DF/HCC Members Awarded New or Competitively Renewed Federal Funding

April 13, 2017 

The NIH continues to recognize DF/HCC as a leader in cancer research by awarding funding to a number of our research initiatives. Recently, this funding included the following new grants:

Molecular Architecture of the Mitochondrial Calcium Uniporter
NHLBI - 1R01HL130143-01A1 – Research Project
PIs: James Chou, PhD (Harvard Medical School), Vamsi Mootha, MD (MGH)

Uptake of calcium by mitochondria via the mitochondrial calcium uniporter (MCU) is known to activate the TCA cycle, while its overload leads to cell death. Recent studies show that misregulated activity of MCU leads to cardiomyopathy and abdominal aorta rupture, while modulation of MCU function may help to protect against autophagy or cell death. The goal of the proposed research is to determine the molecular architecture of this newly discovered supramolecular complex, for understanding its function, regulation, and inhibition, and the results will be extremely valuable for understanding disease mutations associated with MCU as well as for developing new therapeutics targeting this protein complex.

Development of Selective Pin1 Inhibitors to Target a Common Oncogenic Mechanism
NCI - 1R01CA205153-01A1 – Research Project
PIs: Kun Ping Lu, MD, PhD (BIDMC), Nathanael Gray, PhD (DFCI), Xiao Zhen Zhou, MD (Beth Israel Deaconess Medical Center)

Breast cancer is the most commonly diagnosed cancer in women in the US and also around the world, with triple negative breast cancer having the worst prognosis. The investigators have identified a potential enzyme drug target called Pin1 that functions as a “master” regulator of multiple cancer-driving pathways and found a series of drug leads to inhibit Pin1. This grant will optimize prototype drugs directed against Pin1 and evaluate whether they are effective in treating triple negative breast cancer in preclinical breast cancer models. 

Graduate Training in Cancer Research
NCI - 2T32CA009172-42A1 - Institutional National Research Service Award (NRSA)
PI: James DeCaprio, MD (DFCI)

The overall objective of this Training Program is to prepare the next generation of leaders in Medical Oncology in laboratory and clinical translational sciences. The program will provide outstanding mentored laboratory and clinical investigation research experiences from senior and experienced junior faculty and support for the recruitment and mentorship of under-represented minority fellows. It is expected that at the conclusion of their training, those individuals supported by this training program will have the ability to design, initiate, and complete individual clinical or laboratory research projects, will be able to function independently or with minimal supervision, and will be positioned to soon establish themselves as independent research investigators.

Inhibitor-Sensitive and -Resistant EGFR Mutants from Lung Cancer and Glioblastoma
NCI - 2R01CA116020-11 – Research Project
PIs: Michael Eck, MD, PhD (DFCI), Matthew Meyerson, MD, PhD (DFCI)

The epidermal growth factor receptor (EGFR) tyrosine kinase is one of the most commonly activated oncoproteins in lung adenocarcinoma, glioblastoma and other cancers. The identification of cancer-associated EGFR mutants and their predictive power to select patients for treatment with EGFR inhibitors constitutes a major advance in treatment of these cancers. Investigators will work to understand the detailed atomic structure and mechanism of regulation of the epidermal growth factor receptor (EGFR) and how cancer-causing mutations affect it. This information will then be used to develop small- molecules that specifically inhibit mutated versions of the receptor. In the long term, this work should lead to new drugs for lung cancers and glioblastomas that do not respond to current targeted therapies.

MUC1-C Oncoprotein Evades Immune Destruction in Non-Small Cell Lung Cancer
NCI - 2R01CA166480-06 – Research Project
PIs:Donald Kufe, MD (DFCI), Kwok Kin Wong, MD, PhD (DFCI)

Lung cancer is the leading cause of cancer deaths in the United States. The MUC1-C oncogenic protein is expressed at high levels in most non-small cell lung cancers (NSCLCs). The investigators’ proposed research addresses the premise that MUC1-C is of importance to evasion of immune destruction and is a novel target for the treatment of patients with NSCLC.

Brief Behavioral Intervention for Dyspnea in Patients with Advanced Lung Cancer
NINR - 1R01NR016694-01 – Research Project
PIs:Joseph Greer, PhD (MGH), Jennifer Temel, MD (MGH)

At least 50% of patients with advanced lung cancer experience debilitating dyspnea that is associated with worse medical and psychosocial outcomes. The purpose of the present investigation is to test a brief behavioral intervention for dyspnea, delivered by oncology nurses within the outpatient cancer clinic. Through this study, the investigators seek to increase access to much needed symptom management for those diagnosed with advanced lung cancers and ideally improve patients’ overall quality of life.

MYB Family Alterations in Pediatric Gliomas
NCI - 1R01CA215489-01 – Research Project
PIs: Keith Ligon, MD, PhD (DFCI), Rameen Beroukhim, MD, PhD (DFCI)

Pediatric brain tumors are now the most common cause of cancer-related death in children, and astrocytomas are the most frequent of these tumors. Direct alterations in MYB family transcription factors are present in a wide variety of cancer types and we have now identified them in pediatric astrocytomas. This project will leverage the experience of the labs and investigators in combining basic and translational science to make fundamental insights into MYB biology and also develop novel treatments for pediatric astrocytomas based on our new understanding of the genetic mutations that drive these cancers.

Imaging Tumor Associated Macrophage (TAM) Function
NCI - 1R01CA206890-01A1 – Research Project
PIs: Ralph Weissleder, MD, PhD (MGH), Mikael Pitter, PhD (MGH)

Tumor-associated macrophages (TAM) substantially accelerate the progression of untreated tumors; they also markedly influence the efficacy of anticancer drugs, including checkpoint blockade immunotherapies. Furthermore, targeting TAM themselves, e.g. through the colony-stimulating factor 1 receptor (CSF-1R), can effectively control the progression of advanced tumors. However, TAM show considerable plasticity by assuming opposing phenotypes and functions that can be either tumoricidal (e.g. M1-like cells) or tumorigenic (e.g. M2-like cells) and currently there is a significant knowledge gap on how TAM function in vivo and how these cells' activities can be harnessed to improve anticancer therapy.  The investigators will perform high resolution imaging to map functionally distinct tumor-associated macrophage (TAM) subsets in vivo and determine how newly emerging immunotherapies affect these TAM.