Joint Fellowship Training Program

Mentor:
Ashutosh Rao, R.Ph., Ph.D.

Position and Organizational Affiliation:
Staff Fellow, Laboratory of Biochemistry, Division of Therapeutic Proteins, Office of Biotechnology Products, Office of Pharmaceutical Science, Center for Drug Evaluation and Research (CDER), FDA.

Contact Information:
ashutosh.rao@fda.hhs.gov; 301-827-4487

Running Title of Program:
Molecular mechanisms of cancer chemotherapy and cardiotoxicity

Research Project Summary:
Our goal is to understand how oxidative stress and DNA damage from cancer chemotherapy drugs cause damage to normal tissues so that successful protective measures can be identified. The DNA damaging anthracycline doxorubicin is a critical front-line treatment for primary breast cancer. Unfortunately, doxorubicin also causes dose-limiting toxicity to heart tissue. The cardiac damage is thought to result from mitochondrial oxidative stress that causes free radical damage to heart muscle. Previous combination therapies aimed at cardioprotection have used non-specific antioxidants that have failed to show clinical benefit. Our recent findings on iron chelators and cancer chemotherapy have provided preliminary insight into the complex nature of signaling by these agents. Using cellular and animal models, we aim to characterize the molecular pathways by which oxidants and anti-oxidants effect cardiac and tumor biology. Towards this overall goal, we have two ongoing projects: (1) elucidate the mechanisms of cell death by mitochondrially-targeted redox agents, and (2) generate and validate a syngeneic animal model for studying cardiotoxicity and antitumor efficacy.

Proposed Project for IOTF Fellow:
The fellow will have the opportunity to pursue one of several research projects based on his/her interest within the context of cancer chemotherapy. Candidates must have a good understanding of cancer biology and molecular biology. Position is located on the NIH campus in Bethesda, MD. The fellow will also have opportunities to interact and collaborate with NCI laboratories on specific joint projects. The Fellow will also be expected to participate in regular research meetings and seminars.

Regulatory Activity:
The Division of Therapeutic Proteins regulates a broad range of therapeutic agents including, but not limited to, oncology products. The fellow will actively participate in the team-based review of investigational drug applications. The fellow will be expected to attend regulatory training sessions, participate in regulatory meetings, and perform review of IND and pre-IND submissions.

Reference(s):

1. Rao et al., The iron chelator Dp44mT causes DNA damage & selective inhibition of topoisomerase-II? in breast cancer cells. Cancer Research 2008 (in press).
2. Rao et al., Batracylin (NSC 320846), a dual inhibitor of DNA topoisomerases I and II induces histone ?-H2AX as a biomarker of DNA damage. Cancer Research, 2007.
3. Hoke et al., Desferal inhibits breast tumor growth and does not interfere with the tumoricidal activity of doxorubicin. Free Radic Biol Med., 2005.