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.
|Schaefer, Inga-Marie; Wang, Yuexiang; Liang, Cher-Wei et al. (2017) MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation. Nat Commun 8:14674|
|Larimer, Benjamin M; Wehrenberg-Klee, Eric; Dubois, Frank et al. (2017) Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response. Cancer Res 77:2318-2327|
|Yang, Wanshui; Liu, Li; Masugi, Yohei et al. (2017) Calcium intake and risk of colorectal cancer according to expression status of calcium-sensing receptor (CASR). Gut :|
|Lopes-Ramos, Camila M; Paulson, Joseph N; Chen, Cho-Yi et al. (2017) Regulatory network changes between cell lines and their tissues of origin. BMC Genomics 18:723|
|Shi, Yan; Qian, Zhi Rong; Zhang, Sui et al. (2017) Cell Cycle Protein Expression in Neuroendocrine Tumors: Association of CDK4/CDK6, CCND1, and Phosphorylated Retinoblastoma Protein With Proliferative Index. Pancreas 46:1347-1353|
|Keum, NaNa; Yuan, Chen; Nishihara, Reiko et al. (2017) Dietary glycemic and insulin scores and colorectal cancer survival by tumor molecular biomarkers. Int J Cancer 140:2648-2656|
|Lindström, Sara; Finucane, Hilary; Bulik-Sullivan, Brendan et al. (2017) Quantifying the Genetic Correlation between Multiple Cancer Types. Cancer Epidemiol Biomarkers Prev 26:1427-1435|
|Paulson, Joseph N; Chen, Cho-Yi; Lopes-Ramos, Camila M et al. (2017) Tissue-aware RNA-Seq processing and normalization for heterogeneous and sparse data. BMC Bioinformatics 18:437|
|Boland, C Richard; Yurgelun, Matthew B (2017) Historical Perspective on Familial Gastric Cancer. Cell Mol Gastroenterol Hepatol 3:192-200|
|Muranen, Taru; Iwanicki, Marcin P; Curry, Natasha L et al. (2017) Starved epithelial cells uptake extracellular matrix for survival. Nat Commun 8:13989|
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