Dana-Farber/Harvard Cancer Center (DF/HCC) Sponsored Funding
A. David Mazzone Research Awards Program
High Impact Award

Sponsor: Non-federal (DFCI)
Award Amount: Up to $250,000 per year for two years for direct costs only ($500,000 total).

One page Letter of Intent due by February 28, 2013. Submit letter online: Application Form Web Page
Application deadline: 04:59:59 PM EST, Friday, April 5, 2013
Funding decisions will be made through peer review by June 15, 2013
Anticipated award date: August 1, 2013
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SUBMISSION INFORMATION

Submission requirements: Applications must be submitted online: Application Form Web Page
Applications submitted using other means will not be reviewed or considered for this award. Applicants should notify their grant administrator/office and follow their institution’s policies and procedures for approval to submit applications. Applications will not be accepted after 04:59:59 PM EST, Friday, April 5, 2013.

Please direct questions to:
Juan Carlos Hincapie
Tel: (617) 632-6155
Email: mazzoneawards@partners.org

OVERVIEW
The A. David Mazzone Research Awards Program will fund 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.

High Impact Awards are large-scale, prostate cancer research projects for teams of investigators. Designed to accelerate the discovery, development and application of new therapies to treat prostate cancer and/or to address significant problems in prostate cancer research, these grants will be awarded to DF/HCC members and collaborators. Research may span the disciplines of basic biology, population studies, outcomes, or social science and should have a high probability of near-term patient benefit. In addition, the grants are intended to result in multi-year, peer-reviewed funding.

AWARD INFORMATION

Award is for $250,000 per year for up to two years ($500,000 total in direct costs). The next projected award period is August 1, 2013 to July 31, 2015. Two awards remain available in this category to be awarded over a two-year period.

Funding Agency: The funding agency for the program is a grant from the U.S. District Court for the District of Massachusetts. Funding was derived from a pool of unclaimed funds from the settlement in 2004 of a class action suit against TAP Pharmaceuticals. The class action suit was related to marketing and sales practices for the prostate cancer drug Lupron.

The Mazzone Awards Program is a DFCI sponsored award, administered jointly through DF/HCC and the Prostate Cancer Foundation.

ELIGIBILITY CRITERIA

Applications will be accepted from two or more independent investigators, at least one of whom holds a full-time Harvard faculty appointment at the level of Assistant Professor or higher, and is a DF/HCC member. Applications including investigators from more than one DF/HCC member institution will be encouraged. Applicants from institutions throughout the country are encouraged to apply as long as they have a collaborator in one of the DF/HCC institutions. These applications should include significant research components from collaborating institutions throughout the country. The intent is to foster high impact collaborative research. Applicants may apply for multiple grants; however, individuals may only be awarded one A. David Mazzone Research Award at a time.

Employees or subcontractors of a government entity or for-profit private industry are not eligible. Exceptions include applicants holding full-time positions at a veterans' hospital or national laboratory (e.g., Lawrence Berkeley National Laboratory) in the United States. Members of the Program’s Scientific Advisory Board (SAB) are ineligible to apply.

PROPOSAL SUBMISSION INFORMATION
Required items (4):

• Application Form: To be completed online by the Principal Investigator when submitting your proposal at Application Form Web Page. Provide a 250-word abstract description of the project in laymen’s terms.
• Research Proposal: The proposal should describe the research to which this award would be applied if funded. Maximum of 5 pages of text including figures. References and budget pages are not included in this page limit. Appendix material will be accepted with the following restrictions: a two-page limit of relevant supporting text or figures, and only manuscripts that have been accepted for publication with the journal acceptance letter.
• Biosketches: Current NIH Biosketch for each participating PI, including all funding sources.
• Budget: Budget requests (direct costs only) and budget justifications should be submitted as NIH 398 form with major divisions of funds (personnel, equipment, supplies, other, etc.; with adequate rationale). Separate budget pages must be submitted for each individual institution requesting funds. Funds will be distributed directly from DFCI to sub-recipients. A composite budget that includes the total costs of the project should also be included when multiple institutions are involved in the project. PIs may include a level of effort (minimum 5% total) and salary support commensurate with their efforts on the project. Support and effort may be split between the collaborating PIs. Funds may be used for direct research expenses only, which may include salary and benefits of PIs, postdoctoral or clinical research fellows and/or research assistants, research/laboratory supplies, and equipment.
• IRB approval if applicable will be required prior to funding.

Format: Items 2 – 4 (above) must be compiled and submitted as a single PDF file. Please include the PI’s name, project title, and page number at the top of each page.

Submit Proposal Online: Application Form Web Page
Application Deadline: 04:59:59 PM EST, Friday, April 5, 2013.
IN FAIRNESS TO ALL THERE WILL BE NO EXCEPTIONS TO THIS DEADLINE

REVIEW CRITERIA
Applications will be reviewed by members of the Program’s Scientific Review Board. Grants will be awarded on the basis of the following review criteria (in order of importance):

• Significance. The project should address an important problem or a critical barrier to progress in the field. The aims of the project should advance scientific knowledge, technical capability, and/or clinical practice and have near-term patient impact.
• Inter-institutional Links. Proposals that foster inter-institutional research will be favored.
• Investigators. The PIs, collaborators, and other researchers should have the necessary experience and expertise and proven track records of accomplishment. The investigators should have complementary and integrated expertise.
• Innovation. The application should challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions.
• Approach. The overall strategy, methodology, and analyses should be well-reasoned and appropriate to accomplish the specific aims of the project.
• Environment. The scientific environment in which the work will be done should contribute to the probability of success.
• Potential to gain independent funding. There should be a high likelihood that project will lead to NCI or other cancer research foundation funding.

PROGRESS REPORTS
Grantees must submit annual progress reports to DF/HCC including detailed narrative updates, accrual reports (if applicable), and expenditure reports. Progress will be measured through the review of progress reports. Generally, progress that approximately meets benchmarks, timelines, or specific aims that are set forth within corresponding proposals will be funded on a per-year basis through the completion of the grant term.

2012 High Impact Mazzone Awards Recipients

Molecular Characterization Of Gleason 3 Tumors That Progress To Gleason 4
PI: Steven Balk, (Beth Israel Deaconess Medical Center)
Collaborator: Wei Li (Baylor College of Medicine)

Prostate cancer (PCa) detected on needle biopsies in asymptomatic men is frequently low grade (Gleason pattern 3, G3) and appears indolent, and many of these men are managed conservatively ("watchful waiting" or "active surveillance") with interval repeat biopsies. However, it is unknown whether these G3 tumors (or a definable subset of these tumors) progress to higher grades. We recently employed laser capture microdissection and deep sequencing methods to examine a series of adjacent G3 and G4 tumors, and our results establish that G3 and G4 tumors can emerge from the same clone. We further found that two of the four G3 tumors examined in detail had lost one copy of a tumor suppressor gene (PTEN), and that progression from G3 to G4 was associated with further PTEN loss. These results indicate that there may be molecular features that distinguish G3 tumors that can progress to G4 (or are derived from a precursor that can progress) from those that are truly indolent. Our overall objective is to identify molecular features that may distinguish prostate cancers that are truly indolent from those that have the potential to progress to higher grades and metastasize.

Defining the spectrum of resistance to androgen ablation therapy in prostate cancer
PI: Levi Garraway (Dana-Farber Cancer Institute)
Collaborators: William Hahn (Dana-Farber Cancer Institute), Mark Rubin (Weill Cornell Medical College)

Prostate cancer is the most common solid tumor and the second most common cause of cancer death among men in the United States. Prostate cancer malignant cells require the presence of androgens for survival. Thus, while early-stage disease treatment options include surgery, radiation therapy and active surveillance, androgen deprivation therapy (castration) has been implemented as a first-line therapy for metastatic disease. Unfortunately, however, although almost all men with advanced prostate cancer initially respond to castration, most of them gradually develop resistance and their disease progresses. To date researchers have identified several mechanisms of resistance. However, despite recent therapeutic advances, castration-resistant prostate cancer remains a formidable medical challenge. Thus, there is clearly a need to advance in the discovery and understanding of cellular mechanisms that confer resistance to androgen deprivation therapy. To address this need, we are taking systematic and unbiased approaches to identify such mechanisms. Using prostate cancer cell lines models that require androgen for survival, we will perform genome-scale screens that will identify genes whose overexpression (gain-of-function) or silencing (loss-of-function) allow these cells to proliferate in the absence of androgen and to form tumors in castrated mice. Results from these efforts will be integrated with genomic information of patient samples (~500), including aggressive primary prostate cancer tumors and castration-resistant specimens, to determine whether any of the resistance candidate genes are altered in patients, and thus, potentially clinically relevant. This Integrated approach may provide the framework for improved diagnosis and, in the future, application of durable therapeutic approaches for CaP.

2011 High Impact Mazzone Awards Recipients

Functional Annotation of Prostate Cancer Risk Loci Discovered through Genome Wide Association Studies
PI: Matthew Freedman, MD (DFCI)
Collaborator: Gerhard Coetzee, PhD (USC/Norris Cancer Center - Keck School of Medicine)

The understanding of genetic predisposition to complex diseases such as prostate cancer has undergone a revolution during the past five years, mainly due to the utilization of high-throughput genomic technologies and large cohorts. Numerous genome-wide association studies (GWAS) were published during this time in high-impact journals. In these studies genetic variation known as single nucleotide polymorphisms (SNPs) are commonly used to capture genome-wide variation and allele-frequency changes in numerous diseases including prostate cancer cases versus controls. A primary goal of such genetic association studies has been (and still is) to identify genes and associated novel biological pathways/mechanisms involved in the risk for the particular disease. To date prostate cancer-associated SNPs that mark more than 50 genetic regions (loci) have been identified in this way. Remarkably, the risk-associated SNPs in many of these regions are in DNA outside of known protein coding regions. Their biological significance is therefore not immediately obvious. This project’s overall hypothesis is that some of these non-coding genomic regions encompass regulatory DNA, which are affected by risk-SNPs and thus modify the expression of genes and pathways involved in disease predisposition and/or progression. This project intends to identify and study such risk regions. The results will yield novel predisposition genes as well as the biological mechanisms of prostate carcinogenesis, and more broadly solidify critical post-GWAS approaches applicable to a multitude of complex human diseases where risk SNPs are commonly identified far from coding sequences.