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DF/HCC Nodal Awards announced

DF/HCC offers a multitude of funding opportunities to its members to encourage and enhance the collaborative spirit of research within the Harvard medical community. Nodal Awards were specifically designed to enhance or create new “nodal point” interactions between disease- and discipline-based DF/HCC research programs. The Cancer Center also has a particular interest in funding projects that focus on eliminating cancer disparities.

Nodal Awards are a maximum of $75,000 per year for two years ($150,000 in total direct costs), with full indirect costs. Three awards were announced in the last quarter:

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.