Pilot Project Initiative to Support Interprogrammatic Research of DF/HCC Members

Award Amount: $75,000 per year for two years ($150,000 total direct costs), with full indirect costs.
Deadline for submission:  May 3, 2010
Anticipated award date: July 1, 2010

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SUBMISSION INFORMATION

Deadline:  May 3, 2010
Submission requirements: An electronic (PDF) copy of application AND 12 hard copies of application (complete with figures)
Submit to: Dr. Peter Howley
c/o Mabel Duyao, PhD
Department of Pathology
Harvard Medical School
77 Avenue Louis Pasteur, NRB-850
Boston, MA 02115

Contact regarding questions: Mabel Duyao
Tel: (617) 432-1145
Email: mabel_duyao@hms.harvard.edu

OVERVIEW AND GOALS OF NODAL AWARD PROGRAM

A key goal of the Dana-Farber/Harvard Cancer Center (DF/HCC) is to encourage and support the development of scientific collaborations among Center members that promote new translational cancer research as well as research that address issues relevant to the unequal burden of cancer and cancer outcomes in diverse populations.  

To advance this goal, the DF/HCC annually solicits proposals for Pilot Projects that are designed to enhance or create new “nodal point” interactions between disease-based and discipline-based DF/HCC Research Programs. These interactions provide an opportunity to link the research efforts based across Program, with a focus on projects that have the potential of significant human application. The Cancer Center has a particular interest in proposals that focus on eliminating cancer disparities.  Such inter-programmatic research efforts are the “nodal points” that are targeted for support by this award program.  

Nodal points are inter-programmatic research efforts that link DF/HCC discipline-based studies with disease-site specific research.  The Cancer Center is programmatically organized into distinct Research Programs, in accordance with NCI guidelines. Currently, there are 17 Research Programs that are fully established and have been approved by the NCI through the Cancer Center Support Grant process.  Ten other areas are in various stages of development, and as defined by NCI guidelines, are Programs-in-Development.  

DF/HCC Research Programs can be classified by two categories: disease-site programs, such as Prostate Cancer or Breast Cancer, or discipline-based programs, such as Cancer Genetics.  A current list of DF/HCC Programs and Programs-in-Development is available on the website at www.dfhcc.harvard.edu.

AWARD INFORMATION

Two awards will be awarded. Each award is for $75,000 per year for two years ($150,000 total direct costs), with full indirect costs.  Anticipated award date:  July 1, 2010. Projects must be ready to commence immediately after receipt of award.  

One of the awards is specifically intended for a project addressing issues relevant to “Disparities in Cancer”. We encourage applications that include a partnership with UMB faculty, in support of the DF/HCC’s U56 cancer center-minority serving institution partnership grant.

ELIGIBILITY AND REQUIREMENTS

Applicants must be DF/HCC members.

Projects must be submitted as collaboration between two or more DF/HCC members who are members in good standing in the programs the project interaction proposes.  
Proposals must involve the creation of new inter-programmatic “nodal point” interactions or the enhancement of pre-existing interactions between discipline- and disease-based Programs within the Center (these can be Programs-in-Development). 

PROPOSAL SUBMISSION INFORMATION

Required items (4):

• “New Nodal Award” Coversheet: (available on the DF/HCC website at http://www.dfhcc.harvard.edu). or from mabel_duyao@hms.harvard.edu) listing title of proposal, PI, PI’s DF/HCC Program (or Program-in-Development) affiliation, the interprogrammatic nodal collaboration proposed (i.e., the disease- and discipline-based programs to interact on the proposal), indication that this is a disparities-focused project (if appropriate), and the name and DF/HCC programmatic affiliation of each collaborator (some of whom should be active in both interacting Programs or Programs-in-Development listed).  A complete listing of programs and current listing of program members is available on the DF/HCC website.
• Proposal: Maximum of 5 pages of text.  Figures and references are allowable in addition to this page limit.  No other appendix material will be accepted.
• Biosketches: Current NIH Biosketch for each participating PI, including all funding sources.
• Budget Request: Budget estimates should be submitted as NIH 398 form with major divisions of funds (personnel, equipment, supplies, other, etc.; but no itemization or rationale needed). PIs should include a level of effort on all projects (minimum 5%) and salary support commensurate with their efforts on the nodal project. Support and effort may be split between the collaborating PIs (minimum 2.5 % effort per PI). Funds may be utilized for salary and research support.

DEADLINE:  May 3, 2010
Submission requirements:    An electronic (PDF) copy of application AND 10 hard copies of application (complete with figures)
Submit to:
Dr. Peter Howley
c/o Mabel Duyao, PhD (Email: mabel_duyao@hms.harvard.edu)
Department of Pathology
Harvard Medical School
77 Avenue Louis Pasteur, NRB-850
Boston, MA 02115

Contact regarding questions: 
Mabel Duyao
Tel. (617) 432-1145
Email: mabel_duyao@hms.harvard.edu

REVIEW PROCESS

Proposals will be reviewed by a DF/HCC peer-review committee, which has representation from all DF/HCC member institutions.  Projects to be of greatest scientific merit and have greatest potential for fostering nodal inter-programmatic research or enhancing research in the area of “Disparities in Cancer” will be ranked and submitted to the full Executive Committee for final approval for funding.  

Grants will be awarded on the basis of the following review criteria (with this order of importance):

• SCIENTIFC EXCELLENCE and MERIT.  We invite project proposals that are innovative in terms of cancer knowledge, prevention, and/or care.  Proposals need not have extensive preliminary data.  For the disparities award, proposals must address a critical issue in “disparities in cancer.”
• TRANSLATION.  Projects that have the opportunity to stimulate direct application to cancer treatment or prevention are encouraged.
• INTER-INSTITUTIONAL LINKS.  Proposals that stimulate inter-institutional research will be favored in decisions between equally ranked applications. 

PROGRESS REPORTS

Progress reports are required after the first year of the project. The PI may be asked to present results to the DF/HCC Executive Committee. Funding for the second year (commencing July 1, 2010) is contingent upon first-year progress.

A final report and informal spending summary is due at the end of the two-year project period.  Should the PI leave the seven institutions of the DF/HCC, the remainder of the award will be forfeited (i.e. may not be transferred to a non-DF/HCC institution).

ATTACHMENTS
2010 New Nodal Coversheet.doc
2010 New Nodal RFP.doc

Leveraging GEI research to reduce cancer disparities 
PI: Alexandra Shields, PhD (MGH)
Collaborator: David Christiani, MD, MPH, MS (HSPH)

To elucidate the causes of common complex diseases such as cancer, genomics researchers have begun moving beyond identifying polymorphisms significantly associated with disease to understanding complex gene-environment interactions (GEIs) that affect gene function/expression. While GEI research has the potential to generate new insight into causal factors underlying cancer, studies to date have been limited by a narrow conception of the “environment.” Particularly absent are measures of social and environmental exposures that disproportionately affect poor and minority communities. Unless measures of such exposures are included in GEI studies, important interactions that could provide new insight into the etiology of disparities will be missed. Barriers to including robust measures of “the environment” in GEI studies include the lack of readily accessible, validated measures of diverse exposures, and genomics researchers’ lack of expertise to judge measures outside their field. Rigorous transdisciplinary (TD) study designs are needed that take seriously the wealth of current knowledge about cancer risk and disparities across disciplines. This project will address these barriers and build capacity to conduct robust, disparities-focused GEI research within DF/HCC.

A preclinical model to test for tumor-promoting hematopoietic cells and cytokines in the blood of breast cancer patients
PI: Sandra McAllister, PhD (BWH)
Collaborator: Nadine Tung, MD (BIDMC)

Remarkably little is known about the mechanisms that regulate outgrowth of indolent tumors – such as micrometastases that remain dormant for protracted periods of time, latent secondary tumors, or carcinoma in situ – into overt, clinically relevant disease. The lab previously developed an in vivo xenograft system that provided fundamental insights into processes that govern indolent tumor growth, revealing that host systemic factors can support the acquisition of malignant traits. First, they found that certain human breast carcinoma cell lines (termed “instigators”) facilitate growth of otherwise-indolent tumor cells (termed “responders”) located at distant anatomical sites within host mice – a process termed “systemic instigation.” Second, systemic instigation is accompanied by incorporation of bone marrow-derived cells into the stroma of the distant, once-indolent tumors. Importantly, bone marrow cells of hosts bearing instigating tumors are functionally activated in the marrow prior to their mobilization into the circulation. Third, instigating tumor-derived osteopontin, a cytokine that is elevated in the plasma of patients with metastatic cancers and is predictive of poor outcomes, is necessary but not sufficient for systemic instigation. This systemic communication between tumors might explain why patients diagnosed with one malignant neoplasm are at an increased risk of presenting with multiple, independent primary cancers or why patients with recurrent disease often present with multiple metastases that appear to arise suddenly and synchronously. The lab hypothesizes that similar systemic processes operate in human breast cancer patients as a means to promote tumor progression. Therefore, over the next two years, the lab plans to: 1) Determine whether circulating hematopoietic cells from breast cancer patients promotes tumor progression; 2) Determine whether tumor-promoting cytokines can be identified in the plasma of breast cancer patients. In the longer term, the lab hopes to identify biomarkers and prognostic factors that might predict the potential for a cancer patient‘s systemic environment to support outgrowth of otherwise indolent tumors as a prerequisite to finding ways to interdict these processes.

Expression of merkel cell polyoma virus large and small t antigens in merkel cell carcinoma
Co-PIs: James DeCaprio, MD (DFCI) and Linda Wang, MD, JD (BWH)

Merkel Cell Carcinoma (MCC) is a highly lethal skin cancer that typically occurs in sun-exposed areas of elderly patients and in patients with HIV or chronic lymphocytic lymphoma. Given the increased risk for MCC in immunocompromised patients, a search for viruses by next generation sequencing of mRNA transcripts in MCC revealed evidence for a novel human polyomavirus (Feng et al., 2008). Merkel Cell Polyoma Virus (MCV) encodes a large T antigen (LT) and small T antigen (ST) highly similar to these oncoproteins encoded by the DNA tumor virus SV40. Several recent studies have found that approximately 70% of all MCC tumors contain chromosomally-integrated copies of the MCV DNA. Furthermore, sequencing of the viral DNA contained in MCC found consistent evidence for mutations that are predicted to retain expression of MCV ST and the N-terminal half of LT but delete the C-terminal half of MCV LT. The N-terminus of MCV LT, similar to SV40 LT, binds to Rb and Rb-related proteins and likely serves to inactivate the Rb growth-suppressing pathway. If MCV LT is expressed in tumor cells, then it is likely that the Rb pathway remains intact in these cells. In contrast, a MCC tumor that does not contain viral DNA and does not express LT would be expected to have a mutation in the Rb gene or another gene that disrupts the Rb pathway. Although 70% of all MCC contain integrated MCV viral DNA, there are no other features that have been found to distinguish between viral positive and viral negative cases of MCC (Fischer et al., 2010). The central hypothesis is that MCV LT and ST contribute to the oncogenesis of MCC and that their expression will result in a distinct set of genetic changes that distinguish between MCV-positive and negative tumors. To test this hypothesis, the lab will examine tissue obtained from MCC tumors and identify mutations in the LT sequence, determine expression of LT and ST in MCC by immunohistochemistry (IHC), and identify mutations in cellular oncogene and tumor suppressor genes.

A novel therapeutic strategy for colon cancers expressing mutationally activated K-RAS
PI: Kevin Haigis, PhD (MGH)
Collaborator: Nathanael Gray, PhD (DFCI)

The future of colon cancer therapy lies in personalized molecular medicine, where physicians tailor an individual’s treatment to the mutations that have occurred in their cancer. Such an approach requires targeted therapies corresponding to specific oncogenic mutations. Almost half of all colorectal cancers have activating mutations in K-RAS and these mutations are among the best predictive biomarkers for the failure of a cancer to respond to both conventional and targeted therapies. No targeted therapies exist to treat KRAS-mutant cancers. Studies indicate that a novel, therapeutically relevant signaling pathway mediates the oncogenic properties of K-RAS in colorectal cancers. The team has recently identified a small molecule kinase inhibitor, BAY61-3606, that suppresses proliferation in cells expressing activated K-RAS, but not in isogenic cells expressing wild-type K-RAS. In this project, the team will focus on three aims designed to accelerate the development of this novel inhibitor of K-RAS signaling: to identify the relevant molecular target of BAY61-3606; to generate derivatives of BAY61-3606 with improved biological activity; and to measure the in vivo activity of BAY61-3606 and its biologically active derivatives. The ultimate goal is to develop an inhibitor of K-RAS signaling that can be used as an anti-cancer therapy in humans. To this end, it will be critical to identify the inhibitor with the best pharmacologic properties in vivo. In year 2 of the Nodal Award project, the team will initiate preclinical studies for BAY61-3606 and its biologically active derivatives by measuring the PK and determining the effects on the growth of colon cancer xenografts.

Hospital Readmission, Patient-Centered Nursing Care, and Cancer Disparities
Co-PIs: Laurel Radwin, RN, PhD (UMB) and Sanja Percac-Lima, MD, PhD (MGH)
Collaborators: Karen Donelan, EdM ScD (MGH); Amy Rex-Smith, DNSc (UMB); and Jan Mutchler, PhD (UMB)

In this project, the goal is to study racial and ethnic disparities in patient-centered nursing care, patient trust, HRQOL outcomes, readmission rates and emergency room use. A new DF/HCC node will be created, and scientists and clinicians with proven track records in studying cancer care quality and disparities will join together. The purpose of this study is to examine the relationships between patient characteristics (race, ethnicity, age, gender, socioeconomic status), cancer patient outcomes (post-discharge hospital utilization, trust, health-related quality of life), specialty care, and patient-centered nursing care for cancer patients hospitalized within the DF/HCC system. This study is significant because there is very little research on the equitable distribution of nursing care in general and patient-centered cancer nursing care more specifically. Nursing care needs to be examined in order to eliminate cancer disparities. If patient-centered nursing care is equitably distributed, then this care can be leveraged to enhance the quality of patient-centered care to racial and ethnic minorities. If disparities exist in patient-centered nursing care, then practices can be devised to address the inequities. Potential translations of the findings of this study include metrics for monitoring the equity of nursing care, quality improvement projects, clinical education offerings, and policies and procedures to elimination barriers to equal care. Targeted system interventions can be based on study findings and tested in future studies.

Reactivating Apoptosis in Melanoma by Selective Targeting of MCL-1
PI: Loren Walensky, MD, PhD (DFCI)
Collaborators: F. Stephen Hodi, MD (DFCI) and Jeffrey Supko, PhD (MGH)

The lifetime risk for developing melanoma is currently 1 in 65, with the annual incidence increasing at a rate of 4% per year. Surgical excision is curative for most patients who present with relatively thin lesions, and when disease is limited to the primary site, ten-year survival rates range from 60-90%. For patients with lymph node metastases, adjuvant therapy with α-interferon affords a modest increase in overall survival, but this advantage is associated with substantial toxicities. For patients with metastatic disease, there is little convincing evidence that any standard systemic therapy prolongs life. This project represents a new multidisciplinary and inter-institutional effort to apply a breakthrough chemical biology approach to target a key resistance factor in melanoma. By combining the team’s extensive background and knowledge of chemical and apoptosis biology, melanoma biology, cutaneous oncology, and clinical pharmacology, this pilot project is laser-focused on developing and validating a new therapeutic modality for treating chemoresistant melanoma. Importantly, this project was inspired by the life of an astoundingly talented, ebullient, and courageous young girl who died from metastatic melanoma at age fifteen. She challenged the team to find an antidote for this devastating disease; this collaboration represents the commitment to fulfilling her vision of a world without fatal melanoma.

Study to Test the Trice Advanced Cancer and End of Life Treatment Scale
PIs: Jennifer Temel, MD (MGH), Holly Prigerson, PhD (DFCI), Kasisomayajula Viswanath, PhD (DFCI)

The Trice Advanced Cancer and End of Life Treatment (TACT) scale is designed to assess knowledge of end of life (EOL) care options, advance care planning, and common aggressive interventions at EOL among Black and White advanced cancer patients. The goal of the project is to develop a brief inventory to assess knowledge of aggressive and palliative EOL care options, and to evaluate whether its use as an educational tool improves knowledge of EOL treatment options. Specific aims include: refinement and evaluation of the reliability and validity of the TACT scale; pilot determination of whether differences exist among Black and White cancer patients in knowledge of EOL care options, advanced care planning, and common aggressive interventions at EOL; and if the use of TACT as part of an educational intervention can improve knowledge of EOL care options.

The use of histone-deacetylase inhibitors in NUT midline carcinoma
PI: Christopher French, MD (BWH)
Collaborator: James Bradner, MD (DFCI)

NUT midline carcinoma (NMC) is a rare, incurable tumor affecting children and young adults. The French laboratory has characterized the causative oncogene as a fusion of a bromodomain gene and the novel gene, NUT, and hypothesize that the BRD-NUT complex is a tractable, direct target of HDAC inhibitors. Specific aims for the project are to quantitate phenotypic effects of HDAC inhibitors on human NMC cells in a high-throughput format; establish lead therapeutic HDAC inhibitors based on their pro-differentiation and anti-growth effects on NMC in vitro and in vivo; and characterize the changes in gene expression resulting from HDAC inhibition in NMC cells.

Targeting of Leukemia Stem Cells by T-cells Educated by Dendritic Cell/AML Fusions and Anti-CD3/CD28
PI: David Avigan (BIDMC)
Collaborators: Richard Stone (DFCI) and Jacalyn Rosenblatt (BIDMC)

Patients with AML frequently achieve remission via chemotherapy but subsequently develop chemotherapy resistant disease. The cause of this disease is the self-renewal of leukemia stem cells, which appear to be quite resistant to standard chemotherapy. Cellular immunotherapies represent a promising alternative for successfully targeting these cells. This study will evaluate the effectiveness of several cellular immunotherapies – Dendritic Cell/AML fusions and anti-CD3/CD28 – to target leukemia stem cells and antigens, and to assess whether repeated applications of such therapies produce an expansion of AML specific T cells.

Building Capacity to Monitor the Impact of Genetically-Tailored Prevention and Treatment on Cancer Disparities
PIs: Alexandra Shields (MGH)
Collaborators: David Christiani (HSPH), Judy Garber (DFCI) and Sapna Syngal (BWH)

Genomic medicine is a promising new tool for improving health outcomes. However, the impact of genomic medicine on the health of vulnerable populations and health disparities remains relatively unclear, as few studies have been conducted to examine the topic. This pilot project will develop strategies to utilize information-rich national administrative databases to assess patients’ access to, utilization of, and impact from genetically-customized cancer prevention and treatment methods, as well as their ability to access appropriate follow-up care. Data will be analyzed in a variety of ways, but with a particular focus on disparities (by race, ethnicity, and by commercially- vs. Medicaid-insured patients.

Parental Attitudes Toward the HPV Vaccine
PI: Jennifer Allen, DSc (DFCI)
Collaborators: Marcela del Carmen, MD (MGH), Yi Li, PhD (DFCI), JudyAnn Bigby, MD
Inter-programmatic interactions: Gynecological Cancer, Cancer Disparities, Cancer Risk Reduction, Biostatistics

This study will examine the issues and concerns that parents face when deciding whether to allow their age-eligible children to receive the human papillomavirus (HPV) vaccine Gardasil.^® The vaccine is widely considered a significant step toward reducing the public health burden of HPV and may help eliminate the racial and ethnic disparities in cervical cancer incidence. Through information gathered from a web-based survey and focus groups, the study seeks to develop culturally appropriate educational messages, materials, and strategies to maximize vaccine acceptance.

MUC1 Oncoprotein Regulates the Androgen Receptor in Human Prostate Cancer
PIs: Donald Kufe, MD (DFCI) and Glenn Bubley, MD (BIDMC)
Inter-programmatic interactions: Translational Pharmacology and Early Therapeutic Trials, Prostate Cancer

Despite considerable research on the importance of the androgen receptor in regulating prostate cancer cell growth, little is known about why certain subgroups of prostate cancer are more likely to recur and exhibit decreased dependency on androgen stimulation. The aim of this study is to determine whether the MUC1 oncoprotein contributes to the development of aggressive prostate cancer by directly interacting with the androgen receptor. If this is proven correct, this study will establish the experimental basis for studying the effects of small molecules that target the MUC1 C-terminal subunit.

Cancer Risk Factors and Vitamin D Supplementation in Blacks
PI: Gary Bennett, PhD (DFCI)
Collaborators: Bettina Fisher Drake, PhD (DFCI) and Edward Giovannucci, MD, ScD (HMS)
Inter-programmatic interactions: Prostate Cancer, Gastrointestinal Malignancies, Cancer Disparities

Vitamin D deficiency has been associated with increased rates of incidence and mortality of numerous cancer types, while vitamin D supplementation may reduce cancer risk by increasing cell differentiation and decreasing cell proliferation. This study will be among the first to examine the impact of vitamin D in blacks, who are known to have lower vitamin D levels than whites. The study will focus specifically on vitamin D supplementation and uptake on PSA and C-peptide levels among blacks in a non-patient sample, and holds considerable promise in informing future cancer prevention trials that seek to reduce racial disparities in outcomes.