RESEARCH
- Characterization of NF1-mutated Lung Cancer -
- MET exon 14 activation and acquired drug resistance -
- Microenvironmental Cofactors for Pancreatic Cancer -

We use a variety of techniques to interrogate three basic themes in the biology and clinical behavior of these deadly cancers:

(1) Intra-patient tumor heterogeneity at the temporal and anatomic levels,

(2) Inter-patient heterogeneity between different patients, and

(3) Tumor-microenvironmental interactions.

We use a combination of genetically engineered mouse models, cell lines, and clinically derived samples to interrogate multiple genomic outputs with a focus on genomic DNA and mRNA.

Genomics and Functional Characterization of NF1-mutated Lung Cancer 

Lung cancer is the biggest cancer killer and we do not yet have targeted therapeutic strategies for most patients. We do, however, understand the genomic changes that lead to lung cancer in unprecedented and ever-improving detail. The NF1 gene encodes a negative regulator of RAS proteins, and is frequently mutated in lung cancer. This important, large (>10%) patient subset is currently not "actionable" with targeted therapy. This will identify and characterize genes and combinations of genes that drive the formation of lung cancers with NF1 mutations, enabling us to prioritize these co-drivers for therapeutic targeting. We will use clinical sequencing and functional screens in relevant models to identify genes that cooperate with NF1 to cause lung cancer, and use novel in vivo systems to validate and clinically prioritize these targets.

The structural and functional basis of MET exon 14 activation and acquired drug resistance 

MET mutations are the most recent addition to the list of druggable, recurrently mutated kinases in nonsmall cell lung cancer (NSCLC). We have recently defined the frequency of MET aberrations in NSCLC, and identified exon 14 deletion in the juxtamembrane domain of MET as the most common somatic MET event. The mechanism for its action and its susceptibility to existing targeted MET therapies is however poorly defined, preventing targeted treatment of this large population of NSCLC patients. We focus on the many effects MET exon 14 mutations may have on the kinase, with the goal of understanding how this mutation drives cancer. This project focuses on a common and understudied mutation in lung cancer, the most lethal cancer type, by far. Thousands of Americans die each year with MET-mutated lung cancer, and often do so without being considered for targeted therapy against their tumor's genotype. We will clarify the role MET mutation plays in lung cancer and will structurally define how the most common mutations activate this oncoprotein. This project will foster development of therapies targeting MET exon 14 mutations, and optimize approaches to targeting the most common anticipated routes of resistance.

Crucial Microenvironmental Cofactors for Pancreatic Cancer Pathogenesis 

Pancreatic Ductal Adenocarcinoma (PDA) is a deadly disease with few effective treatment options. The PDA cancer cell is nurtured in a complex microenvironment comprised of multiple cell types admixed with matrix and signaling proteins. Like most complicated systems, it has been hard to accurately model the microenvironment in the lab. Our attempts to identify and therapeutically impact microenvironmental targets have and will continue to fail in the clinic without good models, so the need in this area is immediate and real. This innovative project goes far beyond insufficient human xenograft in nude mouse models to both understand and exploit innate dependencies that PDA cells have for cues from their microenvironment. We have invented flexible in vitro and in vivo systems to independently vary microenvironmental composition alongside the presence of drug and tumor cell genomic subtype in robust and dynamic preclinical models. These novel models are now poised to directly test the hypotheses that the microenvironment harbors discrete, unappreciated treatment targets in this difficult to treat disease, and that the transcriptional subtype of the cancer cell might independently impact how such treatments fare clinically. We plan to discover, prioritize and exploit crucial microenvironmental cofactors here i this 100% pancreatic cancer-relevant project through two specific aims focused on personalizing treatment of the PDA microenvironment by subtype.