This proposal seeks effective combination therapies that maximize GIST response to KIT/PDGFRA inhibition by concurrently targeting the biologically key MEK/MAPK pathway. Most GISTs express mutant, constitutively activated forms of the KIT or PDGFRA, and we have shown that these formerly untreatable cancers can be palliated in 80% of patients by oral single-agent therapy with imatinib mesylate. However,patients responding to imatinib have persistent measurable disease and generally develop resistance within two years of starting treatment. Therefore, more effective and broader-spectrum therapies are urgently needed. Notably, our preliminary studies show that KIT/PDGFRA imatinib resistance mechanisms vary from patient to patient, and also between metastatic lesions in a given patient, but uniformly rely upon MEK/MAPK signaling to support cell proliferation.
In Aim 1, by studying MEK/MAPK signaling and response mechanisms, we will develop clinically-relevant biomarkers and - most importantly - we will identify alternate MEK-dependent therapeutic targets which might have greater specificity, in GIST, compared to MEK.
In Aim 2. we will characterize mechanisms of MEKi resistance, since such studies are likely to identify biologically essential regulatory nodes in MEK/MAPK-pathways, which - like those found in Aim 1 - will be candidates as biomakers and therapeutic targets in GIST clinical trials. The collective studies in Aims 1-2, by revealing the scope of MEK/MAPK signaling in GIST, will provide the understanding needed to design more effective and less toxic clinical trials.
In Aim 3 we evaluate combination therapies with imatinib and MEKi, as a strategy to inhibit downstream signals from the varied gain-of-function KIT mutations each imatinib-resistant patient, while maintaining imatinib inhibition of nonprogressing GIST subclones. This will be accomplished through a phase l/ll clinical trial of the MEK inhibitor, MEK162, combined with imatinib, in patients showing progression of metastatic GIST on imatinib or sunitinib. Through these studies, we will translate the basic science proposed in this SPORE through to clinical application.
We expect this GIST research will enable clinical progress by developing therapies that are not stymied by the diversity of KIT/PDGFRA inhibitor resistance mechanisms. The proposed studies seek to maximize response by targeting KIT/PDGFRA oncogenic signals as they pass through the MEK/MAPK conduit, and such strategies are also relevant in other kinase-driven human cancers.
|Ananthakrishnan, Ashwin N; Du, Mengmeng; Berndt, Sonja I et al. (2015) Red meat intake, NAT2, and risk of colorectal cancer: a pooled analysis of 11 studies. Cancer Epidemiol Biomarkers Prev 24:198-205|
|Song, Mingyang; Gong, Jian; Giovannucci, Edward L et al. (2015) Genetic variants of adiponectin and risk of colorectal cancer. Int J Cancer 137:154-64|
|Lochhead, Paul; Chan, Andrew T; Nishihara, Reiko et al. (2015) Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 28:14-29|
|Inamura, Kentaro; Yamauchi, Mai; Nishihara, Reiko et al. (2015) Prognostic significance and molecular features of signet-ring cell and mucinous components in colorectal carcinoma. Ann Surg Oncol 22:1226-35|
|Serrano, César; Wang, Yuexiang; Mariño-Enríquez, Adrián et al. (2015) KRAS and KIT Gatekeeper Mutations Confer Polyclonal Primary Imatinib Resistance in GI Stromal Tumors: Relevance of Concomitant Phosphatidylinositol 3-Kinase/AKT Dysregulation. J Clin Oncol 33:e93-6|
|Rosenthal, Michael H; Kim, Kyung Won; Fuchs, Charles S et al. (2015) CT predictors of overall survival at initial diagnosis in patients with stage IV colorectal cancer. Abdom Imaging 40:1170-6|
|Arteaga, Carlos L; Engelman, Jeffrey A (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303|
|Wu, Chen; Kraft, Peter; Stolzenberg-Solomon, Rachael et al. (2014) Genome-wide association study of survival in patients with pancreatic adenocarcinoma. Gut 63:152-60|
|Ma, Tianle; Jang, Eun Jeong; Zukerberg, Lawrence R et al. (2014) Recurrences are common after endoscopic ampullectomy for adenoma in the familial adenomatous polyposis (FAP) syndrome. Surg Endosc 28:2349-56|
|Blaszkowsky, L S; Ryan, D P; Szymonifka, J et al. (2014) Phase I/II study of neoadjuvant bevacizumab, erlotinib and 5-fluorouracil with concurrent external beam radiation therapy in locally advanced rectal cancer. Ann Oncol 25:121-6|
Showing the most recent 10 out of 259 publications