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Title page for ETD etd-12112014-120700


Type of Document Dissertation
Author Hutchinson, Katherine Emily
URN etd-12112014-120700
Title Identification of Novel Targets for Therapy in Solid Tumors
Degree PhD
Department Cancer Biology
Advisory Committee
Advisor Name Title
Jin Chen Committee Chair
Ann Richmond Committee Member
Graham Carpenter Committee Member
Jeffrey A. Sosman Committee Member
William Pao Committee Member
Keywords
  • next-generation sequencing
  • targeted therapy
  • cancer
  • melanoma
Date of Defense 2014-12-08
Availability unrestricted
Abstract
Solid tumor treatment paradigms have drastically improved in recent decades through direct targeting of the protein products of somatic, constitutively active “driver” mutations and their effector signaling pathways. Prior to these advances, metastatic solid tumors were primarily managed through administration of traditional cytotoxic chemotherapy. A prime example of this success is evident in melanomas expressing alterations at codon V600 of the serine-threonine kinase, BRAF. Compared to the chemotherapeutic standard-of-care in metastatic melanoma, dacarbazine, patients with BRAF V600E/K/M/R/D-mutated tumors exhibit significantly higher response and survival rates when treated with V600-variant specific small molecule inhibitors, vemurafenib and dabrafenib. However, potential driver mutations have not been identified for all tumors, and a large fraction of tumors are still “driver negative”. Herein, we sought to uncover new ‘drivers’ in pan-negative melanoma and pancreatic acinar cell carcinoma (PACC). While approximately 70% of melanomas harbor actionable driver alterations, the remaining one-third of patients are considered pan-negative. No driver alterations have yet been identified in patients with PACC, likely due to the rarity of this tumor type. Through whole-genome sequencing (WGS), we identified BRAF non-V600 alterations (L597, K601) in pan-negative melanomas that activate the mitogen-activation protein kinase (MAPK) signaling pathway and confer sensitivity to MEK1/2 inhibitors. Using comprehensive targeted, next-generation sequencing platforms, we identified MAPK-pathway activating RAF fusions in both pan-negative melanomas and PACCs. Finally, efforts to distinguish further pan-negative melanomas from one another revealed that a subset of pan-negative melanomas exhibit baseline activation of the ERBB family receptor tyrosine kinases (RTKs) EGFR, HER2 and HER3, suggesting a potential avenue for ERBB kinase inhibition in this disease. Collectively, this work describes the identification of novel and clinically actionable targets in previously un-druggable cancer subtypes.
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