Pancreatic cancers have one of the highest fatality rates of all cancers and their response to therapies is highly variable. We have recently shown that inhibition of lactate dehydrogenase A (LDHA) and glutaminase (GLS) through small drug-like molecules causes pancreatic tumor regression. These studies indicate that targeting the metabolic reprogramming of cancer cells is a promising new approach to pancreatic cancer therapy. In order to translate these metabolic inhibitors to the clinic, our goal is to characteriz and enable targeted selection of patients based on predicted metabolic response. Although genetic mutations may ultimately be the prime causes of early stage cancer, they can also lead to changes in cancer metabolism which enable cancer cells to proliferate and survive even under the hypoxic and nutrient deprived conditions often encountered in the tumor microenvironment. The biochemical changes in cancer cells, which determine their behavior in terms of growth, survival and mobility, represent a functional readout of responses to external agents. We hypothesize that the metabolites of tumors that are sensitive to metabolic inhibitors are measurably different from those of resistant ones. We can therefore propose these metabolites as potential functional predictors of response. The proposed research will also study the metabolic reprogramming of cancer cells in the tumor microenvironment that can affect pancreatic cancer sensitivity to LDHA and GLS inhibition. The proposed experiments will use Metabolomics technologies to trace the metabolic prototypes of pancreatic orthotopic xenografts to identify the metabolic signature of FX11 or BPTES-sensitive tumors as compared to resistant ones. For an analysis of the effects due to the tumor hypoxic microenvironment, we will use our innovative tool, the HypoxCR reporter system, which can simultaneously detect hypoxic cells and proliferating cells to define the effects of the pancreatic cancer tumor microenvironment on their sensitivity to metabolic inhibitors. This will be the first evaluation of the hypoxic tumor microenvironment regarding how it affects the response of subfractions of pancreatic orthotopic xenograft tumor cells to metabolic inhibitors.

Public Health Relevance

Pancreatic cancers have one of the highest fatality rates of all cancers and response to therapies is highly variable. The proposed research identifies factors that can predict sensitivity of pancreatic cancers to drugs that inhibit cancer metabolism. This research will also study how tumor areas that lack access to oxygen respond to these drugs.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA169757-02
Application #
8624671
Study Section
Drug Discovery and Molecular Pharmacology Study Section (DMP)
Program Officer
Misra, Raj N
Project Start
2013-04-01
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
$170,891
Indirect Cost
$65,403
Name
Johns Hopkins University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Le, Anne; Stine, Zachary E; Nguyen, Christopher et al. (2014) Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc Natl Acad Sci U S A 111:12486-91