Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma with ~6,000 new cases annually in the U.S. GIST therapy is predicated upon KIT "oncogene-addiction" which drives sarcomagenesis. As a result, the ATP-dependent (-mimetic) KIT inhibitor, imatinib, is the first-line treatment for advanced GIST. Despite imatinib therapy, disease recurrence/progression remain frequent because GISTs develop imatinib-resistance caused by secondary KIT mutations. These mutations decrease the efficacy of other ATP-mimetics. Thus, compounds that target kinases, while avoiding ATP-mimetic resistance mechanisms, are of distinct interest. My mentor, David Cheresh, has reported the development of allosteric kinase inhibitors (AKI) that prevent KIT/BRAF/CRAF/PDGFR kinase activation in an ATP-independent manner. While current ATP-mimetics hit the "right" target(s), AKIs may: 1) have higher specificity than ATP-mimetics;2) avoid "gatekeeper" mutations which render ATP-mimetics inactive;and 3) produce strong activity against imatinib-resistant GIST with fewer concerns for AKI-resistance. We hypothesize that this novel class of AKIs with KIT inhibition may be used to treat imatinib-resistant GIST, a disease for which there are limited therapeutic options.
We aim to define the functional/mechanistic roles of allosteric kinase inhibition within the context of imatinib-resistant GIST.
In Aim 1, we will characterize a series of highly potent AKIs using imatinib-sensitive and -resistant GIST cell lines. We will define AKI effects on cell viability, apoptosis, and cell cycle arrest in a time-/dose-dependent fashion.
In Aim 2, we will perform biochemical/mechanistic analyses to determine the kinetic effects and binding affinities of lead AKIs on wild-type versus mutant KIT enzymes.
In Aim 3, we will employ genetic and pharmacologic analyses to investigate how KIT (and BRAF/CRAF/PDGFR) AKIs influence intracellular kinase signaling pathways, which control fundamental processes such as tumor cell proliferation, survival, apoptosis and necrosis in imatinib-resistant lines. [We will also define AI effects upon KIT adapter protein interactions.] In Aim 4, we will investigate the lead AKIs identified in Aims 1-3 for inhibition of GIST growth using tumor xenograft/transgenic mouse models according to our IACUC-approved protocol. We will study novel compounds that target KIT via a distinct mechanism both in vitro and in vivo in order to target imatinib- resistant GIST and identify innovative anti-tumor agent(s). These studies will serve as the basis for clinical examination of AKIs directed against these validated kinase targets in patients with imatinib-resistant GIST. If efficacious agents are identified in vitro and in vivo, we intend to pursue additional funding to support moving these agent(s) to "the bedside" in the form of clinical trials
Although Gastrointestinal Stromal Tumor (GIST), the most common sarcoma, is treatable with imatinib (an ATP-dependent KIT inhibitor), half of patients develop drug-resistance within 20-months of initiating therapy. Because compounds that target KIT, while avoiding ATP-mimetic resistance mechanisms, are of distinct interest, my mentor, Dr. David Cheresh, has reported the development of allosteric kinase inhibitors that prevent KIT/BRAF/CRAF/PDGFR kinase activation in an ATP-independent manner. The overall objective of this project is to define the role of allosteric inhibition within the context of imatnib-resistant GIST.
|Niemiec, Steve M; Vinetz, Joseph M; Sicklick, Jason K (2016) Porta Hepatis Mass. JAMA Surg 151:187-8|
|Fox, Raymond G; Lytle, Nikki K; Jaquish, Dawn V et al. (2016) Image-based detection and targeting of therapy resistance in pancreatic adenocarcinoma. Nature 534:407-11|
|Sicklick, Jason K; Fanta, Paul T; Shimabukuro, Kelly et al. (2016) Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design. Cancer Metastasis Rev 35:263-75|
|Shi, Eileen; Chmielecki, Juliann; Tang, Chih-Min et al. (2016) FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med 14:339|
|Postlewait, Lauren M; Ethun, Cecilia G; Tran, Thuy B et al. (2016) Outcomes of Adjuvant Mitotane after Resection of Adrenocortical Carcinoma: A 13-Institution Study by the US Adrenocortical Carcinoma Group. J Am Coll Surg 222:480-90|
|Margonis, Georgios Antonios; Kim, Yuhree; Prescott, Jason D et al. (2016) Adrenocortical Carcinoma: Impact of Surgical Margin Status on Long-Term Outcomes. Ann Surg Oncol 23:134-41|
|Amini, Neda; Margonis, Georgios Antonios; Kim, Yuhree et al. (2016) Curative Resection of Adrenocortical Carcinoma: Rates and Patterns of Postoperative Recurrence. Ann Surg Oncol 23:126-33|
|Kim, Yuhree; Margonis, Georgios A; Prescott, Jason D et al. (2016) Nomograms to Predict Recurrence-Free and Overall Survival After Curative Resection of Adrenocortical Carcinoma. JAMA Surg 151:365-73|
|Margonis, Georgios Antonios; Amini, Neda; Kim, Yuhree et al. (2016) Incidence of Perioperative Complications Following Resection of Adrenocortical Carcinoma and Its Association with Long-Term Survival. World J Surg 40:706-14|
|Coe, Taylor M; Fero, Katherine E; Fanta, Paul T et al. (2016) Population-Based Epidemiology and Mortality of Small Malignant Gastrointestinal Stromal Tumors in the USA. J Gastrointest Surg 20:1132-40|
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