This project will continue studies on the use of pharmacological inhibitors of fatty acid synthase (FAS) for lung cancer treatment in both the setting of clinical trials (with correlative markers) and in the laboratory setting for refinement of this treatment strategy. Under current funding from the SPORE mechanism, we have 1) confirmed that FAS is a promising target for lung cancer treatment, 2) identified a class of pharmacological compounds that can selectively inhibit FAS activity without significantly affecting fatty acid oxidation (with associated anorexia), and 3) demonstrated that these compounds effectively inhibit growth of human lung cancer xenograftsand mouse lung tumors, without causing significant toxicity. Furthermore, our work has evaluated pharmacokinetics of a FAS inhibitor and demonstrated the ability to administer these compounds orally, which support our expectations of moving this project to clinical trials for lung cancer treatment. Finally, experiments conducted during the initial funding period have demonstrated the ability of positron emission tomography (PET) imaging to monitor response to FAS inhibitors, and also found additive or synergistic effects when FAS inhibitors are used in combination with other chemotherapeutic agents. In the first specific aim of this proposed project, we will evaluate a pharmacological inhibitor of fatty acid synthase in early stage clinical trials. We expect to initiate a phase 1 trial in the current funding period, and phase 2 clinical trails in the proposed funding period. Both phase 1 and phase 2 clinical trials will include monitoring patients with the candidate markers of response developed in Specific Aim #2 (including FDG/PET imaging), in addition to standard measures of patient response.
Specific aim #2 will determine the effect of fatty acid synthase inhibitors on signal transduction pathways and cellular metabolism in pre-clinical models of lung cancer, to identify potential markers for predicting and monitoring response to these agents. As noted above, these markers will be applied to the clinical trial setting. Finally, in specific aim #3, we will evaluate the potential role for fatty acid synthase inhibitors in combination cancer therapy. We will evaluate potential additive or synergistic effects of combining FAS-inhibiting compounds with conventional chemotherapeutic agents for lung cancer, as well as with novel agents that target specific signal transduction pathways. Understanding how a FAS inhibitor can be effectivelycombined with other agents will provide a framework for effective use of this compound in the clinical setting. Relevance to Public Health: This project will develop a new therapeutic strategy for lung cancer treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA058184-16
Application #
8208625
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-12-01
Budget End
2011-11-30
Support Year
16
Fiscal Year
2011
Total Cost
$158,168
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Zhong, Yi; Macgregor-Das, Anne; Saunders, Tyler et al. (2017) Mutant p53 Together with TGF? Signaling Influence Organ-Specific Hematogenous Colonization Patterns of Pancreatic Cancer. Clin Cancer Res 23:1607-1620
Hulbert, Alicia; Jusue-Torres, Ignacio; Stark, Alejandro et al. (2017) Early Detection of Lung Cancer Using DNA Promoter Hypermethylation in Plasma and Sputum. Clin Cancer Res 23:1998-2005
Chiappinelli, Katherine B; Zahnow, Cynthia A; Ahuja, Nita et al. (2016) Combining Epigenetic and Immunotherapy to Combat Cancer. Cancer Res 76:1683-9
Singh, Anju; Venkannagari, Sreedhar; Oh, Kyu H et al. (2016) Small Molecule Inhibitor of NRF2 Selectively Intervenes Therapeutic Resistance in KEAP1-Deficient NSCLC Tumors. ACS Chem Biol 11:3214-3225
Chiappinelli, Katherine B; Strissel, Pamela L; Desrichard, Alexis et al. (2015) Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses. Cell 162:974-86
Vendetti, Frank P; Topper, Michael; Huang, Peng et al. (2015) Evaluation of azacitidine and entinostat as sensitization agents to cytotoxic chemotherapy in preclinical models of non-small cell lung cancer. Oncotarget 6:56-70
Belinsky, Steven A (2015) Unmasking the lung cancer epigenome. Annu Rev Physiol 77:453-74
Sussan, Thomas E; Gajghate, Sachin; Thimmulappa, Rajesh K et al. (2015) Exposure to electronic cigarettes impairs pulmonary anti-bacterial and anti-viral defenses in a mouse model. PLoS One 10:e0116861
Kim, Jung-Hyun; Thimmulappa, Rajesh K; Kumar, Vineet et al. (2014) NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation. J Clin Invest 124:730-41
Ahuja, Nita; Easwaran, Hariharan; Baylin, Stephen B (2014) Harnessing the potential of epigenetic therapy to target solid tumors. J Clin Invest 124:56-63

Showing the most recent 10 out of 255 publications