumor DNA found in patient blood will be assessed for mutations that associate with treatment resistance and disease progression.
• If successful, this project will establish a curative treatment paradigm for patients with high risk prostate cancer and identify mechanisms and biomarkers of response and resistance to this treatment.

What this means to patients:  There is currently no curative treatment for men who are diagnosed with metastatic prostate cancer or those who relapse after treatment for primary prostate cancer.  This team will test whether an intense, multimodal treatment strategy can be curative in these patients, and establish biomarkers for identifying the patients who should receive this treatment.

2017 PCF Challenge Award ($1 Million)

Award Donor: Stein Erik Hagen

Principal Investigators: Scott Tagawa, MD (Weill Cornell Medicine and NewYork-Presbyterian), Neil Bander, MD (Weill Cornell Medicine and NewYork-Presbyterian), Shankar Vallabhajosula, PhD (Weill Cornell Medicine and NewYork-Presbyterian)

Co-Investigators: John Babich, PhD (Weill Cornell Medicine and NewYork-Presbyterian), Karla Ballman, PhD (Weill Cornell Medicine and NewYork-Presbyterian), Himisha Beltran, MD (Weill Cornell Medicine and NewYork-Presbyterian), Yuliya Jhanwar, MD (Weill Cornell Medicine and NewYork-Presbyterian), Oliver Sartor, MD (Tulane University), Lauren Harshman, MD (Harvard: Dana-Farber Cancer Institute), Johannes Czernin, MD (University of California, Los Angeles), Sacha Gnjatic, MD (Icahn School of Medicine at Mount Sinai Hospital), Francesca Khani, MD (Weill Cornell Medicine and NewYork-Presbyterian)

Project Title: Optimization of Prostate-Specific Membrane Antigen-Targeted Radiation

Description:

• There are currently no curative therapies for men with advanced prostate cancer. However, promising recent studies have suggested that radiation-emitting therapies that target PSMA, a protein specifically expressed by prostate cancer cells, may be highly effective in men with advanced prostate cancer. Clinical trials are needed to validate efficacy and optimize the use of this type of treatment.
• Tagawa and team will conduct clinical trials testing several PSMA-targeting radiation therapies for the treatment of prostate cancer.
• A phase I clinical trial will be conducted to test ¹⁷⁷Lu-PSMA-617, a PSMA-targeted small molecule that is attached to a beta particle-emitting radioactive molecule. This trial will determine safety and efficacy of this treatment as well as determine the optimal dose and schedule.
• Once safe doses of ¹⁷⁷Lu-PSMA-617 have been established, the team will initiate a clinical trial testing increasing doses of ¹⁷⁷Lu-PSMA-617 combined with ¹⁷⁷Lu-J591, which is a PSMA-targeted antibody attached to a beta particle-emitting radioactive molecule. These agents will be given on alternating weeks.
• Tumor samples will be collected from the patients on these trials and studied to identify biomarkers that select patients most likely to benefit from ¹⁷⁷Lu-labeled PSMA-targeting agents.
• In addition, a phase I/II clinical will be conducted to evaluate the safety and efficacy of ²²⁵Ac-J591, a PSMA-targeted antibody that is attached to an alpha particle-emitting radioactive molecule, in patients with mCRPC.
• If successful, this project will prioritize several PSMA-targeted radiation therapies according to safety and efficacy and result in a powerful new therapy that uses targeted radiation to eliminate prostate cancer.

What this means to patients:  Recent studies have suggested that PSMA-targeted radiation therapy may be highly effective in men with advanced prostate cancer, however controlled clinical trials have not yet been conducted for these agents.  This team will test several PSMA-targeted radiation therapies in clinical trials and optimize the use of these powerful new treatments for prostate cancer.

2017 PCF Challenge Award ($1 Million)

Award Donor: Stein Erik Hagen

Principal Investigators: Shahneen Sandhu, MBBS (University of Melbourne), Rodney Hicks, MD, MBBS (Peter MacCallum Cancer Centre), Michael Hofman, MBBS (Peter MacCallum Cancer Centre), Scott Williams, MD, MBBS (Peter MacCallum Cancer Centre), Carleen Cullinane, PhD, ScD (Peter MacCallum Cancer Centre), John Violet, MBBS, PhD (Peter MacCallum Cancer Centre), Paul Neeson, PhD, ScD (Peter MacCallum Cancer Centre)

Co-Investigators: David Goode, PhD, ScD (Peter MacCallum Cancer Centre), Lisa Horvath, MBBS, PhD (Chris O’Brien Lifehouse), Anthony Joshua, MBBS, PhD (St Vincents Hospital, Kinghorn Cancer Centre), Carmel Pezaro, MBBS, (Monash University), Luc Furic, PhD, ScD (Peter MacCallum Cancer Centre)

Project Title: Harnessing Synergies between ¹⁷⁷Lutate Therapy and Olaparib to Improve Clinical Outcome of Men with Metastatic Castration Resistant Prostate Cancer.

Description:

• New therapeutic targets are urgently needed for the treatment of advanced prostate cancers that have developed resistance to current standard therapies.
• Prostate specific membrane antigen (PSMA) is a protein that is specifically and highly expressed on virtually all prostate cancers and correlates with disease severity. PSMA may thus be an optimal therapeutic target for the treatment of prostate cancer.
• Radiation therapy kills cancer cells by damaging DNA. PARP-inhibitors are therapies that kill cancer cells by preventing their ability to repair damaged DNA.
• Sandhu and team hypothesize that PARP-inhibitors may synergize with radiation therapy in killing cancer cells by preventing DNA repair after radiation-induced DNA damage.
• The team will conduct a phase I clinical trial to test the efficacy and safety of combining Lutetium-177 (¹⁷⁷Lu)-PSMA, a PSMA-targeted therapy attached to a radioactive molecule, with the PARP-inhibitor olaparib.
• Tumor samples will be collected from the patients on the study over time, and studied to identify the mechanism of action and identify biomarkers that can predict response or resistance to this combination treatment.
• Animal models of human prostate cancer will be treated with the combination therapy and studied to better understand the mechanism of action and to examine whether the treatment induces anti-tumor immune responses.
• If successful, this treatment will result in a highly effective new treatment for advanced prostate cancer.

What this means to patients:  Combining targeted radiation therapy with agents that prevent the repair of damaged DNA may be highly effective in the treatment of cancer.  This team will conduct clinical trials to test the efficacy of combining a prostate cancer-targeting radiation therapy, ¹⁷⁷Lu-PSMA, with the PARP-inhibitor olaparib, in advanced prostate cancer patients, and will identify mechanisms of action and biomarkers that can be used to select patients most likely to benefit from this treatment.

2017 PCF Challenge Award ($1 Million)

Award Donor: Stein Erik Hagen

Principal Investigators: Johannes Czernin, MD (University of California, Los Angeles), Caius Radu, MD (University of California, Los Angeles)

Co-Investigators: Robert Reiter, MD (University of California, Los Angeles), Matthew Rettig, MD (University of California, Los Angeles), Nicholas Nickols, MD, PhD (University of California, Los Angeles)

Project Title: Elucidating mechanisms of effectiveness and resistance to Prostate Specific Membrane Antigen (PSMA) targeted Radioligand Therapy (RLT) using ¹⁷⁷Lu-PSMA-617

Description:

• Metastatic castration-resistant prostate cancer (mCRPC) remains a highly lethal disease due to aggressive tumor biology and resistance to standard therapies.
• ¹⁷⁷Lu-PSMA-617, a novel radioactive treatment that targets the prostate-specific membrane antigen (PSMA), a protein highly overexpressed in prostate cancer, has been recently introduced as a therapeutic alternative for this disease. However, clinical trials are urgently needed to verify the activity of this therapy.
• Czernin and team are studying the activity of ¹⁷⁷Lu-PSMA-617 in animal models and clinical trials.
• The team will use prostate cancer animal models to determine the relationship between ¹⁷⁷Lu-PSMA-617 efficacy and PSMA expression in cancer cells and determine whether tumor cells may develop resistance to this treatment by losing expression of PSMA.
• The team will also conduct a phase I clinical trial testing the safety and efficacy of ¹⁷⁷Lu-PSMA-617 in advanced prostate cancer patients.
• To better understand mechanisms of action of this treatment and identify possible targets for combination treatments that will increase efficacy, the levels and activities of various proteins will be studied in prostate cancer samples from patients on the trial.
• If successful, this project will validate the clinical efficacy of a new powerful treatment for prostate cancer and determine how the treatment works and how treatment resistance may occur.

What this means to patients:  Cases reports have suggested that new PSMA-targeted radiation therapies such as ¹⁷⁷Lu-PSMA-617 have much promise for the treatment of prostate cancer.  This team will conduct a clinical trial testing ¹⁷⁷Lu-PSMA-617 in advanced prostate cancer patients, and will identify possible mechanisms of treatment resistance and potential therapeutic targets for combination treatments that may improve patient outcomes.

2017 PCF VALOR Challenge Award ($1 Million)

Award Donors: Richard Merkin, Todd Boehly

Principal Investigators: Isla Garraway, MD, PhD (University of California, Los Angeles), Beatrice Knudsen, MD, PhD (Cedars-Sinai Medical Center), Peter Kuhn, PhD (University of Southern California)

Co-Investigators:

Matthew Rettig, MD (University of California, Los Angeles), Nicholas Nickols, MD, PhD (University of California, Los Angeles), Stephen Freedland, MD (Cedars-Sinai Medical Center), James Hicks, PhD (Cold Spring Harbor Laboratory), Sungyong You, PhD (Cedars-Sinai Medical Center), Arkadiusz Gertych, PhD (Cedars-Sinai Medical Center), Michael Lewis, MD (Greater Los Angeles Veterans Affairs Healthcare System), Jeremy Shelton, MD (University of California, Los Angeles)

Project Title: Multiplatform Profiling of Lethal Prostate Cancer in the Veterans Affairs Population

Description:

• The majority of US Veterans who die from prostate cancer were diagnosed with metastatic disease. Studying prostate cancer samples from these patients may enable a better understanding of the biology of metastatic prostate cancer and lead to improved treatment strategies.
• Garraway and team are defining biomarkers that will enable the identification of lethal prostate cancer as early as possible during the clinical course.
• The team has assembled a prostate cancer research database and biobank consisting of clinical records and prostate cancer samples from over 2,000 patients treated at the VA Hospital system. The team will expand this databank by leveraging the VA network and identifying metastatic prostate cancer cases from other VA centers nationwide.
• These samples will be comprehensively profiled for mutations and genes expressed in order to identify features of metastasis at diagnosis that are shared with metastatic hormone therapy-resistant prostate cancer.
• The team will also compare mutations present in primary and metastatic tumor samples at diagnosis with mutations that are acquired during the course of treatment to distinguish mutations that drive tumor evolution in the absence of treatment vs in response to treatments.
• If successful, this project will result in the development of a rich resource for studies in metastatic prostate cancer, and significantly increase our understanding of the biology of de novo metastatic disease vs metastatic disease that developed following treatment for primary prostate cancer.

What this means to patients:  Increasing our understanding of the biology of metastatic prostate cancer will improve prostate cancer staging, prognosis and treatment. This team will profile mutations and genes expressed in prostate cancer samples from US Veterans throughout the course of clinical treatment to identify mechanisms and biomarkers of prostate cancer metastasis and treatment resistance.

2017 PCF VALOR Challenge Award ($1 Million)

Award Donors: Peter Grauer, Robert Citrone

Principal Investigators: Jeffrey Jones, MD, MSc (Baylor College of Medicine and Michael E. DeBakey Veteran Affairs Medical Center), Michael Ittmann, MD (Baylor College of Medicine and Michael E. DeBakey Veteran Affairs Medical Center)

Co-Investigators: Rao Mandalapu, MD (Baylor College of Medicine), Arun Sreekumar, PhD (Baylor College of Medicine),  Nancy Weigel, PhD (Baylor College of Medicine),  Nora Navone, PhD (University of Texas MD Anderson Cancer Center),  Curtis Pettaway, MD (University of Texas MD Anderson Cancer Center), Cheryl Walker, PhD (Baylor College of Medicine), Aihua Ed Yen, MD (Baylor College of Medicine), Nicholas Mitsiades, MD (Baylor College of Medicine), Cristian Coarfa, PhD (Baylor College of Medicine), Nagireddy Putluri, PhD (Baylor College of Medicine), Zhandong Liu, PhD (Baylor College of Medicine)

Project Title: Clinicopathological Correlation and Molecular Signature Identification and Risk Stratification of Prostate Cancer in African-American U.S. Veterans, With and Without Exposure to Battlefield Chemicals

Description:

• US Veterans with prostate cancer represent an ethnically diverse population. Studies in these men can elucidate the reasons why prostate cancer appears to be more aggressive in men of African descent.
• Veterans who were exposed to battlefield chemicals such as Agent Orange are at increased risk for development of prostate cancer. Studies into the relationship between battlefield chemicals and prostate cancer are of vital need.
• Jones and team will create a databank of tumor and other biologic samples from US veterans with prostate cancer. All samples will be ancestry typed and associated with extensive epidemiological and clinical follow up data.
• These samples will be used to investigate the biology of prostate cancer in African-American (AA) vs. European American (EA) men. The team will investigate whether racially distinct aspects of metabolism associate with prostate cancer aggressiveness.
• Whether expression of various hormone receptor gene variants associates with the development of resistance to androgen-targeted therapy in AA and/or EA men with prostate cancer will be investigated.
• Finally, whether patients who were exposed to battlefield chemicals including Agent Orange exhibit unique tumor biology will be explored. The team will investigate whether prostate cancer in AA vs EA Veterans exposed to battlefield chemicals is associated with differences in metabolism or in epigenomics, which are modifications of DNA that regulate gene expression.
• If successful, this project will improve our understanding of why AA men and veterans exposed to battlefield chemicals have an increased risk for lethal prostate cancer.

What this means to patients:  Factors such as race and chemical exposures can affect risk for prostate cancer and need to be better understood in order to improve prevention and treatment strategies. This team will study prostate cancer samples from US Veterans to better understand the biology of prostate cancer in African-American men and to elucidate the effects of exposure to battlefield chemicals such as Agent Orange on the development and progression of prostate cancer.

2017 PCF Challenge Award ($1 Million)

Award Donors: Igor Tulchinsky, Milken Family Foundation

Principal Investigators: Amina Zoubeidi, PhD (Vancouver Prostate Centre; Vancouver Coastal Health Research Institute; University of British Columbia), Himisha Beltran, MD (Weill Cornell Medicine and NewYork-Presbyterian)

Co-Investigators: Robert Young, PhD (Simon Fraser University), Ravi Munuganti, PhD (University of British Columbia)

Project Title: Targeting BRN2 in Neuroendocrine Prostate Cancer

Description:

• Neuroendocrine prostate cancer (NEPC) arises in a subset of patients who relapse following androgen receptor (AR)-targeted therapy. There is urgent need to develop new and effective treatments for patients with this highly aggressive and lethal subtype of prostate cancer.
• Zoubeidi and team have identified the neural transcription factor BRN2 as a major driver and a promising therapeutic target in NEPC.
• A major goal of this research is to assess if BRN2 inhibitors should be deployed alone or in combination with current standard-of-care to block the emergence and/or progression of NEPC.
• The team is now fine-tuning the structure of BRN2 inhibitors for optimal selectivity, pharmacokinetic properties, and safety.
• These preclinical studies will utilize patient-derived organoids to characterize “responders” and develop biomarkers to stratify patients who will be most amenable to BRN2 inhibition in preparation for translation of BRN2 inhibitors into clinical trials.
• If successful, this team will develop a novel new therapy for an aggressive subtype of advanced prostate cancer that is poised for rapid integration into the clinic.

What this means to patients:  Neuroendocrine prostate cancer (NEPC) is an aggressive and lethal subtype of prostate cancer that does not respond to hormonal therapy.  This team will develop clinical trial-ready inhibitors of BRN2, a driver of NEPC, which may become a new treatment option for these patients.

2017 PCF Challenge Award ($515,000)

Principal Investigators: Alicia Morgans, MD, MPH (Northwestern University), Charles Ryan, MD (University of California, San Francisco)

Co-Investigators: Lei Wang, PhD (Northwestern University), Glenn Heller, PhD (Memorial Sloan Kettering Cancer Center), Jennifer Yokoyama, PhD (University of California, San Francisco)

Project Title: SEARCH: Survivorship Enhancement in Men with Prostate Cancer At Risk for Poor Cognitive Health During Treatment with ADT.

Description:

• Studies have suggested that androgen deprivation therapy (ADT) used for the treatment of prostate cancer may increase risk for cognitive disorders such as dementia and Alzheimer’s disease. Prospective, controlled clinical trials are needed to validate these hypotheses and if found true, identify men who are at risk and outline measures to reduce cognitive impairment without reducing the efficacy of prostate cancer treatments.
• Morgans and Ryan and team will assess the association between cognitive function and various genetic markers in prostate cancer patients being treated with ADT plus abiraterone in a clinical trial. This will enable the identification of genetic markers that can predict which patients may be at increased risk for cognitive decline during treatment with androgen-targeted therapy.
• Whether androgen-targeted therapy is associated with structural and functional changes in the brain will be investigated. A specialized MRI test will be used to image the brain of prostate cancer patients during the performance of various cognitive tests prior to and following 24 weeks of treatment with ADT plus abiraterone.
• In addition, a pilot clinical trial will be conducted to test whether computer-based cognitive exercises that improve multi-tasking and reduce depression in aging populations can also benefit prostate cancer patients who exhibited cognitive decline during treatment with ADT plus abiraterone.
• If successful, this project will identify risk factors for cognitive impairment during treatment with androgen-targeted therapy, validate an imaging test to measure cognitive impairment, and credential the feasibility of an intervention to prevent or reverse cognitive impairment associated with ADT in men with prostate cancer.

What this means to patients:  Androgen deprivation therapy may increase risk for cognitive disorders in prostate cancer patients. This team will develop tests to measure cognitive impairment and identify men at risk, and test an intervention to prevent cognitive decline in prostate cancer patients being treated with androgen-targeted therapy.

2017 PCF Challenge Award ($1 Million)

Award Donors: Steve Roth, Janssen Pharmaceuticals

Principal Investigators: Karen Knudsen, PhD (Thomas Jefferson University), Johann de Bono, MD, PhD (The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust), Myles Brown, MD (Harvard: Dana Farber Cancer Institute)

Co-Investigators: Matthew Schiewer, PhD (Thomas Jefferson University), Adam Sharp, PhD, MSc (The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust), Gunther Boysen, PhD (The Institute of Cancer Research and Royal Marsden Hospital), Henry Long, PhD (Harvard: Dana Farber Cancer Institute), Laura Cato, PhD (Harvard: Dana Farber Cancer Institute)

Project Title: Targeting CBP/p300 to Suppress Oncogenic Transcription Factors in Advanced Prostate Cancer

Description:

• The primary treatment for metastatic prostate cancer is androgen receptor (AR)-targeted therapy. However, resistance to this treatment is inevitable and these tumors will go on to progress to lethal disease. New treatment strategies are urgently needed.
• Knudsen and team are exploring the role of CBP/p300 in driving prostate cancer progression and its potential as a treatment target in advanced prostate cancer.
• CBP/p300 is a regulator of gene expression that works in partnership with AR.
• The team will examine whether CBP/p300 becomes dysregulated during progression to castrate-resistant prostate cancer (CRPC). Mutations, gene expression patterns, and clinical parameters that associate with CBP/p300 alterations during prostate cancer progression will be determined.
• Genes that repair damaged DNA are commonly altered in prostate cancer and contribute to disease progression. This project will examine the molecular impact of CBP/p300 on DNA repair activity in prostate cancer models. Whether CBP/p300-inhibitors synergize with therapies that induce DNA damage or inhibit DNA repair will be examined in preclinical models.
• Biomarkers that can identify patients most likely to benefit from treatment with CBP/p300-inhibitors will be identified. These biomarkers will be validated in a phase I/II clinical trial testing the CBP/p300 inhibitor CCS1477.  Access to the compound is made possible through collaboration with CellCentric, and clinical development of the compound is currently underway.
• Studies will also be conducted to identify the molecular mechanisms and downstream consequences of CBP/p300 inhibition in prostate cancer using preclinical models and tissues from patients treated with CBP/p300-inhibitors. These studies have the potential to identify combination treatment strategies and mechanisms of treatment resistance.
• If successful, these studies will discern the role and mechanisms of CBP/p300 in prostate cancer and be used to optimize the design of clinical trials testing CBP/p300-inhibitors.

What this means to patients:  New treatments are urgently needed for men with advanced prostate cancer to prevent death from this disease.  This team will determine the mechanisms by which CBP/p300 drives prostate cancer progression and identify biomarkers that can be used to select patients most likely to benefit from treatment with CBP/p300-inhibitors.

2017 PCF VALOR Challenge Award ($1 Million)

Award Donors: Richard Ressler, Emanuel J. Friedman Philanthropies, James Cox Foundation

Principal Investigators: Maha Hussain, MD (Northwestern University), Edward Schaeffer, MD, PhD (Northwestern University), Joshua Meeks, MD, PhD (Northwestern University; Jesse Brown VA Medical Center)

Co-Investigators: Sarki Abba Abdulkadir, MD, PhD (Northwestern University), Benedito Carneiro, MD (Northwestern University), Alicia Morgans, MD, MPH (Northwestern University), Barko Jovanovic, PhD (Northwestern University), Ami Shah, MD (Northwestern University), Scott Tomlins MD, PhD (University of Michigan), Philip Palmbos, MD, PhD (University of Michigan), Roohollah Sharifi, MD (Jesse Brown VA Medical Center)

Project Title: Clinical, Environmental, Genetic and Genomic profile of Men with Early-Onset Lethal Prostate Cancer

Description:

• Metastatic prostate cancer is a heterogeneous disease, with survival varying from months to a decade. Understanding the mechanisms that drive these disparate outcomes is critical and will enable the development of new treatments and improve patient outcomes.
• Hussain and team will define the clinical, environmental, genetic and genomic features associated with lethal prostate cancer in younger men presenting with metastatic disease, and in men with metastatic hormone sensitive prostate cancer (mHSPC) who rapidly progress on androgen deprivation therapy (ADT).
• Clinical trials will be initiated to enroll 30 men under 60 years of age presenting with metastatic disease or who developed metastasis in under 5 years after local therapy, and 30 men with mHSPC who progress within 12 months after initiating treatment with ADT +/- docetaxel chemotherapy. Patients will receive standard of care treatment or may be enrolled onto clinical trials for experimental treatments, and followed for outcomes. These trials will be conducted at several institutions including the Jesse Brown VA Veterans Administration (VA) Medical Center.
• Metastatic and primary tumor tissue and blood samples will be collected from patients and assessed for tumor mutations and expressed genes that correlate with patient outcomes.
• Clinical profiles including race, ethnicity, family history, environmental and battlefield chemical exposure, hormonal levels, and metastatic disease extent and distribution, will be examined for features that correlate with outcomes.
• Prostate cancer patients will be studied to identify inherited cancer risk genes that contribute to the development of lethal prostate cancer.
• If successful, this project will identify clinical and molecular predictors of early lethal and ADT-resistant metastatic prostate cancer that will provide the foundation for novel interventional approaches.

What this means to patients:  Prostate cancers can appear clinically and pathologically similar yet have distinct natural histories and responses to therapy.  This team will identify clinical and molecular predictors of early-onset, imminently lethal prostate cancer, which will lead to improved detection, prevention, and treatment strategies for this aggressive subtype of prostate cancer.

2017 PCF Challenge Award ($1 Million)

Award Donor: KBBO Group

Principal Investigators: Ronald DePinho, MD (The University of Texas MD Anderson Cancer Center), Yoaqi Alan Wang, PhD (The University of Texas MD Anderson Cancer Center), Glen Traver Hart, PhD (The University of Texas MD Anderson Cancer Center)

Co-Investigators: Di Zhao, PhD (The University of Texas MD Anderson Cancer Center)

Project Title: Synthetic Essential Approach to Identify Novel Therapeutic Targets for Prostate Cancer

Description:

• Loss of tumor suppressor genes, which act to suppress tumor cell growth, occurs in nearly every cancer. Identifying a means to target these deletion events could profoundly impact therapeutic options for cancer patients.
• ‘Synthetic essential’ genes, are genes that are only essential in tumor cells that have mutated or deleted a specific tumor suppressor gene, and represent potential therapeutic targets in these cancers.
• DePinho and team are working to identify synthetic essential genes in prostate cancer and validate their utility as therapeutic targets.
• The team has identified CHD1 as a synthetic essential gene required in prostate cancer cells with mutations in the PTEN tumor suppressor gene. PTEN is the most commonly mutated tumor suppressor gene in prostate cancer, occurring in ~20% of primary prostate cancer and in ~40% or greater of advanced disease.
• Mouse models will be used to evaluate the impact of deleting CHD1 in PTEN-deficient prostate cancer. Gene expression will be studied in these models to clarify the biological functions of CHD1 in PTEN-deficient tumors.
• CHD1 appears to play a role in regulating inflammation and immune responses. The impact of CHD1 on expression of immune genes and infiltration of tumors with immune and other cell types will be evaluated.
• Whether treatment with the cancer immunotherapies anti-PD1 and anti-CTLA4 is synergistic with CHD1-inhibition in PTEN-deficient prostate cancer will be evaluated in mouse models.
• To identify new synthetic essential genes in prostate cancer, CRISPR will be used to knockout genes in a panel of human prostate cancer cells lines and identify those necessary for cancer cell fitness in the context of specific mutations.
• Candidate synthetic essential genes will be validated using human prostate cancer datasets, as genes that are rarely deleted but typically show compensatory increased expression in the context of tumor suppressor gene deletion.
• Candidate synthetic essential genes will also be validated functionally by determining whether targeting these genes impacts the growth of tumor cells lacking the tumor suppressor gene.
• If successful, this project will result in the identification of novel precision medicine drug targets for the treatment of prostate cancer.

What this means to patients:  The identification of novel ways to target prostate cancer is essential for improving treatments and outcomes for patients. This team will validate the potential for targeting CHD1 in PTEN-mutant prostate cancer alone or in combination with immunotherapy, and will identify other novel precision medicine drug targets that are effective against tumors with certain mutations.

2017 PCF Challenge Award ($1 Million)

Award Donors: Steve Klinsky, Patrick Racz, Ted and Dani Virtue

Principal Investigators: Michael Morris, MD (Memorial Sloan Kettering Cancer Center), Steven Larson, MD (Memorial Sloan Kettering Cancer Center), Jens Voortman, MD, PhD (VUmc Cancer Center Amsterdam)

Co-Investigators: Wassim Abida, MD, PhD (Memorial Sloan Kettering Cancer Center), Howard Scher, MD (Memorial Sloan Kettering Cancer Center), Mithat Gönen, PhD (Memorial Sloan Kettering Cancer Center), Daniel Danila, MD (Memorial Sloan Kettering Cancer Center), Adriaan Lammertsma, PhD (VUmc Cancer Center Amsterdam), Daniela Oprea-Lager, MD, PhD (VUmc Cancer Center Amsterdam), Otto Hoekstra, MD, PhD (VUmc Cancer Center Amsterdam), Gem Kramer, MD (VUmc Cancer Center Amsterdam)

Project Title: Characterizing Mechanisms of Sensitivity and Resistance to Anti-Androgen Therapy with Whole-Body Molecular Imaging

Description:

• New imaging methods that are more sensitive and specific than standard imaging will improve the detection of prostate cancer and enable clinicians to make treatment decisions earlier.
• Morris and team are evaluating two new positron emission tomography (PET) imaging methods to determine their prognostic value and clinical utility for prostate cancer.
• F-18-labeled prostate-specific membrane antigen (F-18 PSMA) and F-18 labeled dihydrotestosterone (FDHT) are two new PET imaging agents that are highly promising for the detection of prostate cancer metastases and as prognostic biomarkers for metastatic castrate-resistant prostate cancer (mCRPC).
• Morris and team are conducting a prospective, multi-center clinical trial to test F-18 PSMA and FDHT PET/CT imaging in patients with mCRPC undergoing treatment with AR-targeted therapy.
• Patients will be imaged with F-18 PSMA and FDHT PET/CT before the start of treatment, after one month of treatment, and at the first sign of disease progression. Tumor biopsies and blood samples will be collected to evaluate other potential prognostic biomarkers including tumor mutations, circulating tumor cell (CTC) counts in blood, and the expression of AR-V7, an indicator of resistance to AR-targeted therapy.
• The performance of pre-treatment F-18 PSMA and FDHT PET/CT scans for predicting clinical outcomes will be determined and compared with CTC and AR-V7 biomarkers and with standard prostate cancer prognosticators.
• Whether PET parameters correlate with the presence of tumor or hereditary mutational profiles will also be determined.
• To determine the utility of FDHT and F-18 PSMA PET imaging as response indicator biomarkers, post-treatment changes on F-18 PSMA and FDHT PET/CT scans will be correlated with changes observed on conventional bone scans, changes in other biomarkers including CTC levels and AR-V7 expression, and changes in tumor mutational profiles.
• If successful, this project will result in the validation of new PET imaging biomarkers to prognosticate or monitor tumor response to therapy in patients with mCRPC.

What this means to patients:  New molecular imaging methods have the potential to not only improve the detection of prostate cancer, but may act as predictive and prognostic biomarkers for treatment response and clinical outcomes. This team will evaluate two experimental PET imaging methods, F-18 PSMA and FDHT, for their prognostic value and clinical utility in patients with mCRPC undergoing treatment with AR-targeted therapy, and compare these with standard imaging methods and other promising biomarkers.

2017 PCF Challenge Award ($1 Million)

Award Donors: Lewis Ranieri, Steve Ross, Anonymous Donor

Principal Investigators: Owen Witte, MD (University of California, Los Angeles)

Co-Investigators: John Lee, MD, PhD (University of California, Los Angeles), Stephen Forman, MD (City of Hope), Saul Priceman, PhD (City of Hope)

Project Title: CEACAM5-Directed Chimeric Antigen Receptor T Cell Therapy for Lethal Neuroendocrine Prostate Cancer

Description:

• Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that is defined by stem-like, neuroendocrine differentiation and a lethal clinical course. There are currently no effective therapies for NEPC and the average survival is less than one year from the time of diagnosis. New therapies are urgently needed for the treatment of NEPC.
• Witte and team have identified CEACAM5 as a protein frequently expressed on the surface of NEPC cells that may act as an ideal therapeutic target.
• This team will develop CEACAM5-targeted chimeric antigen receptor T cell (CAR-T) therapy for the treatment of NEPC.
• CAR-T cells are a type of immunotherapy in which a patients’ own T cells are genetically engineered to target and kill tumor cells by inserting a CAR gene that targets a tumor cell marker, such as CEACAM5.
• Optimized CEACAM5-targeted CAR T cells will be tested in preclinical models for efficacy against NEPC and to identify potential toxicities.
• Tumors that are resistant to CEACAM5-targeted CAR T cells will be evaluated to determine mechanisms of resistance.
• To minimize toxicities caused by targeting non-tumor cells that express low levels of CEACAM5, a “dual-gate’ CAR T strategy will be developed in which T cells will be uploaded with a TROP2-inhibitory CARs in addition to the CEACAM5-activating CARs. The TROP2-inhibiotory CAR will block the T cells from killing any cells that also express TROP2, a protein overexpressed on many normal and cancer cell types, but is downregulated in NEPC.
• The specificity of CEACAM5-activating / TROP2-inhibitory CAR T cells for killing only CEACAM5-positive/TROP2-negative cells will be validated and evaluated for safety profiles in preclinical models.
• If successful, this project will develop a novel CAR T cell immunotherapy that can selectively kill NEPC.

What this means to patients:  Neuroendocrine prostate cancer (NEPC) is a highly aggressive and lethal subtype of prostate cancer for which treatments are urgently needed.  This team will develop a novel CAR T cell immunotherapy that selectively targets NEPC but not normal cells, and demonstrate its feasibility and safety in preclinical studies in preparation for clinical development.

2017 PCF Challenge Award ($1 Million)

Award Donor: The Stupski Foundation

Principal Investigators: Eric Small, MD (University of California, San Francisco), Lawrence Fong, MD (University of California, San Francisco), Bin Liu, PhD (University of California, San Francisco)

Co-Investigators: Rahul Aggarwal, MD (University of California, San Francisco)

Project Title: CD46 as a Novel Means to Target Immune Defense Mechanisms and Androgen Pathway Inhibitor Resistance in Metastatic Lethal Prostate Cancer

Description:

• Immunotherapy has the powerful potential to eliminate cancer. However, immunotherapy has not yet been widely successful in treating prostate cancer, necessitating the development of new immunotherapy strategies.
• Small and team have discovered that CD46, a protein that helps cancer cells to evade killing by immune cells, is highly upregulated in castrate resistant prostate cancer (CRPC) but not normal cells and represents a promising target for prostate cancer immunotherapy.
• The team has developed a CD46-targeting treatment (CD46 ADC) and are conducting a phase I clinical trial to test efficacy and safety in patients with metastatic CRPC.
• In this project, the team will investigate whether targeting CD46 is synergistic with anti-PD1/PD-L1 checkpoint immunotherapy in mouse models of prostate cancer. Checkpoint immunotherapy is a type of treatment that reawakens hibernating tumor-killing immune cells.
• Patients in the CD46 ADC clinical trial will undergo pre- and post-treatment tumor biopsies and blood draws. These samples will be used to investigate the expression of PD-L1, a biomarker of responsiveness to anti-PD1/PD-L1 treatment, the diversity and stability of T cell clones over the course of treatment, and treatment-induced changes in the types and functions of immune cells that enter the tumor.
• Whether targeting CD46 can synergize with the androgen receptor (AR)-targeted treatment enzalutamide, or is able to reverse enzalutamide-resistance, will be investigated in preclinical models.
• Tumor samples from clinical trials will be evaluated for whether treatment with CD46 ADC upregulates the expression of AR, and if AR-targeted therapy upregulates expression of CD46. These studies will provide additional rationale for combining these treatments.
• If successful, this project will improve understanding of the mechanisms of action of CD46 ADC treatment and establish rationale for combining CD46-targeted therapy with checkpoint immunotherapy or AR-targeted treatments.

What this means to patients:  Immunotherapy retains significant promise for prostate cancer but has yet to be largely successful in treating this type of cancer.  This team will investigate the mechanisms of action and efficacy of targeting the immune-regulatory protein CD46 and test CD46-targeting treatment in combination with checkpoint immunotherapy and AR-targeted treatment.

2017 PCF Challenge Award ($1 Million)

Award Donor: The Stupski Foundation

Principal Investigators: Richard Lee, MD, PhD (Massachusetts General Hospital Cancer Center), Othon Iliopoulos, MD (Massachusetts General Hospital Cancer Center)

Co-Investigators: Keith Flaherty, MD (Massachusetts General Hospital Cancer Center), Gad Getz, PhD, (Massachusetts General Hospital Cancer Center), Philip Saylor, MD (Massachusetts General Hospital Cancer Center), Matthew Smith, MD, PhD (Massachusetts General Hospital Cancer Center), Gregory Stephanopoulos, PhD (Massachusetts Institute of Technology), Danos Christodoulou, PhD (Massachusetts General Hospital Cancer Center), Shyamala Maheswaran, PhD (Massachusetts General Hospital Cancer Center), Hang Lee, PhD (Massachusetts General Hospital Cancer Center)

Project Title: Glutamine Metabolism in Prostate Cancer: Preclinical and Clinical Evaluation of Dual Inhibition of Glutaminase and PARP

Description:

• Cancer cells grow continually and much faster than normal cells, thus altered cellular metabolism is a hallmark of cancer. For example, cancer cells often depend on glutamine instead of glucose as a key source of carbon.  Targeting altered metabolic pathways in cancer cells is a promising therapeutic strategy in need of further study.
• Lee, Dr. Iliopoulos and team are investigating the therapeutic efficacy of targeting glutamine metabolism pathways for the treatment of prostate cancer.
• CB-839 is a novel, orally bioavailable inhibitor of glutaminase, a key enzyme in the metabolism of glutamine. Cancer cells treated with CB-839 experience glutamine depletion and consequent nucleotide depletion, DNA replication stress, and cell death.
• PARP-inhibitors are a precision medicine effective in prostate cancers with mutations in genes that repair damaged DNA. Lee hypothesizes that PARP-inhibitors may synergize with CB-839.
• The team will test the efficacy of combining CB-839 with the PARP-inhibitor olaparib in mouse models of prostate cancer.
• Following this, the team will initiate a phase I clinical trial to test the safety and efficacy of CB-839 in combination with olaparib in metastatic castrate-resistant prostate cancer (mCRPC).
• Tumor and blood samples from patients on this trial will be evaluated to identify genetic mutations, gene expression profiles and metabolic biomarkers that predict response to treatment.
• If successful, this project will validate the utility of targeting metabolic alterations in prostate cancer for treatment of mCRPC and identify biomarkers that predict response to the combination of glutaminase plus PARP inhibitors.

What this means to patients:  Novel therapeutic approaches that can prolong survival for men with mCRPC remain a critical medical need.  This team will conduct preclinical and clinical studies testing a novel inhibitor of altered prostate cancer metabolism in combination with PARP-inhibitors for the treatment of mCRPC.

2017 PCF Challenge Award ($1 Million)

Award Donor: The Stupski Foundation

Principal Investigators: Jindan Yu, MD, PhD (Northwestern University), Maha Hussain, MD (Northwestern University), Peter Nelson, MD (Fred Hutchinson Cancer Research Center)

Co-Investigators: Yongik Lee, PhD (Northwestern University), Massimo Cristofanilli, MD (Northwestern University), Richard Miller, PhD (Northwestern University), Gary Schiltz, PhD (Northwestern University), Ximing Yang, PhD (Northwestern University), Bin Zhang, PhD (Northwestern University), Changsheng Zhao, MD (Northwestern University), Colm Morrissey, PhD (University of Washington), Eva Corey, PhD (University of Washington), Matthew Rettig, MD (University of California Los Angeles)

Project Title: Targeting Chemokine Signaling and MAPK/ERK Pathway in Advanced Prostate Cancer

Description:

• Castrate-resistant prostate cancer (CRPC) is an advanced and lethal from of prostate cancer that occurs when prostate cancer develops resistance to androgen receptor (AR)-targeted treatment.

New treatment strategies to avoid or overcome progression to CRPC are urgently needed.

• Yu and team hypothesize that the CXCR7/CXCL12 pathway plays a critical role in progression to CRPC by activating the cancer-driving MAPK/ERK pathway and are studying the impact of therapeutically targeting this pathway.
• CXCR7 is upregulated in prostate cancer following treatment with AR-targeted therapy and during to CRPC. The team will validate whether CXCR7 activates the MAPK/ERK pathway in CRPC models and investigate the mechanisms by which the CXCR7/MAPK/ERK pathway drives prostate cancer progression and resistance to AR-targeted therapy.
• A molecular signature of CXCR7/MAPK/ERK activation in prostate cancer will be identified.
• Patient samples from clinical trials will be used to validate whether the CXCR7/MAPK/ERK molecular signature correlates with response to AR-targeted therapies or with the MAPK/ERK-targeting treatment trametinib.
• The CXCR7/CXCL12 pathway plays an important role in the immune system. Whether activity of the CXCR7/MAPK/ERK pathway correlates with the types and numbers of immune cells infiltrating tumors will be examined in clinical CRPC samples.
• Preclinical studies in mouse models of prostate cancer will be conducted to evaluate the potential for combining trametinib with enzalutamide for the prevention or treatment of CRPC.
• Finally, computer algorithms that predict chemical properties of small molecules will be used to identify putative inhibitors of CXCR7 that may be effective in prostate and other cancers.
• If successful, this project will determine the mechanisms by which the CXCR7/MAPK/ERK pathway drives CRPC and identify promising treatment strategies.

What this means to patients:  New treatment strategies are urgently needed to prevent the development or progression of lethal CRPC.  This team will identify mechanisms by which the CXCR7/MAPK/ERK pathway drives CRPC and test the therapeutic efficacy of targeting this pathway.