This proposal outlines a 5 year program designed to develop the principal investigator into an independent translational researcher and investigate the role of altered metabolism in leukemia cell viability and therapy resistance. The principal investigator is a junior faculty member at Wake Forest University. The mentoring and training program will focus on development of a deeper understanding of metabolism in cancer, data interpretation, animal modeling and experimental design. Additional mentoring in grantsmanship and scientific writing will also be undertaken. Dr Frank Torti will be the primary mentor. He is a renowned clinician and well funded researcher as well as the chairman of the department of Cancer Biology and director of the Wake Forest University Comprehensive Cancer Center. He has successfully developed many students and post-doctoral candidates into independent researchers. His mentorship will be in conjunction with a group of senior faculty members. Drs Kridel, Powell, Almeida-Porada and High will comprise the faculty mentoring committee. These investigators have a wealth of clinical and research experience in acute leukemias, cancer metabolism and animal models of cancer. The research plan will explore the contribution of fatty acid synthase (FASN) and pyruvate dehydrogenase complex (PDH) to cell viability and resistance to therapy in the acute leukemias. Acute myeloid and lymphocytic leukemias are aggressive malignancies characterized by resistance to therapy and poor outcomes in adults. Altered mitochondrial metabolism is associated with resistance in leukemia cells.
The specific aims will: 1) Determine the effect of PDH and FASN inhibition on leukemia cell viability and mitochondrial metabolism in vitro and in vivo. 2) Determine the effects of PDH and FASN inhibition on response to standard and targeted therapy in acute leukemia cells in vitro and in vivo. 3) Determine the effects of exogenous fatty acids in vitro and dietary fatty acids in vivo on therapy response in the acute leukemias. Completion of these studies will provide novel insights on therapy response and lead to novel treatment strategies for patients who suffer from these aggressive malignancies. The Section on Hematology and Oncology, Department of Cancer Biology and the NCI designated Comprehensive Cancer Center at Wake Forest University will provide a rich environment, core facilities and expertise necessary for the successful completion of the proposed experiments. It is an ideal place to complete training towards becoming an independent translational researcher.
The Acute Leukemias are aggresive cancers of the white blood cells. Every year approximately 19,000 Americans are diagnosed with these diseases and more than 10,000 die from them. This research project will increase our understanding of how these cancers resist therapy and identify novel strategies to reverse this resistance in an effort to impove outcomes for these patients.
|Alexander, Peter M; Caudell, David L; Kucera, Gregory L et al. (2017) The novel phospholipid mimetic KPC34 is highly active against preclinical models of Philadelphia chromosome positive acute lymphoblastic leukemia. PLoS One 12:e0179798|
|Klepin, Heidi D; Tooze, Janet A; Pardee, Timothy S et al. (2016) Effect of Intensive Chemotherapy on Physical, Cognitive, and Emotional Health of Older Adults with Acute Myeloid Leukemia. J Am Geriatr Soc 64:1988-1995|
|Tawfik, Bernard; Pardee, Timothy S; Isom, Scott et al. (2016) Comorbidity, age, and mortality among adults treated intensively for acute myeloid leukemia (AML). J Geriatr Oncol 7:24-31|
|Alexander, Peter; Kucera, Gregory; Pardee, Timothy S (2016) Improving nucleoside analogs via lipid conjugation: Is fatter any better? Crit Rev Oncol Hematol 100:46-56|
|Gmeiner, William H; Jennings-Gee, Jamie; Stuart, Christopher H et al. (2015) Thymineless death in F10-treated AML cells occurs via lipid raft depletion and Fas/FasL co-localization in the plasma membrane with activation of the extrinsic apoptotic pathway. Leuk Res 39:229-35|
|Ahmed, Tamjeed; Holwerda, Scott; Klepin, Heidi D et al. (2015) High dose cytarabine, mitoxantrone and l-asparaginase (HAMA) salvage for relapsed or refractory acute myeloid leukemia (AML) in the elderly. Leuk Res 39:945-9|
|Pang, Changlee S; Pettenati, Mark J; Pardee, Timothy S (2015) Clinicopathological analysis of near-tetraploidy/tetraploidy acute myeloid leukaemia. J Clin Pathol 68:236-40|
|Elliot, Kathleen; Tooze, Janet A; Geller, Rachel et al. (2014) The prognostic importance of polypharmacy in older adults treated for acute myelogenous leukemia (AML). Leuk Res 38:1184-90|
|Cook, Guerry J; Caudell, David L; Elford, Howard L et al. (2014) The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML. PLoS One 9:e112619|
|Klepin, Heidi D; Rao, Arati V; Pardee, Timothy S (2014) Acute myeloid leukemia and myelodysplastic syndromes in older adults. J Clin Oncol 32:2541-52|
Showing the most recent 10 out of 15 publications