DF/HCC Members Awarded New or Competitively Renewed Federal Funding

JUNE, 2018 

The NIH continues to recognize DF/HCC as a leader in cancer research by awarding several new multi-investigator grants to DF/HCC members.

Targeting DOT1L for Degradation in MLL-Rearranged Leukemia
NCI - 2R01CA176745-07 – Research Project
PIs: Scott Armstrong (DFCI), Jun Qi (DFCI)

Despite recent progress in our understanding of MLL-rearranged (MLL-r) leukemias, the disease remains difficult to cure, establishing an area of significant unmet medical need. While the first targeted therapies against DOT1L, an enzyme important for survival of MLL-r leukemia, have been realized in human clinical trials, early evidence suggests that resistance to these inhibitors has emerged. In this study, we will seek to define the biological foundation for acquired resistance to DOT1L therapy and overcome resistance through the development and optimization of a new class of small molecules that can degrade DOT1L protein, thus developing the tools and fundamental preclinical knowledge to help overcome this devastating disease.

The Role of RHOA in Diffuse Gastric Cancer
NCI - 1R01CA224428-01 – Research Project
PIs: Adam Bass (DFCI), Channing J. Der (UNC Lineberger), Timothy Cragin Wang (Columbia University, Irving)

Diffuse Gastric Cancer (DGC) is a highly lethal cancer lacking effective therapies. This project follows findings of recurrent mutations in GTPase protein RHOA in human DGC and that RHOA activation is critical for the development of DGC in murine models. In this proposal, we will validate our hypothesis regarding the role of RHOA in DGC development and evaluate mechanisms of action of novel RHOA mutations, building towards development of new means to prevent and treat these cancers. 

Identification of Genomic Drivers of Brain Metastases in Lung Adenocarcinoma
NCI - 1R01CA227156-01 – Research Project
PIs: Priscilla Brastianos (MGH), Scott Carter (DFCI)

In this study, we propose to identify potential drivers and therapeutic targets of newly diagnosed and recurrent brain metastases from lung adenocarcinoma. Our application is relevant to the public health because there are no effective systemic therapies for patients with brain metastases from lung adenocarcinoma. Relevant to the NIH mission, the overarching objective of this study is to identify genetic changes that are associated with brain metastases, with the goal to identify optimal therapeutic approaches for this common neoplasm. 

Tumor and Host Markers of Clinical Outcomes After MIBG Therapy in Neuroblastoma
NCI - 1R01CA214912-01A1 – Research Project
PIs: Steven Dubois (DFCI), Rochelle Bagatell (Children's Hospital of Philadelphia)

Radiation therapy plays a key role in the treatment of many malignancies in both adults and children. A phase III clinical trial, ANBL1531, will compare survival in patients with newly diagnosed high-risk neuroblastoma after randomization to standard therapy with or without the addition of the radiopharmaceutical 131I-MIBG. Identification of tumor and host markers that are predictive of clinical outcomes after 131I-MIBG is of paramount importance to improve patient selection and improve our understanding of differential responses to therapeutic radiation in neuroblastoma and other cancers.

Dana Farber/Harvard Cancer Consortium Career Development Program in Clinical Oncology
NCI - 2K12CA087723-16 - Physician Scientist Award (Program) (PSA)
PIs: Timothy Graubert (MGH), Bruce Chabner (MGH)

New insights from genome sequencing and technical advances in genome editing, chemical biology, and cellular engineering are providing unprecedented opportunities for advances in cancer treatment. The emerging complexity of cancer biology and increasing sophistication of experimental therapeutics demand a level of understanding and training in research methodology beyond the scope of conventional fellowship programs. To address these challenges, the goal of the Dana Farber/Harvard Cancer Consortium Career Development Program in Clinical Oncology (DF/HCC K12) is to recruit and select a highly qualified and diverse group of Scholars to complete a rigorous five year program of didactic instruction and mentored research that will prepare them for independent careers in clinical oncology research.

Mechanisms of Tumorigenesis in BRG1 Mutant Lung Cancer
NCI - 1R01CA216188-01A1 – Research Project
PIs: Carla Kim (BCH), Kwok-Kin Wong (NYU Langone, Formerly DFCI)

Current treatment modalities for lung cancer patients are usually ineffective, and lung cancer will claim the lives of over 170,000 individuals this year in the United States alone. This work will define new precision medicine opportunities for a common genetic subtype of lung cancer, namely those with BRG1 mutations. The work will also help to define how BRG1 loss affects DNA damage repair and the immune system, which will be informative in a wide variety of cancers. 

Assessing the Integration of Tobacco Cessation Treatment into Lung Cancer Screening
NCI - 1R01CA218123-01A1 – Research Project
PIs: Elyse Park (MGH), Jennifer Haas (BWH), Nancy Rigotti (MGH)

Lung cancer accounts for 27% of cancer deaths in the United States. The National Lung Screening Trial (NLST) demonstrated that lung cancer screening (LCS) with low-dose computed tomography (LDCT) reduces lung cancer mortality for individuals with 30+ pack-years of smoking history. For those who are still smoking, having an LDCT-LCS test provides a teachable moment to promote smoking cessation and to offer smoking cessation treatment. The optimal way to help smokers undergoing LDCT-LCS to quit smoking is uncertain. This proposal will compare the effectiveness and implementation of the optimal tobacco treatment intervention, across a healthcare system, which could be implemented in radiology sites providing LDCT-LCS nationwide.

Abbreviated Targeted Therapy to Improve Anti-PD-1 Inhibitor Efficacy in Melanoma
NCI - 1R01CA229851-01 – Research Project
PIs: Ryan Sullivan (MGH), Arlene Sharpe (HMS)

This project will determine the effectiveness of abbreviated mitogen activated protein kinase (MAPK)-targeted (MTT) therapy combined with anti-PD-1 therapy, identify patients most likely to benefit, determine the effects of this therapy on the tumor microenvironment and immune memory subsets, and identify novel candidate targets to combine with MTT and anti-PD1, based on an in vivo CRISPR screens in melanoma mouse models.

Metastasis and Biophysics of Clusters of Circulating Tumor Cells in the Microcirculation
NCI - 1U01CA214297-01A1 – Research Project – Cooperative Agreements
PIs: Mehmet Toner (MGH), Daniel Haber(MGH), Shyamala Maheswaran (MGH)

Multicellular aggregates of tumor cells are potent initiators of the progression of cancer from localized tumors to multi-organ metastases by transiting through the circulation to establish metastases in distant organs. Recent evidence has shown that the forces applied to cancer cells while they travel through the smallest vessels of the body, cause dramatic changes to the behavior of adhesions and nuclei within clusters and that these forces may be responsible for the increased potency of aggregates vs. single tumor cells. We aim to study how physical forces interact with the biological components of clusters to initiate metastasis and to devise methods of combating it.