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The 2013 Mazzone Awards Program Funds $2.7 Million for Prostate Cancer Research

DF/HCC member, Lisa Signorello, ScD (HSPH), leads the Mazzone-funded research project focused on chronic stress and racial disparities in prostate cancer.

October 3, 2013 | eNews

Dana-Farber/Harvard Cancer Center and the Prostate Cancer Foundation announce the ten awardees of the 2013 Mazzone Awards Program. The A. David Mazzone Research Awards Program funds a series of collaborative and innovative cancer research, career development, community outreach, and training projects to address a range of needs in prostate cancer and Lupron-treatable diseases.

Projects Funded through the DF/HCC Mazzone Awards Program by Category:

Career Development

Title: Impact on Prognosis of Inter- and Intratumor Heterogeneity In Prostate Cancer           

Principal Investigator: Jennifer Sinnott, PhD

Mentors: Lorelei Mucci, ScD (HSPH), Giovanni Parmigiani, PhD (DFCI)

Collaborators: Massimo Loda, MD (DFCI), Kathryn Penney, ScD (BWH)

One of the most pressing goals in prostate cancer research is to improve prediction of cancer outcomes at the time of diagnosis so that men can more confidently know how their disease may progress and make better decisions on intervention strategies. A serious impediment to identifying new predictors of cancer progression is heterogeneity. One aspect of heterogeneity is differences between tumors in different individuals. Tumors may progress to lethal disease through a variety of biological pathways, and attempts to identify single markers of lethal disease may fail to improve prediction among men whose cancer is following a different course. Another aspect of heterogeneity is variability within a single tumor. Within a tumor, there can be significant diversity in expression of key genes and proteins, which can severely impact a potential biomarker’s usefulness as a predictor of lethal disease since it may only be measured in biopsy samples. Alternatively, within-tumor heterogeneity may itself be predictive of progression if it reflects widespread disruption of normal cell function. Both types of heterogeneity have been ignored by most prior studies. In this project, we seek to capture heterogeneity and use it to improve risk prediction. We will use tumor gene and protein expression data available in two large cohort studies with decades of follow-up and information about metastases and death. We will build models to predict disease prognosis that allow for different latent subtypes of disease, and account for within-tumor heterogeneity by quantifying it and considering it as a potential predictor of disease progression.

Community Outreach

Title: Shared Medical Appointments: An Innovative Approach to Prostate Cancer Survivorship Care

Principal Investigator: Larissa Nekhlyudov, MD, MPH (HMS)

Collaborators: Ann Partridge, MD, MPH (DFCI); Wilmer Roberts, MD, PhD (Harvard Vanguard Medical Associates); Michael Pistiner, MD, MMSc (Harvard Vanguard Medical Associates); Aymen Elfiky, MD, MPH (DFCI); Christopher Recklitis, PhD, MPH (DFCI); Sarah Reed, MPH, MSW (DFCI)

Approximately 200,000 new cases of prostate cancer are diagnosed in the U.S. per year; there are two million survivors. Following diagnosis and treatment, many face physical and psychological long-term and late effects. Since the vast majority are elderly, most have chronic medical conditions that require management. Care may be complicated by involvement of multiple providers. Racial disparities may further affect the quality of care. Our study responds to the existing gaps in the care of prostate cancer survivors, focusing on improving the quality of life and quality of care in a community based setting. Shared medical appointments (SMAs), also known as group visits, offer an interactive and engaging clinical environment for patient care. We will pilot test SMAs with prostate cancer survivors to determine the effect of the intervention on patient-oriented outcomes, such as depression, anxiety, fear of recurrence, quality of life and communication. We will also develop and pilot test a medical record abstraction tool to evaluate health care utilization and quality of care. The multidisciplinary, multi-institutional project team fosters an academic-community collaboration. The setting for the intervention is community-based, with a large representation of elderly prostate cancer survivors, the majority being African American. Our approach is innovative and is based on a strong theoretical framework. Both the survey and the medical record abstraction findings will provide preliminary data that will lead to a future large scale study evaluating the potential of SMAs in transforming prostate cancer survivorship care in a racially diverse community-based patient population.

Disparities Research

Title: Chronic stress and racial disparities in prostate cancer

Principal Investigator: Lisa Signorello, ScD (HSPH)

Collaborators: Jennifer Rider, ScD (HSPH); Sebastien Haneuse, PhD (HSPH); Unnur Valdimarsdottir, PhD (University of Iceland)

Prostate cancer incidence and mortality among black men are 60% and 140% higher, respectively, than the group with the next highest prostate cancer burden in the U.S., non-Hispanic whites. In addition to racial disparities, men of low socioeconomic status have a significantly higher burden of prostate cancer mortality. Unfortunately, we have yet to conclusively identify modifiable factors that underlie these important disparities. A common encumbrance of minority and underserved populations is their elevated exposure to chronic life stress. As we increasingly understand the biological consequences of high levels of chronic stress, we see that several of these are potentially cancer-promoting, and via pathways that could reasonably be expected to increase prostate cancer risk. Recent animal studies are also suggestive in this regard, and hint that the effects of stress on prostate cancer could be blunted by beta-blocker drugs. We thus propose a project within the Southern Community Cohort Study (SCCS), a unique cohort study established to investigate cancer disparities. We will leverage the existing resources of the SCCS to carry out novel prospective analyses of stress in relation to subsequent risk of prostate cancer, to explore potential interactions between stress and other factors (e.g., beta-blocker use, tumor aggressiveness), and to directly estimate the proportion of the black/white disparity that may be explained by stress. We expect our results to help elucidate a modifiable underpinning of this disparity and serve as a launching point for additional cross-disciplinary investigations aimed at improving prevention and prognosis for prostate cancer in health disparity populations.

High-Impact Projects

Title: Co-targeting AR and ERG to treat advanced prostate cancer

Principal Investigator: Karen Knudsen, PhD (Thomas Jefferson University)

Co-Principal Investigators: Felix Feng, MD (University of Michigan), Myles Brown, MD (DFCI)

Means to durably treat advanced prostate cancers remains elusive. It is well appreciated that prostate cancers of all stages remain dependent on the action of a steroid hormone receptor, the androgen receptor (AR), for growth and progression.Recent improvements have been made in castration-based therapies; however, these are only transiently effective, and new, durable approaches are urgently needed. This High Impact Award submission builds on provocative new findings, and is dedicated to developing effective means for treating advanced prostate cancer. Our research plan leverages the expertise of 3 laboratories; Knudsen (Thomas Jefferson University) and Feng (University of Michigan) independently identified a protein called ‘PARP1’ as a master regulator of two key factors that control aggressive tumor growth, AR and a cooperating pro-tumor factor called ERG. The Brown laboratory (Harvard/Dana-Farber) has expertise in studying the molecular basis of cancer, and brings significant strength in the ability to better understand how PARP1 controls these most critical of factors (AR and ERG) that promote advanced disease. Given our promising preliminary observations, the three laboratories joined forces, and are working together to rapidly translate these basic science discoveries into the clinic, and to determine what patients would best benefit from treatment with a PARP1 inhibitor. Together, our findings strongly support the hypothesis that PARP1 function is critical for prostate cancer progression and for the maintenance of lethal tumor phenotypes, and that suppressing PARP1 activity can be utilized to successfully treat advanced disease.

Title: Genome-wide analysis of response to androgen deprivation therapy

Principal Investigator: Mark Pomerantz, MD (DFCI)

Collaborators: Matthew Freedman, MD (DFCI); Christopher Sweeney, MBBS (DFCI); Manish Kohli, MBBS (Mayo Clinic); Svitlana Tyekucheva, PhD (DFCI)

Prostate cancer is highly dependent on androgens. Androgen deprivation therapy (ADT), which effectively blocks the androgen activity, has been the mainstay of treatment for advanced prostate cancer for decades. Response to treatment varies dramatically, from a couple of months to greater than a decade. A fatal form of disease, castration-resistant prostate cancer (CRPC), ultimately emerges. Improved understanding of the factors associated with response to ADT is needed to improve physicians’ prognostic capabilities, to make treatment decisions and to define the biological pathways responsible for resistant disease. Genetic factors appear to figure significantly in ADT response, but the inherited basis of the trait remains largely unknown. The goal of the present proposal is to perform a genome-wide association study (GWAS) to identify inherited genetic variants associated with ADT response. GWAS have revolutionized our ability to define the genetic basis of specific human traits. These studies typically call for large numbers of cases in order to achieve adequate statistical power. As a result, opportunities to conduct GWAS for important clinical traits, such as ADT response, are often stymied by the difficulty of assembling cohorts of adequate size. In a collaboration of Dana-Farber Cancer Institute, Mayo Clinic and the Eastern Cooperative Oncology Group, we have isolated DNA from approximately 2300 subjects who initiated ADT for advanced disease and whose long-term clinical outcomes have been richly annotated. This dataset enables sufficient statistical power to perform the first comprehensive interrogation of the genome for inherited markers associated with ADT response.

Title: Targeting Androgen Receptor Pathway-Independent Prostate Cancer (APIPC)

Principal Investigator: Peter Nelson, MD (Fred Hutchinson Cancer Research Center)

Co-Principal Investigator: Marc Vidal, PhD (DFCI)

Collaborator: Muneesh Tewari, MD, PhD (Fred Hutchinson Cancer Research Center)

The Androgen Receptor (AR) may be the earliest known example of a lineage onco-gene: a master regulator of cell survival and growth to which neoplastic cells derived from prostate epithelium are addicted. Recognizing this unique feature, concerted efforts have focused on developing therapeutics capable of suppressing AR signaling. Emerg-ing strategies, mirroring successes in treatment for infectious diseases, will eventually deploy combinations of drugs that will likely extinguish AR signaling, an event that may cure a subset of prostate cancers. However, the plasticity of carcinomas, in part gener-ated by highly unstable genomes, suggests that prostate cancers are likely to emerge from this therapeutic pressure with a phenotype/genotype that is entirely independent of AR signaling. This proposal is designed to anticipate that combinatorial AR pathway in-hibition will select for subpopulations of resistant tumor cells that are completely inde-pendent of AR signaling and do not exhibit neuroendocrine characteristics. We will test the hypothesis that AR Pathway-Independent Prostate Cancers (APIPC) activate, and are dependent upon, a limited set of specific survival and growth regulatory pathways that are activated via de-repressed feedback loops and/or genetic/epigenetic alterations in specific oncogenic networks. We further hypothesize that sequential and co-targeting approaches designed to suppress these AR-bypass pathways will inhibit the progressive growth of AR-pathway-independent prostate cancers.

High-Impact Clinical Trials

Title: Clinical Trials Assessing Mechanisms Mediating Sensitivity and Resistance to Enzalutamide

Principal Investigator: Mary-Ellen Taplin, MD (DFCI)

Co-Principal Investigators: Bruce Montgomery, MD (University of Washington); Elahe Mostaghel, MD, PhD (Fred Hutchinson Cancer Research Center); Xin Yuan, MD, DSc (BIDMC)

Collaborators: Steven Balk, MD, PhD (BIDMC); Glenn Bubley, MD (BIDMC); Mark Pomerantz, MD (DFCI); Colm Morrissey, PhD (University of Washington)

Enzalutamide is a novel androgen receptor antagonist that was recently approved for castration-resistant prostate (CRPC) after chemotherapy failure, and will probably be approved for CRPC prior to chemotherapy. To build on the success of this agent and other new agents targeting androgen receptor (including the related antagonist ARN-509 and abiraterone), it will be critical to understand the basis for intrinsic and acquired resistance to these agents. We have an ongoing multi-institutional clinical trial of neoadjuvant enzalutamide, a soon to be initiated multi-institutional clinical trial of enzalutamide in CRPC, and additional trials pending that incorporate enzalutamide or ARN-509 (PIs Mary-Ellen Taplin and Bruce Montgomery). Using clinical material (radical prostatectomy specimens, biopsies and peripheral blood) from patients enrolled in these trials, we propose to conduct a comprehensive series of molecular studies to identify clinically relevant mechanisms that determine sensitivity and resistance to enzalutamide and ARN-509, and propose novel approaches to detect and monitor minimal residual disease. Finally, we propose novel approaches to enhance our ability to obtain tumor biopsies and assess for tumor heterogeneity. The Specific Aims of the proposal are as follows: 1) Identify mechanisms of AR antagonist resistance and metastatic relapse in phase II neoadjuvant clinical trials; 2) Identify mechanisms of AR antagonist resistance in phase II CRPC clinical trials; and 3) Develop methods to enhance tumor recovery and assess tumor heterogeneity in CRPC. These studies will have immediate clinical impact, and will improve our ability to conduct informative clinical trials in the future.

Project Development

Title: Developing Novel Targeted Therapies for Advanced Prostate Cancer

Principal Investigator: Karen Cichowski, PhD (BWH)

While screening and early detection have reduced prostate cancer deaths, there is still no curative treatment for advanced disease. Therefore there is an imperative to develop more effective therapies for castration-resistant, metastatic tumors. Surprisingly, little is known about the signals that drive and maintain advanced prostate cancer. However, one gene that has been implicated in this process is the polycomb group gene EZH2. EZH2 encodes the histone methyltransferase component of the Polycomb Repressive Complex 2, which regulates epigenetic gene silencing. EZH2 is overexpressed or amplified in prostate cancer and expression levels progressively increase in advanced tumors. Notably, EZH2 is one of the most significantly upregulated genes in metastatic disease and has been shown to play a causal role in driving metastasis and castration- resistance in animal models. EZH2 has also been reported to function as an oncogene in other cancers and is mutated in lymphomas. As such there are several companies that are currently developing EZH2 inhibitors. We have been evaluating the therapeutic effects of EZH2 inhibitors in vitro and in animal models in vivo. Our preliminary data demonstrate that two classes of drugs synergize with EZH2 inhibitors to kill castration-resistant prostate cancer cells. In this application we will thoroughly evaluate the therapeutic efficacy of 2 drug combinations in several mouse prostate cancer models. These studies will serve as a basis for developing future combination therapies with EZH2 inhibitors and will begin to provide mechanistic insight into pathways/genes that are required for the survival of castration-resistant prostate cancers.

Title: Targeting the Co-Activator Site on the Androgen Receptor

Principal Investigator: Gregory Verdine, BS, PhD (Harvard University, Chemistry Department)

Collaborator: Levi Garraway, MD (DFCI)

In prostate cancer, uncontrolled cell proliferation is driven by the androgen receptor, a protein that activates gene expression in response to dihydrotestosterone (DHT). All androgen receptor inhibitors currently used to treat prostate cancer work either by reducing systemic DHT levels or by directly inhibiting the binding of DHT to the androgen receptor. Unfortunately, the development of clinical resistance to these types of drugs marks a transformation to castration-resistant prostate cancer (CRPC), a more deadly form of the disease. Because this resistance involves a restoration of androgen receptor activity even in the presence of the aforementioned types of drugs, there is a great impetus to discover inhibitors of the androgen receptor that function through a mechanism that will circumvent the resistance seen in CRPC. Here we propose to discover pharmacologically useful androgen receptor inhibitors that function by preventing the association of the androgen receptor with protein partners required for its activity in CRPC. We will exploit ?-helix peptide stapling technology, pioneered in our lab, to construct these novel inhibitors. These molecules will be evaluated for the ability to interact with the intended site on the androgen receptor and then will be further evaluated for their ability to slow the growth of castration-resistant prostate cancer in standard cell-based assays. By the completion of the proposed two-year study, we expect to have identified a new class of androgen receptor inhibitors that will be poised to enter evaluation in animal models of castration-resistant prostate cancer.

Project Funded through the Prostate Cancer Foundation Mazzone Challenge Award

Title: Synergistic Immune and lipid Metabolism Targeting for Metastatic Prostate Cancer Therapy

Principal Investigator: Jennifer Wu, PhD, (Medical University of South Carolina)

Co-Principal Investigators: James S. Norris, PhD (Medical University of South Carolina); Michael Lilly, MD (Medical University of South Carolina); Xiang Liu, MD, PhD (Medical University of South Carolina); Ali Goshayan, MD (Medical University of South Carolina)

Collaborators: Richard Drake, PhD (Medical University of South Carolina); Ann-Marie Broome, PhD (Medical University of South Carolina); Elizabeth Garrett-Mayer, PhD (Medical University of South Carolina)

This application is based on our novel findings that tumor-derived cancer-specific soluble mediator abrogates NK cell immunity in men with metastatic prostate cancer. With this understanding, we developed a novel antibody which has shown preliminary to be very effective in suppressing prostate cancer metastasis in a novel “humanized” prostate cancer mouse model by inducing death of cancer cells. With the realization that cancer cells have metabolic capacity to fight their ways to survival by self-regulating the sphingolipid ceramide signaling to escape potential death signals, the current study is to seek perturbing cancer metabolic pathway during a novel antibody-based treatment. Specifically, the present application proposes to restore and preserve NK cell immunity in prostate cancer patients with an antibody and to further sensitize cancer cell to the “renewed”  or “awaking” NK cell activity with inhibition of cancer ceramide catabolism. Neither the idea of the novel immune-therapy itself to restore the role of NK cell in controlling cancer metastasis or the concept of the immune/cancer-metabolic co-targeting has been tested before. This approach represents an entirely new paradigm that elicits the patient’s own immune system to eliminate castration-resistant prostate cancer (CRPC) and by enhancing natural immune responses in patients leading to suppression and or eradication of metastatic diseases.