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

Sponsor: Non-federal (DFCI)
Award Amount: Up to $50,000 per year for two years for direct costs only ($100,000 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.

Career Development Awards will support junior investigators transitioning from training to independent investigators. Research may focus on any aspect of prostate cancer prevention (health promotion, modifiable risk factors, new animal models and extrapolation of these models to human cancer, genetic predisposition to prostate cancer, detection of precursor lesions, chemoprevention, trials in human populations, behavioral research and behavioral intervention trials); epidemiology (classic, genetic, molecular); biostatistics; human cancer genetics; human nutrition; health services and health policy research; and medical decision analysis. Research may also focus on survivorship and quality of life as they relate to prostate cancer; basic and applied research in the behavioral sciences that independently or in combination with biomedical approaches reduces prostate cancer risk, incidence, morbidity, and mortality over the lifespan and across the entire process of carcinogenesis from primary behavioral prevention in youth, to screening, treatment, and survivorship.

AWARD INFORMATION

Award is for $50,000 per year for up to two years ($100,000 total in direct costs). The next projected award period is August 1, 2013 to July 31, 2015. One award remains 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 AND REQUIREMENTS

Proposals will be accepted from applicants in their final year of clinical fellowship or postdoctoral fellowship (MD, PhD, or MD/PhD) or within their first three years on staff, or in an academic appointment not higher than Assistant Professor at Harvard. A track record of interest and productivity in prostate cancer research is required. Awardees will be encouraged to apply for DF/HCC membership and will be invited to attend program activities (meetings, retreats, research presentations). Applications including investigators from more than one DF/HCC member institution will be encouraged. Applicants are also encouraged to have collaborators at other institutions throughout the country.

Past or present recipients of a Prostate Cancer Foundation young investigator award or DF/HCC Specialized Programs of Research Excellence (SPORE) career development award are not eligible for this Mazzone award. 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 (8):

1. 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.
2. Research Proposal: The proposal should describe the research to which this award would be applied if funded. Maximum of 3 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.
3. Applicant’s Career goals
4. Mentor’s letter of support
5. Applicant’s NIH Biosketch
6. Mentor’s NIH Biosketch
7. 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. 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.
8. IRB approval documents and Human Subject Training if applicable: IRB approval will be required prior to funding.

Format: Items 2 – 7 (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. The 3 page research proposal should include an introduction, specific aims, and research strategy (significance, innovation, and approach). Use standard size paper (8 ½” x 11”), Arial or Helvetica font, 11 points or larger with margins ½ inch or larger (top, bottom, left, and right). Figures and legends must be of legible size and legible when printed in black and white.

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 scientific merit/quality of the proposal (coherent presentation, candidate's own work, prostate cancer focus, translational nature)
• Candidate. Quality of prior mentored period of cancer research training; demonstrated interest in problems relevant to prostate cancer, and potential ability to successfully manage an independent research project.
• Mentor(s): Mentor's statement describing the potential and capability of the candidate to become a successful independent investigator.
• Research Plan. Appropriateness of the proposed research project for the candidate’s stage of research development; proposed research relevance to stated career objectives.
• Career Development Plan. Appropriateness of the career development plan and the likelihood that the award will contribute substantially to the scientific development of the candidate and consistency of the career development plan with the candidates prior research experiences and current research career goals.
• Environment and Institutional Commitment to the Candidate. The quality of the research environment (mentor support, resources available) and institutional commitment to fostering the career development of the candidate.

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 Career Development Mazzone Awards Recipients
Within-Person Molecular Differences in Primary Versus Metastatic Prostate Cancer
PI: Julie Kasperzyk (Brigham and Women’s Hospital)
Collaborators: Steven Balk (Beth Israel Deaconess Medical Center), Giovanni Parmigiani (Harvard School of Public Health, Meir Stampfer (Brigham and Women’s Hospital)

Approximately 36-70% of prostate cancer patients harbor disseminated tumor cells in bone marrow prior to radical prostatectomy, though only a fraction will develop overt bone metastases. Our understanding of the biological mechanisms underlying the progression of metastatic disease has been limited in part by the difficulty in obtaining bone lesions for research purposes and the molecular heterogeneity of primary and metastatic tumors. The few studies that have explored gene expression patterns in bone metastases versus primary tumor identified multiple general pathways that could be implicated in metastatic progression. We plan to identify a more focused and biologically relevant gene signature of metastatic progression by integrating online data mining tools of existing studies with gene expression data from our study population of 15 patients with matched specimens of bone marrow metastases and primary tumors. First, we will use the ncbi gene expression omnibus (geo) to construct our candidate gene list of ~800 transcripts to test in our study population. We will then put our findings in a biological context in 3 ways: 1) using bioinformatics techniques to detect which genes or pathways we identify are present in current prognostic signatures; 2) using a separate patient population to test whether our signature distinguishes lymph node metastases from primary prostate tumors; and 3) using the broad institute’s connectivity map to screen for drugs that could potentially alter our gene targets. Overall, our study provides a focused, innovative approach toward identifying therapeutic targets to prevent and treat metastatic prostate cancer.

Inflammation and Tissue Microenvironment As Predictors Of Prostate Cancer Risk, Mortality And Therapy Response Among Men With An Initially Benign TURP
PI: Jennifer Rider (Harvard School of Public Health)
Collaborators: Lorelei Mucci (Harvard School of Public Health), Giovanni Parmigiani (Dana-Farber Cancer Institute), Christopher Sweeney (Dana-Farber Cancer Institute), Michelangelo Fiorentino (Harvard School of Public Health), Ove Andren (University of Orebro)

The objective of our study is to determine whether risk of total and lethal prostate cancer, along with response to androgen-deprivation therapy, can be determined early in prostate carcinogenesis, before the cancer has been diagnosed. We will use turp samples collected from 596 Swedish men between 1979-1997 at örebro university hospital. Some of these men later developed prostate cancer, providing an opportunity to relate pre-diagnostic biological markers to risk of total or lethal disease. We will focus on three pathways functioning in the tumor environment: inflammation, the formation of new blood and lymph vessels (angiogenesis), and the supporting framework of the prostate (stroma). All three pathways are active in a normally functioning prostate; however, alterations in these pathways play important roles in early tumor development, and may also contribute to metastasis. Our study will help us understand the biology of prostate cancer growth and progression, and whether biomarkers associated with prostate cancer can be informative when measured in benign tissue collected before diagnosis. This information could later be developed into a clinical test for men with bph or with an apparently benign prostate biopsy to determine the potential for developing aggressive prostate cancer later in life. If the markers are associated with response to adt, a test could influence patient and physician decisions regarding treatment, or could guide new therapeutic approaches. Several of the proposed research aims will be investigated for the first time in men with tissue collected before diagnosis, thus representing a high level of innovation.

2011 Career Development Mazzone Awards Recipients

Probing androgen receptor signaling in circulating tumor cells in prostate cancer
PI: David Miyamoto, MD, PhD (Massachusetts General Hospital)
Collaborator: Daniel Haber, MD, PhD (Massachusetts General Hospital)

Prostate cancer progression critically depends on a molecular signaling pathway called the androgen receptor (AR) pathway. The first-line treatment for metastatic prostate cancer is hormonal therapy, which works by turning off the AR pathway in cancer cells and preventing their growth. Several promising new prostate cancer drugs also target the AR pathway, but with even greater effectiveness. However, at the present time, there are no reliable assays to determine whether or not these drugs are working effectively during treatment. This project proposes to use a new technology called the “CTC-chip,” which isolates cancer cells circulating in the bloodstream of patients (circulating tumor cells, or CTCs), to perform molecular tests to determine whether cancer drugs are properly hitting their target. Specifically, the project will use the CTC-chip to isolate CTCs from patients with advanced prostate cancer before and after hormonal therapy, and perform tests on these CTCs to determine whether the AR pathway has been effectively turned off. In addition, the project will examine AR signaling activity at the single cell level using a combination of high resolution imaging and sophisticated molecular analyses. If successful, these studies may provide a blood test that can show whether hormonal therapy is effectively attacking a patient’s prostate cancer, and will yield new scientific insights into the AR signaling pathway that may provide clues to new approaches to prostate cancer treatment.

Prostate cancer genetic variants, molecular alterations and mRNA expression
PI: Kathryn Penney, ScD, BA (Brigham and Women’s Hospital)
Collaborator: Massimo Loda, MD (Brigham and Women’s Hospital)

Prostate cancer is known to be highly heritable; numerous germline genetic variants have been identified through genome-wide association studies that are significantly associated with PCa risk. However, the function of these genetic variants and their biological mechanisms are generally unknown. mRNA expression levels can offer clues to these mechanisms, providing insight into opportunities for prevention. Additionally, men with specific genetic risk variants may be more likely to develop particular molecular subtypes of Prostate Cancer. This prospective study of 413 men with Prostate Cancer will assess the association of each confirmed Prostate Cancer germline risk variant with the mRNA expression of 29,000 gene targets in prostate tumor and adjacent normal tissue to identify possible genes and pathways involved. The study will also examine the association of the risk variants with the most common and relevant Prostate Cancer molecular alterations, TMPRSS2:ERG fusion, loss of PTEN, and MYC amplification. This comprehensive study will ascertain biological pathways that explain the link between genetic risk variants and Prostate Cancer; identifying these genes and pathways is a necessary step in developing targeted therapies. If a man’s genetic risk variant profile makes him more susceptible to developing specific molecular subtypes of Prostate Cancer, this new information could influence treatment choices among men carrying these particular risk variants.

Phosphorus and calcium intake, tumor microenvironment and prostate cancer progression
PI: Kathryn Wilson, Sc.D. (Harvard School of Public Health)
Collaborators: Lorelei Mucci, MPH, ScD (Brigham and Women’s Hospital), Edward Giovannucci, MD, ScD (Harvard School of Public Health), Michelangelo Fiorentino, MD, PhD (Harvard School of Public Health)

Prostate cancer mortality is often due to bone metastasis, which occurs frequently in Prostate Cancer. Factors that increase the affinity of tumor cells for bone are likely to be related to prostate cancer progression and mortality. Previous findings have suggested that bone-related nutrients (calcium, vitamin D, phosphorus) may be risk factors for prostate cancer. The Health Professionals Follow-up Study found that higher dietary intakes of calcium and phosphorus are associated with increased risk of prostate cancer, particularly with more aggressive forms of the disease. This project hypothesizes that calcium and phosphorus intakes may influence tumor cell expression of bone metabolism-related proteins: osteopontin, calcium-sensing receptor, PTH-related protein, and its receptor, all of which have been linked to bone metastasis and cancer progression. This project proposes to study this hypothesis using the Health Professionals Follow-up Study, which has a unique combination of data on dietary habits of men before and after prostate cancer diagnosis, prostate cancer tissue specimens, and long-term follow up of patients. This will allow a study of the relationship between dietary phosphorus and calcium intakes and tumor expression of bone-related proteins, and how these factors relate to long-term survival in prostate cancer patients. By combining diet, tumor tissue, and survival information, this unique patho-epidemiology investigation will help to clarify previous results on the role of diet in prostate cancer, support public health efforts to improve prostate cancer survival, and shed light on underlying disease mechanisms.