Protein phosphorylation plays a vital role in coordinating information flow within the cell and regulating emergent tumor phenotypes ranging from proliferation to invasion and angiogenesis. Quantitative analysis of protein signaling circuits in human tumor specimens can provide insight into intracellular signaling networks underlying tumor behavior while identifying activated kinases and their substrates, signaling components that may represent druggable targets.
Our objectives are to understand the protein 'wiring maps' within human tumor specimens, xenograft and in-vitro cell based models, identify signaling 'nodes' in pathways that are functioning abnormally, and also understand how these networks are regulated in response to specific cancer therapies. This work includes discovery-based quantitative mass spectrometry approaches as well as complementary in situ proximity ligation techniques to understand in vivo protein phosphorylation and protein interaction dynamics.
Cancer Drug Resistance
The last decade has witnessed a remarkable shift in the cancer therapy from cytotoxics to targeted therapeutics; in fact, 50% of the drugs approved by FDA over the past few years target specific molecular pathways necessary for growth, progression and spread of cancer cells. Despite the initial efficacy of these drugs in patients, development of acquired resistance seems inevitable. Tumor cells, upon treatment with a drug, re-wire their signaling networks such that they are no longer dependent on the same survival networks as before. This adaptive response causes patients to relapse and the surviving cancer cells are often more aggressive in nature. Therefore, one of the main goals of the lab is to study the mechanisms of cancer drug resistance using a systems level approach and then define novel combination therapies to improve the current standard of care.
Ras Signaling in Cancer
Oncogenic Ras mutations are present in 30% of all cancers, with isoforms specific mutations seen in up to 90% of specific tumors. Furthermore, it has been shown that different mutations in the same codon of the same isoform can lead to different prognoses. Until recently, it has been thought that all activating mutations in Ras should have the same effect in activating downstream pathways. Our work uses an isogenic colorectal cell line with unique Ras mutations to study the effect of these unique mutations on a systems level. We aim to quantify changes in basal and dynamic cellular signaling networks and correlate them with changes in quantitative phenotypes. Ultimately, we seek to develop a model to predict how unique Ras mutations lead to changes in cell signaling and how these changes may lead to potential new therapies.
Glioblastoma is a devastating disease with minimal benefit from targeted therapeutics. With the current standard of care (surgery, radiation, and temozolomide), survival is only about a year. In order to understand the signaling cascades that drive tumor progression, invasion, and therapeutic resistance, we are quantifying signaling in tumors pre- and post-treatment with broad spectrum chemotherapies (e.g. temozolomide) or targeted therapeutics against driver oncogenes. With this data we aim to identify activated signaling network alterations in tumors relative to normal brain and thus uncover novel potential targets in GBM. By quantifying the changes in cell signaling that occur after resistance arises, we aim to better understand the failure of targeted therapeutics in GBM. Our overriding goal is to develop improved therpaeutic strategies of disease intervention to improve patient outcomes.