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

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA168999-05
Application #
9545686
Study Section
Subcommittee I - Transistion to Independence (NCI)
Program Officer
Lim, Susan E
Project Start
2014-09-10
Project End
2019-08-31
Budget Start
2018-09-01
Budget End
2019-08-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Surgery
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nguyen, Vi; Marmor, Rebecca A; Ramamoorthy, Sonia L et al. (2018) The Use of Solicited Publishing by Academic Surgeons. Surgery 164:212-218
Wiley, Shu Z; Sriram, Krishna; Liang, Wenjing et al. (2018) GPR68, a proton-sensing GPCR, mediates interaction of cancer-associated fibroblasts and cancer cells. FASEB J 32:1170-1183
Goodman, Aaron M; Piccioni, David; Kato, Shumei et al. (2018) Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors. JAMA Oncol 4:1237-1244
Schrock, Alexa B; Pavlick, Dean; Klempner, Samuel J et al. (2018) Hybrid Capture-Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Cancers of the Gastrointestinal Tract or Anus. Clin Cancer Res 24:1881-1890
Charo, Lindsey M; Burgoyne, Adam M; Fanta, Paul T et al. (2018) A Novel PRKAR1B-BRAF Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy. J Natl Compr Canc Netw 16:238-242
Marincola Smith, Paula; Kiernan, Colleen M; Tran, Thuy B et al. (2018) Role of Additional Organ Resection in Adrenocortical Carcinoma: Analysis of 167 Patients from the U.S. Adrenocortical Carcinoma Database. Ann Surg Oncol 25:2308-2315
Fong, Zhi Ven; Pitt, Henry A; Strasberg, Steven M et al. (2018) Diminished Survival in Patients with Bile Leak and Ductal Injury: Management Strategy and Outcomes. J Am Coll Surg 226:568-576.e1
Nguyen, Vi; Sicklick, Jason K (2018) ASO Author Reflections: Towards Better Metrics for Judging Academic Productivity in Surgical Oncology. Ann Surg Oncol :
Poorman, Caroline E; Ethun, Cecilia G; Postlewait, Lauren M et al. (2018) A Novel T-Stage Classification System for Adrenocortical Carcinoma: Proposal from the US Adrenocortical Carcinoma Study Group. Ann Surg Oncol 25:520-527
Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG) (2018) Management of metastatic retroperitoneal sarcoma: a consensus approach from the Trans-Atlantic Retroperitoneal Sarcoma Working Group (TARPSWG). Ann Oncol 29:857-871

Showing the most recent 10 out of 53 publications