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DF/HCC members awarded grants amid tight funding environment

The NIH continues to recognize DF/HCC as a leader in cancer research by awarding funding to a number of our research initiatives. Recently, these awards included five new or competitively renewed program project grants:

Atomic resolution in biological electron ($11 million)
PI: Kenneth Anderson, MD (DFCI)
Project 1 will identify the pDC-induced MM cell growth, survival, and drug resistance mechanisms within the BM milieu, and provide the basis for either targeting pDCs or blocking the pDC-MM interaction in novel therapeutic strategies to enhance MM cytotoxicity, overcome drug resistance, and improve patient outcome. Project 2 will identify and target cellular and soluble factors modulating autologous anti-MM responses to develop effective strategies targeting these pathways to improve immune reponses and inhibir myeloma cell growth.

Dietary and hormonal determinants of cancer in women ($27 million)
PI: Susan Hankinson, MPH, ScD (HSPH)
Project 1 examines the relation of vitamin D, melatonin, and dietary intake (including 1-carbon nutrients and change in alcohol intake) in relation to breast cancer risk. Project 2 will assess vitamin D and melatonin, including associations with tumor characteristics, and the roles of insulin, adiponectin, and insulin-like growth factors as well as inflammation markers in colon cancer and survival. Project 3 will evaluate vitamin D, melatonin, dietary factors (flavonoids, lactose, and acrylamide) and plasma markers of inflammation in relation to ovarian cancer risk. Project 4 will extend and apply analytic methods to improve modeling of cumulative exposures that influence risk at different times in life, extend ploytomous logistic regression models in a complex tumor biomarker setting, and improve evaluation of breast and colon cancer risk prediction models.

Molecular pathways to thynmic lymphoma and leukemia ($11 million)
PI: A. Thomas Look, MD (DFCI)
Project 1 will identify downstream target genes within TAL1-mediated transcriptional networks that contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in human T-cell malignancies. Project 2 will identify molecular pathways that cooperate with Notch1 signaling in lymphomagenesis by analyzing the impact of insertional mutagenesis, epigenetic regulation, and miRNA-dependent regulation on the generation of T-ALL from in Notch1 overexpressing T-cell progenitors. Project 3 will study the molecular function of D-cyclins in Notch-driven murine T-ALL model and in human T-ALL. Project 4 will elucidate molecular mechanisms and activated pathways associated with recurrent chromosomal translocations in thymic leukemias and lymphomas. Project 5 will identify the epigenetic mechanisms regulating normal T-cell development and leukemogenesis and link them to the oncogenic action of TAL1 and Notch1 in T-ALL.

Mechanistic pharmacology of anti-mitotics and apoptosis regulation ($10 million)
PI: Timothy Mitchison, PhD (HMS)
The goal of the project is to understand how individual cancer cells and tumors respond to drug treatment, from target engagement to induction of apoptosis to eventual tumor regression. The four specific aims are: determine the molecular mechanisms that regulate MOMP in response to anti-mitotic drugs and ABT737; investigate the causes of variation in cell responses to anti-mitotics and targeted inducers of apoptosis; determine to what extent drug responses are the same in cell culture and mouse tumors, using intravital imaging and other methods; and pursue several approaches towards translating mechanistic understanding into improved patient care.

Lung cancer disparities center: Jointly addressing race and socioeconomic status ($9 million)
PI: David Williams, MPH, PhD (HSPH)
Project 1 will design and test a tobacco control intervention that focuses on an upstream factor—the public agenda—with the goal of influencing media coverage and public opinion to garner support for structural solutions to cancer disparities. Project 2 will develop and evaluate a multilevel approach to tobacco treatment for low-SES and minority patients. Project 3 will assess racial, ethnic, and socioeconomic disparities in the processes and outcomes of care for population-based cohorts of patients diagnosed with lung and colorectal cancer in half of the state population of California (nine counties). Project 4 will perform high-throughput cancer mutation profiling on 500 non-small cell lung cancer speciments from white and African-American populations to test the hypothesis that common somatic cancer mutations vary in frequency as a race. Project 5 will develop novel life-tables that stratify SES using geocoding and area-based socioeconomic measures.