PCF vetted the 10 2011 Challenge Awards from a field of 59 research proposals from highly-qualified research teams at prestigious cancer centers around the globe. Following an extensive peer review, consisting of an external advisory board, PCF selected the top research proposals for funding. These projects represent a range of focus and expertise and will address the most challenging problems in basic or translational research in prostate cancer. The 10 Challenge Awards include two Judge A. David Mazzone-PCF Challenge Awards.
2011 PCF Challenge Award
Steven Balk, MD, PhD – Beth Israel Deaconess Medical Center
Identifying and Exploiting Mechanisms of Response and Resistance to Androgen Receptor Pathway Directed Therapeutics
Co-investigators: Peter Nelson, MD; Trevor Penning, PhD; Glenn Bubley, MD; Toni Choueiri, MD; Phillip Kantoff, MD; Christopher Sweeney, MD; Mary-Ellen Taplin, MD; Steven Plymate, MD; Robert B. Montgomery, MD; Robert Vessella, PhD; Lawrence True, MD; Alvin Matsumoto, MD; Elahe Mostaghel, MD, PhD
Abiraterone acetate (Zytiga), recently approved by the FDA for treatment for metastatic prostate cancer and soon to be approved within the European Union, is a new drug currently used after chemotherapy. As with previously approved treatments, patients invariably become resistant to abiraterone by mechanisms largely unknown. Dr. Balk and his team of cancer biology experts propose to investigate treatment resistance mechanisms in abiraterone-resistant patients. Based on these findings, the team will design new androgen receptor (AR) pathway-targeted medications that should result in durable cancer remission.
Potential patient benefit: The findings from Dr. Balk’s team will provide reasons for the failure of therapy in patients of advanced prostate cancer. This will help design more effective and targeted therapy for metastatic treatment-resistant disease.
2011 PCF Challenge Award
Leland W.K . Chung, PhD – Cedars-Sinai Medical Center
Targeting Cell Death Programs in the Tumor and its Microenvironment
Co-investigators: Edwin Posadas, MD; Neil Bhowmick, PhD; Hyung L Kim, MD;
Andre Rogatko, PhD; Beatrice Knudsen, MD, PhD; Stuart Holden, MD; Mahul B. Amin, MD; Martin Gleave, MD; Michael Freeman, PhD; Daqing Wu, PhD; Matthew Bui, MD
There are very few effective medications for patients whose cancer has spread and metastasized to different parts of the body. XL184 (Cabozantinib) has shown promise in the remission of prostate cancer in bone and soft tissue metastases. This medication is known to target multiple critical cellular functions, thereby handicapping a tumor cell. Dr. Chung and his team will explore the mechanisms of action of XL184 in detail. The effects of combining this medication with other available therapies will also be evaluated. Further, the team will study the various cell death mechanisms switched off in XL184-treated cancer cells that lead to resistance and uncontrolled growth of tumors.
Potential patient benefit: The proposed studies will improve our understanding of the mechanism of action of XL184 and will identify combinative therapies to guide optimal use of this promising medication for better patient outcomes
2011 PCF Challenge Award
Johann S. de Bono, MD, PhD – The Institute of Cancer Research and The Royal Marsden Hospital
Identification, Characterization and Validation of Novel Inhibitors of the AR N-Terminus
Co-investigators: Gerhardt Attard, MD, PhD; Jun Luo, PhD; Michael Carducci, MD; Mario Eisenberger, MD; Peter Campbell, PhD
This talented team of scientists who have played key roles in the development of two very effective anti-prostate cancer medications, abiraterone and cabazitaxel, have come together to study the root cause of metastatic treatment-resistant prostate cancer, namely, the dysregulation of the Androgen Receptor (AR) signaling pathway. Understanding the aberrations in pathways will help answer why and how patients develop resistance to currently available therapeutics. The team’s studies in patient tumor samples will also identify specific biomarkers of the disease that can be used for monitoring the spread of cancer in metastatic patients. These findings have implications in personalizing medicine for patients of metastatic treatment-resistant prostate cancer.
Potential patient benefit: Understanding the mechanisms by which tumors develop resistance to currently available medications is essential for the design and development of newer therapies, as well as enhancing the efficacy of the currently available treatments. These studies by Dr. de Bono and colleagues are a major step in one day being able to deliver highly-personalized treatments for individuals.
2011 PCF Challenge Award
Philip G. Febbo, MD – University of California, San Francisco
Understanding the Clinical and Radiological Impact of XL184 through Treatment Science
Co-investigator: Celestia Higano, MD, Beatrice Knutson, PhD, Peter Nelson, MD, Edwin Posadas, MD, Ravi Salgia, MD, Evan Yu, MD
Drs. Febbo and Higano propose a phase II trial of the experimental medication, XL184 (Cabozantinib) that has shown very promising results in reducing bone and soft tissue metastases in patients with metastatic castration-resistant prostate cancer. Since the mechanism of action of this promising therapeutic is largely unknown, this study will help us understand how the medicine works in the body and the specific tissues it targets. This team, in collaboration with researchers at the University of Washington, will use PET imaging to study bone tumor biopsies from patients of advanced prostate cancer. These findings will help to further enhance the efficacy of this therapy as well as identify new drug combination treatments. The findings from this Phase II trial will also help us understand the exact pathways affected by XL184, which will help in the development of sequential therapies in the future, when the cancer eventually becomes resistant to XL184.
Potential patient benefit: In this phase II trial of XL184, Drs. Febbo and Higano are studying the exact mechanism by which this medication benefits patients with metastatic prostate cancer. This knowledge will inform clinical investigations of this medication as well as its potential use in new combinative and sequential treatments to improve outcomes.
2011 A. David Mazzone-PCF Challenge Award
Dr. Glenn Liu, MD – UW Carbone Cancer Center
Imaging Biomarkers of Treatment Response Using NaF PET/CT Imaging: a Prostate Cancer Clinical Trials Consortium (PCCTC) Effort
Co-investigators: Michael Morris; William Dahut, MD; Steven Larson, MD; Peter Choyke, MD; Robert Jeraj, PhD
As prostate cancer advances and spreads, it homes in on the bones. Monitoring the establishment and spread of cancerous tumors in the bone poses a major challenge. It is also crucial for the evaluation of anti-cancer therapies in patients for tracking both individual lesions and total disease progression in the bone. Dr. Liu, with his team of notable experts in prostate cancer drug development, nuclear medicine and quantitative molecular imaging, is evaluating a novel tool for tracking the spread of prostate cancer and treatment response using 18F-Sodium fluoride (NaF), which is highly specific for cancerous bone lesions. Imaging NaF in the bone with periodic PET/CT scans will help study both the spread of prostate cancer to the bone and the effectiveness of medications that target prostate cancer bone metastases. Dr. Liu and his team will also evaluate different Imaging Biomarkers of Clinical Response (IBCR) that can confidently report the effectiveness of treatment and select the strongest biomarker demonstrating the highest detection rate.
Potential patient benefit: The work of Dr. Liu and his team has the potential to deliver greater confidence to patients and their physicians through enhanced diagnostic and treatment response tools.
2011 PCF Challenge Award
Christopher J. Logothetis, MD – The University of Texas MD Anderson Cancer Center
Mechanisms of Resistance to Androgen Biosynthesis Inhibition in Castration-Resistant Prostate Cancer Bone Metastases
Co-investigators: Gary Gallick, PhD; Sankar Maity, PhD; Randall Millikan, MD, PhD; Mark Bedford, PhD; Eleni Efstathiou, MD, PhD
Despite initial response, most prostate cancers will invariably become resistant to available therapies. Therefore, it is essential to understand these mechanisms of resistance operating in tumor cells as this will not only inform current drug treatment modalities but also future medication design. Dr. Logothetis and his team of experts propose to explore the resistance mechanisms for the recently FDA-approved medication, Zytiga (abiraterone acetate). Zytiga functions by inhibiting the synthesis of tumor-associated androgen, the male hormone testosterone, which plays a critical role in prostate cancer survival and metastasis. This team will study the androgen receptor signaling pathway in detail to understand the mechanisms that mediate resistance to therapy.
Potential patient benefit: This team’s work will help us understand the reasons for the failure of medications in castration-resistant prostate cancer (CRPC) patients and provide valuable data for the future design of new and better therapies for CRPC patients.
2011 A. David Mazzone-PCF Challenge Award
William G. Nelson, MD, PhD – Johns Hopkins Medicine
Induction of Synthetic Lethality with Epigenetic therapy (ISLET) for Systemic Treatment of Prostate Cancer
Co-investigators: Srinivasan Yegnasubramanian, MD, PhD; Jun O. Liu, PhD; Stephen B. Baylin, MD; Michael A. Carducci, MD; Martin J. Aryee, PhD
One of the causes for the initiation of cancer is the switching off or complete shutdown of certain critical genes (gene silencing) that should remain active. Tumor cells also use this mechanism as the cancer spreads and becomes resistant to treatment. Cancer cells adapt to currently available drugs by switching off the targets of these medications and rendering them ineffective. Dr. Nelson and his team of scientists plan to discover innovative new medicines that will turn switched-off genes back on so that currently available medications can effect tumor regression. The reversal of gene-silencing by new medications will have a two-pronged effect; one, switching on the ‘good’ genes that cancer switches ‘off’ and two, switching on the ‘bad’ genes so that currently available medications can more effectively identify and target them.
Potential patient benefit: New medications discovered by Dr. Nelson’s team could attack tumors in new ways. Combined with currently available treatments, these new therapies for metastatic prostate cancer have the potential to improve patient outcomes.
2011 PCF Challenge Award
Mark A. Rubin, MD – Weill Cornell Medical College
Recurrent SPOP Mutations in Prostate Cancer: Characterization of a Potentially Targetable Sub-class of Prostate Cancer
Co-investigators: Pengbo Zhou, PhD; Hao Wu, PhD; Francesca Demichelis, PhD
Dr. Rubin and colleagues have identified a unique class of prostate cancer patients that have mutations in the gene for SPOP (Speckle-type POZ Protein). These mutations result in the loss of the critical function of SPOP that leads to increased invasiveness of the tumor cells and metastatic spread of prostate cancer. Dr. Rubin and his team will study in detail the mechanisms by which the SPOP gene is inactivated and the downstream effects of genetic dysregulation at the SPOP level. These findings will help in the design of effective therapeutics for this class of prostate cancer patients. The team will also assess the prevalence of these gene mutations in all patients of prostate cancer. This will help in the overall classification of the disease into distinct classes of patients, with specific therapies directed at each class.
Potential patient benefit: Dr. Rubin’s research will help in the stratification of prostate cancer patients based on genetic subtypes. Discovery of SPOP inhibitors will potentially create a new therapy for metastatic prostate cancer and, in time, will support highly personalized treatment for patients.
2011 PCF Challenge Award
Martin Sanda, MD – Beth Israel Deaconess Medical Center
Nanoparticle-Targeted Peptide Vaccines for Prostate Cancer: The Harvard – Hopkins – Carolina Consortium
Co-investigators: Joseph M DeSimone, PhD; Simon M Arredouani, PhD; Charles Drake, MD, PhD
Dr. Sanda and his cross-disciplinary team of nano-material chemists and immunologists are developing a new immunotherapy with the potential to boost a patient’s immune system to fight cancer. This new medicine formulation will contain two components. One is a nanoparticle vaccine that will stimulate the body’s immune system to produce cancer-fighting agents. The second component is one that will further boost the patients’ immune system to attack cancer cells. This team of experts is using an ingenious method to deliver the medication right to the tumor cells, using prostate cancer-specific, biodegradable nanocarriers that will carry the medicine directly to the requisite immune cells of the body and stimulate them for a disease-specific response.
Potential patient benefit: The new medication being developed by Dr. Sanda and colleagues has the potential to efficiently deliver new agents to stimulate a patient’s own immune system to fight cancer. This work represents continued progress in immunotherapy for cancer—a now validated concept that was once thought to be impossible.
2011 PCF Challenge Award
Howard Scher, MD – Memorial Sloan-Kettering Cancer Center
Development of Combined Inhibition of AR and PI3K Signaling as a Therapeutic Strategy for Advanced Prostate Cancer
Co-Investigators: Charles Sawyers, MD; Brett Carver, MD; Neal Rosen, MD, PhD
Cell signaling in cancer causes uncontrolled cell growth and many clinical properties of cancer, such as metastases. Two major pathways of cell signaling in prostate cancer are initiated through a cascade of biochemical pathways. One is regulated through the androgen receptor (AR), the engine of prostate cancer, another is called PI3 Kinase (PI3K) which responds to growth factors on the outside of the cell that send signals for inappropriate cell growth. This team recently showed that targeting just one of these pathways in anticancer therapy has limited benefit because cancer cells adapt to the medication by turning on the other pathway. Therefore, it is crucial to target both the PI3K and AR pathways through combination therapy for effective and durable treatment. Dr. Scher and his team plan to inhibit individual steps in the PI3K pathway and investigate the cancer cell adaptation and survival response in detail. The technical plan will involve investigations of the results of inhibiting either of these pathways and the benefit of combined therapy. This information will then be used to design clinical trials that co-target these two dominant signaling pathways in prostate cancer patients.
Potential patient benefit: Successful clinical trials with combined signaling inhibition with medications against PI3K and AR will provide patients with improved therapy for advanced prostate cancer and better outcomes.