R01CA268601

Metabolic Imaging of Targeted Therapies in Cancer - Project Summary/Abstract

Given the paradigm shift in cancer therapy, including the ever-growing increase in the use of targeted therapies, foremost small-molecule kinase inhibitors in cancer therapy, there is an urgent need to develop reliable imaging techniques to detect and monitor the efficacy of such inhibitors in cancer patients.

Because direct evaluation of cell signaling is practically not feasible and changes in tumor volume occur late after treatment initiation given the predominantly cytostatic effect of the inhibitors, we are proposing an alternative approach to monitor changes in tumor metabolism induced by kinase inhibition. This will be achieved in three stages:

1) Analysis of gene expression/proteomic/phosphoproteomic to identify metabolic pathways perturbed by inhibition of the signaling pathway performed both in vitro and in vivo in the mouse xenotransplant models using patient-derived cultured and primary cells (PDX).

2) Metabolomic and metabolic fluxomic analysis of the effect of kinase inhibition on metabolic pathways, also done in in vitro and in vivo settings.

3) Analysis of biomarkers of inhibitor response validated by the above "-omics" studies by imaging techniques, preferably non-invasive, such as 1H MRS or chemical exchange saturation-transfer (CEST) with standard FDG PET imaging serving as control.

In these proof-of-principle studies, we will focus on mTOR, the serine/threonine kinase hyperactive in the majority of cancer types, and employ direct and indirect inhibitors of mTOR, rapamycin/rapalog and torin2, respectively, as the index kinase/kinase inhibitor system. We will use diffuse large B-cell lymphoma (DLBCL) as the experimental cancer model.

In preliminary studies, we have demonstrated that rapamycin decreased concentrations of lactic acid in patient-derived lymphoma cell lines, both cultured in vitro and xenotransplanted into mice, as detected by unique 1H MRS imaging-based detection pulse sequences developed by us and our collaborators. The rapamycin-induced decrease in glycolytic metabolism correlated with, and importantly, markedly preceded inhibition of tumor cell growth, strongly supporting the notion that image-based evaluation of the key metabolic response is predictive of biological tumor cell response to the inhibition. The response also correlated with, and hence, was at least in part attributable to decreased expression of hexokinase II, other glycolytic enzymes, and enzymes from other key metabolic pathways including phosphoribosyl-amidotransferase and other enzymes involved in glutaminolysis.

Utilizing 13C MRS and 13C LC-MS, we have confirmed mTOR control of glycolysis and also noted decreases in fatty acid and sterol metabolism as well as inhibition of the pentose phosphate shunt and the TCA cycle.

We anticipate that the proposed studies will extend our knowledge of the impact of mTOR inhibition on malignant cell metabolism and, ultimately, set the stage for future clinical evaluation of MRS or other imaging method(s) for monitoring response to inhibitors of mTOR and other cell-signaling kinases in DLBCL and other types of cancer.

Trustees Of The University Of Pennsylvania

TO IMPROVE SCREENING AND EARLY DETECTION STRATEGIES AND TO DEVELOP ACCURATE DIAGNOSTIC TECHNIQUES AND METHODS FOR PREDICTING THE COURSE OF DISEASE IN CANCER PATIENTS. SCREENING AND EARLY DETECTION RESEARCH INCLUDES DEVELOPMENT OF STRATEGIES TO DECREASE CANCER MORTALITY BY FINDING TUMORS EARLY WHEN THEY ARE MORE AMENABLE TO TREATMENT. DIAGNOSIS RESEARCH FOCUSES ON METHODS TO DETERMINE THE PRESENCE OF A SPECIFIC TYPE OF CANCER; TO PREDICT ITS COURSE AND RESPONSE TO THERAPY, BOTH A PARTICULAR THERAPY OR A CLASS OF AGENTS; AND TO MONITOR THE EFFECT OF THE THERAPY AND THE APPEARANCE OF DISEASE RECURRENCE. THESE METHODS INCLUDE DIAGNOSTIC IMAGING AND DIRECT ANALYSES OF SPECIMENS FROM TUMOR OR OTHER TISSUES. SUPPORT IS ALSO PROVIDED FOR ESTABLISHING AND MAINTAINING RESOURCES OF HUMAN TISSUE TO FACILITATE RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS; TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT; AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Philadelphia, Pennsylvania 191044865 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 383% from $625,478 to $3,022,209.