Development of a Synthetic Lethal Drug Combination that Targets the Energy Generation Triangle for Liver Cancer Therapy
Abstract
Principal Investigator s Career Goals in Cancer Research: Despite the increasing prevalence and mortality of liver cancer in the United States and among US Veterans, there is a lack of effective and safe drug treatment for them. My experimental observations of fundamental differences in energy metabolism between normal liver and liver cancer shed light on an "Achilles heel" of liver cancer, and convinced me in setting, (1) as my goal as a postdoctoral fellow, to develop an effective and safe preclinical treatment for liver cancer, and (2) as my career goal, to further my intellectual development as an independent cancer researcher to design and develop effective and safe therapeutics for treating liver cancer. The Horizon Award will enable me to perform research on the preclinical development of what we believe is an innovative, promising therapy. My proposed research will decrease the current gap in liver cancer treatment (Fiscal Year 2015 Military Focus Area). The research will have a profound impact on the health and well-being of US Veterans and will benefit the general population. With Horizon Award support, my researcher development plan will enable me to acquire the necessary skills, competence, and expertise for (1) tumor imaging in live animals and for (2) the generation of nanoparticles for the specific delivery of a gene therapy to liver cancer. The skills and expertise for tumor imaging will be acquired through discussions with my mentor, Dr. Herschman, who is a well-known expert in this field; he is both Crump Professor of Molecular Imaging and initial and continuing Principal Investigator of the NCI-UCLA (National Cancer Institute; University of California, Los Angeles) In Vivo Cellular and Molecular Imaging Center. The skills and expertise for making the nanoparticles for a gene therapy will be acquired through consulting and collaborating with Dr. Jeffrey Zink, Distinguished Professor of Chemistry at UCLA, a recognized expert in nanoscience. In addition, the researcher development plan will provide me with opportunities to attend important national and international meetings and conferences related to liver cancer and cancer metabolism, where I can exchange research ideas with the world experts to expand my knowledge in these fields. Therefore, I will develop as a cancer researcher able to develop better therapeutics to treat liver and other cancers. Scientific Objective and Rationale: Previous studies and our preliminary data have shown that, compared to normal liver cells, liver cancers use different approaches to generate the energy necessary to survive and to grow: (1) liver cancer cells are more dependent on glucose (sugar) for energy and utilize glucose in a different manner than normal cells, providing a liver cancer-specific target for developing therapies; (2) cells within liver tumors have limited oxygen availability and they have decreased oxygen utilization, suggesting that oxygen-dependent energy generation makes liver cancer cells more sensitive to specific inhibiting agents; and (3) liver cancer cells preserve lipids (fats) to make building blocks to support cell growth; to do so they decrease lipid degradation for energy generation, suggesting that energy generation from lipids is more sensitive to inhibition in liver cancer than in normal tissue. Our preliminary data show that combined inhibition of these three sources of energy generation (glucose, oxygen, and lipid) is effective in killing liver cancer cells. This therapy is not toxic in cells from other cancer types including breast, lung, and colon cancers, suggesting it will be tolerated by normal tissues. In this study, we propose to perform further preclinical development of this triple combination with (1) a gene-targeted therapy to specifically inhibit glucose-dependent energy generation in liver cancer, (2) a well-tolerated chemical compound (diphenyleneiodonium, DPI), which we found to inhibit oxygen-dependent ene
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610162
Entities
People
- Shili Xu
Organizations
- United States Army
- University of California, Los Angeles