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Alan Eastman, Ph.D.

Contact Information:

Professional Interests:

Cancer chemotherapy: mechanisms of drug action, novel drug combinations, and proof-of-principle clinical trials. Mechanisms of cell-cycle arrest by DNA-damaging agents and analysis of drugs that abrogate arrest. Modulation of signal transduction pathways as a means to enhance the induction of apoptosis.

Dr. Eastman received his B. Tech. from Brunel University in London in 1972 and his Ph.D. from the Chester Beatty Research Institute, University of London, in 1975. He trained as a postdoctoral research associate at the Medical College of Georgia and the University of Vermont. In 1979, he was appointed research assistant professor at the University of Vermont. In 1983, he took a position as associate professor at the Eppley Institute for Research in Cancer, University of Nebraska Medical Center. In 1989, he joined the faculty at Dartmouth.

Cell death by a pathway known as apoptosis occurs as a physiological process required for the normal homeostasis of a multicellular organism. Of particular interest to cancer is the observation that certain oncogenes and tumor suppressor genes can either enhance or prevent apoptosis. There are many inducers of apoptosis such as anticancer agents, immune signals, and removal of growth factors that activate multiple pathways converging on a final common execution phase. This research program is aimed at understanding these pathways as an approach to identifying novel targets for improving therapeutic outcome. We have shown that the rate of apoptosis induced by anticancer vinca alkaloids (e.g. vinblastine) can be greatly enhanced and accelerated by inhibiting the anti-apoptotic proteins of the Bcl-2 family; the majority of cell die within 4 h. Various leukemia and myeloma cell lines depend on different members of this family and are therefore sensitized by different inhibitors and strategies. Vinblastine also activates the c-Jun N-terminal kinase (JNK) as a required step in this rapid apoptosis. Current experiments are directed to understanding the role of JNK and identifying the other proteins that play a role. We are also proposing to screen samples from leukemia patients for their sensitivity to these drug combinations as a prelude to performing a clinical trial

Other studies are directed at understanding how anticancer DNA damaging agents kill cells, and how this can be enhanced. After a potentially lethal insult, cells progress through the cell cycle and arrest in both the S and G2 phase. The arrest permits time for repair such that the cells can recover. Inhibitors of these checkpoints have been developed that overcome arrest, driving the cells through S and G2 such that they then undergo a lethal mitosis. The primary inhibitor studied is UCN-01 (7-hydroxystaurosporine) that inhibits Chk1. This lethal mitosis is only induced in the absence of the p53 tumor suppressor protein, thereby providing a therapy targeted at >50% of tumors. We performed a clinical trial of the combination cisplatin + UCN-01, and demonstrated that the target was inhibited in tumor biopsies from patients. Current experiments are directed to understanding the mechanisms by which tumors can become resistant to this promising therapeutic drug combination. Novel checkpoint proteins have been implicated and novel pathways regulating cell cycle arrest identified. As patient tumors will likely present with a range of sensitivities, it is critical to determine in advance whether their tumors will be responsive to these strategies.

These studies are important in establishing that tumors can have defects (in this case p53) that render them sensitive to therapy. Tumors frequently have defects in other damage response genes/proteins that may also render them sensitive to specific agents. We have screened 60 cell lines for defects in another checkpoint pathway, Mre11/Rad50/Nbs1, and find several that are defective. These cells are being screened for drugs that may selectively kill tumors with this phenotype. We have identified other cell lines with defects in their ability to arrest when damaged. Current experiments are attempting to define these defects as a precursor to identifying novel drug targets.

Courses Taught:

Pharmacology 126: Cancer Biology (Course Director)

Grant Information:

Cell Death Induced by Anticancer Agents (NCI/NIH)
Mechanisms of Resistance to Cell Cycle Checkpoint Kinase Inhibitors (NCI/NIH)
Improved Therapy for Breast Cancer by Inhibiting Autophagy (DOD Breast cancer program)
Training Grant in Cancer Biology and Carcinogenesis (NCI/NIH)