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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:

2P01CA119070-06A1: Oncogenic Notch Signaling
PI: Jon Aster, MD, PhD (BWH)

The overarching goal of this program is to elucidate fundamental properties of Notch signaling that are central to the pathogenesis of cancer. The Notch pathway is one of perhaps 15 or so signaling pathways that regulate development and tissue homeostasis in metazoan animals and which are frequently deranged in human diseases, including cancer. The clearest example of an oncogenic role for Notch is in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), in which gain-of-function Notchl mutations are common. Notchl is a compelling rational therapeutic target in T-ALL, but attempts to treat T-ALL patients with Notch inhibitors to date have been unsuccessful. Thus, it is apparent that more basic and translational research is needed if Notch-directed therapies are to be effective. With this need in mind, Projects 1 and 2 of this Program have complementary aims focused on filling critical gaps in our basic understanding of how Notchl activates its target genes, which are ultimately responsible for driving T-ALL cell growth and survival. The specific overall objectives of Project 1 and Project 2 are to determine how Notchl regulates the genomes of T-ALL cells and normal thymocytes The mutations in Notchl that lead to T-ALL often result in ligand-independent proteolysis and receptor activation, but such mutations are rare to non-existent in other cancers. On the other hand, there is abundant evidence that ligand-mediated Notch receptor activation has important roles in cancer, both within tumor cell populations and benign stromal elements, such as endothelial cells and immune cells. Thus, understanding how ligands activate Notch receptors has broad cancer relevance, yet many basic aspects of the events underlying ligand-mediated Notch activation remain unknown. Project 3 will address major gaps in current knowledge by testing the hypothesis that mechanical force is responsible for Notch receptor activation, and exploring  the molecular "logic" of ligand endocytosis, an event that is essential for activation of Notch receptors by ligands.

2P01GM062580-11: Atomic Resolution in Biological Electron Microscopy
PI: Stephen Harrison, PhD (BCH)

The broad goals of this Project, now entering its tenth year, are to develop the experimental and computational tools of electron cryomicroscopy (cryoEM) in the context of a widening range of biological applications. We seek in particular to connect electron microscopy (EM) with x-ray crystallography and to move molecular EM toward becoming a high-resolution tool. One of several advances during the past funding period has been to reach near-atomic resolution (<4A) for several virus structures, fulfilling a conjecture made 15 years ago by Henderson that it would be possible to image biological assemblies by cryoEM at this level of detail. Three principal themes are proposed for the coming project period. 1) Extension of computational methods for near-atomic resolution structures to include images of multi-state single particles and helical assemblies; Improvement of sample preparation for uniformity and homogeneity, building on the development of Affinity Grids during the last grant period; Exploration of methods to reduce beam-induced movement; Resolution improvement for cellular imaging. 2) Electron cryotomography (cryo-ET) as a bridge between visualizing near-atomic resolution structures and studying their intracellular dynamics by optical microscopy and live-cell imaging. Rotavirus entry and clathrin-coat dynamics are two specific projects for which structures determined as part of this Project and results from live cell fluorescence microscopy raise mechanistic questions best answered by frontier methods in cryo-ET. 3) Analysis of transient and multi-state assemblies, including enhancements made possible by the methods developed as part of theme 1. In pursuit of this theme, the focus will be on the large-scale organization of dynamic structures such as kinetochores, cilia, and transport-vesicle tethering complexes.

2P01CA069246-15A1: Experimental Therapeutics and Biomonitoring for Brain Tumors
PI: Fred Hochberg, MD (MGH)

The goals of this proposal are to improve treatment for gliomas by enhancement of oncolytic therapy and to develop serum microvesicles as biomarkers for genetic and phenotypic properties of individual GBM tumors and their response to therapy. Project 1 (Chiocca/Kaur) will evaluate whether viral RNA in microvesicles produced by HSV-infected glioma cells increases susceptibility of tumors to oncolysis, and assess viral and cellular mRNAs in tumor-derived serum microvesicles as biomarkers of oncolytic therapy. Project 2 (Weissleder/Hahko) will apply nanotechnology-based diagnostic magnetic resonance (DMR) to characterize micro vesicle number and antigenic profiles in serum based on proteins critical to oncogenesis using serum from mice and patients bearing glioblastoma (GBM) and undergoing different treatment paradigms. Project 3 (Breakefield) will characterize and enrich tumor-derived microvesicles serum using antibody-capture microfluidic chambers and quantities levels and mutations in GBM-related RNAs using serum samples as in Project 2. This program will develop and evaluate new accessible serum biomarkers to facilitate evaluation of therapeutic paradigms in mouse models and human patients both in terms of real time response to therapy and mechanisms of resistance to therapy.

2P01CA080124-11A1: Integrative Pathophysiology of Solid Tumors
PI: Rakesh Jain, PhD (MGH)

The overarching hypothesis of this translational program is that judicious manipulation of the tumor microenvironment can improve treatment outcome. This application builds upon discoveries made by the Program investigators that the local and distal stroma collaborate with cancer cells to thwart the effectiveness of anti-VEGF treatments and/or to reduce the delivery and effectiveness of conventional therapeutics. New Projects 1, 2 and 3 leverage our observation that both common (SDF1a/CXCR4) and specific (ANG2, IL-6, MEK) pathways are activated during anti-VEGF treatments of human glioblastoma, colorectal and hepatocellular carcinomas and this activation correlates with tumor progression during anti-VEGF treatment. Remarkably, the source of these molecules and their target cells are different in each disease, underscoring the need for careful, systematic and separate, yet complementary, molecular and cellular dissection of these pathways for improving outcome in each tumor type. Project 4 leverages the finding that paracrine interactions between tumor-associated fibroblasts and cancer cells contribute to desmoplasia and reduce the blood supply in pancreatic tumors via angiotensin 11 and its downstream effectors, including SDF1a/CXCR4. To this end, all four Projects will test the causal role of the proposed pathways by genetic and pharmacologic inhibition.

1P01CA154303-01A1: Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma
PI: Matthew Meyerson, MD, PhD (DFCI)

This Program will develop three protein kinases, inhibitor-resistant EGFR, TBK1, and DDR2, as therapeutic targets in non-small cell lung cancer (NSCLC). These targets were chosen because patients are treated with mutation-selective therapy but typically develop resistance (EGFR), because the mutation is common and there is no effective targeted agent but we have an excellent candidate downstream target (TBK1 for mutant KRAS), or because there is a new genomic alteration providing an opportunity for a lung cancer histology, squamous cell carcinoma, for which there is no validated target (DDR2). Our program integrates molecular and cellular pharmacology, chemistry, structural biology, and mouse modeling with the overarching aim of developing specific kinase inhibitors that are active in cell-based and genetically engineered mouse models, through the following specific aims. Overall aims are to: develop potent and where possible mutant-selective inhibitors of inhibitor-resistant EGFR, TBK1, and DDR2 using medicinal chemistry and structure-based drug design; characterize kinase inhibitors and their targets pharmacologically using cellular and animal therapeutic models of lung cancer; and employ rational design and cell-based approaches to identify inhibitor resistance mutations and use this information in kinase inhibitor design and optimization. Our insight into resistance to EGFR inhibitors will be used to design new inhibitors that overcome drug resistance mutations for all three targets.