Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal diseases despite continual improvements in therapy. Thus new approaches are sorely needed. Mutations in the oncogenic KRAS gene occur in over 90% of PDACs. KRAS is a known regulator of glutamine metabolism that renders cancer cells dependent on glutamine. Therefore, targeting glutamine metabolism may be particularly effective in treating a large portion of patients with pancreatic cancer. The first step of glutamie metabolism is the conversion of glutamine to glutamate via glutaminase. We have demonstrated that small molecule glutaminase inhibitors, such as BPTES (bis-2-[5-(phenylacetamido)-1,3,4-thiadiazol-2-yl]ethyl sulfide), block the production of glutamine in pancreatic cancer cells and attenuate growth rates in both in vitro and in vivo preclinical models. However, BPTES and other available glutaminase inhibitors are generally poorly soluble, metabolically unstable, nonselective, and/or require high doses, which reduce their efficacy and therapeutic index. Recently, nano-sized vehicles to enhance drug delivery in cancer have been approved (e.g. Doxil(r), Abraxane(r)) and have been rationalized as an approach to circumvent the stromal barrier which is a clinical challenge to drug delivery in pancreatic cancer. We recently demonstrated that nanoparticle delivery of BPTES can be safely administered and relative to free BPTES, provides dramatic improvement in tumor drug exposure and retention, resulting in greater efficacy. We have now identified several proprietary BPTES derivatives that are 10- to 100-fold more potent than BPTES and, at the same time, retain the key physicochemical properties (cLogP, PSA) required for nanoparticle encapsulation and delivery. We plan to further optimize the potency of the glutaminase inhibitors (Aim 1) and their compatibility to encapsulation (Aim 2) and evaluate their effectiveness in orthotopic xenografts from KRAS mutated patient-derived pancreatic tumors as well as KrasLSL.G12D/+; p53R172H/+; PdxCretg/+ (or KPC) mice that develop natural pancreatic tumors with characteristic stroma (Aim 3). Ultimately, we seek to translate these findings into the clinic and improve outcomes for pancreatic cancer patients. The proposal builds on the complementary strengths of the three collaborating laboratories - Slusher (small molecule drug discovery), Hanes (nanoparticle design), and Le (cancer metabolism).

Public Health Relevance

Genetic alterations that occur in over 90% of human pancreatic cancers render the tumors dependent on an amino acid, called glutamine, as a source of energy for growth and proliferation. Small molecule drugs which inhibit glutaminase, a critical enzyme in glutamine metabolism, have been shown to cause regression of human pancreatic cancer tumors in mice. We propose to develop novel and potent glutaminase inhibitor whose tumor delivery and retention will be enhanced by encapsulation into tumor-penetrating nanoparticles that we have found greatly enhances effectiveness. Our goal is to ultimately translate our findings into the clinic to improve outcomes for pancreatic cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193895-04
Application #
9601649
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Alley, Michael C
Project Start
2015-12-01
Project End
2020-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Kirsch, Brian James; Chang, Shu-Jyuan; Le, Anne (2018) Non-Hodgkin Lymphoma Metabolism. Adv Exp Med Biol 1063:95-106
Tan, Jessica; Le, Anne (2018) Breast Cancer Metabolism. Adv Exp Med Biol 1063:83-93
Li, Ting; Le, Anne (2018) Glutamine Metabolism in Cancer. Adv Exp Med Biol 1063:13-32
Bose, Sminu; Le, Anne (2018) Glucose Metabolism in Cancer. Adv Exp Med Biol 1063:3-12
Nabi, Karim; Le, Anne (2018) The Intratumoral Heterogeneity of Cancer Metabolism. Adv Exp Med Biol 1063:131-145
Park, Joshua K; Coffey, Nathan J; Limoges, Aaron et al. (2018) The Heterogeneity of Lipid Metabolism in Cancer. Adv Exp Med Biol 1063:33-55
Walker, Alyssa; Singh, Anju; Tully, Ellen et al. (2018) Nrf2 signaling and autophagy are complementary in protecting breast cancer cells during glucose deprivation. Free Radic Biol Med 120:407-413
Camelo, Felipe; Le, Anne (2018) The Intricate Metabolism of Pancreatic Cancers. Adv Exp Med Biol 1063:73-81
Lemberg, Kathryn M; Vornov, James J; Rais, Rana et al. (2018) We're Not ""DON"" Yet: Optimal Dosing and Prodrug Delivery of 6-Diazo-5-oxo-L-norleucine. Mol Cancer Ther 17:1824-1832
Heerma van Voss, M R; Vesuna, F; Bol, G M et al. (2018) Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment. Oncogene 37:63-74

Showing the most recent 10 out of 21 publications