Alan Eastman, PhD
Professor of Molecular and Systems Biology
Molecular and Systems Biology
Chester Beatty Research Institute, University of London, Ph.D. 1975
Norris Cotton Cancer Center
Program in Experimental and Molecular Medicine
7936 Rubin 662, One Medical Center Drive
Norris Cotton Cancer Center
Geisel School of Medicine
Lebanon NH 03756
Office: Rubin 662
Molecular Therapeutics of Cancer Research projects in Dr. Eastman’s laboratory are focused on preclinical development of novel cancer chemotherapeutic strategies, using novel therapeutic agents often as modulators of the response to established drugs. Cancer cell lines exhibit very variable responses to these strategies, so it is predicted that tumors will also have variable response such that some will be highly sensitive. The goal therefore is to define the mechanisms of sensitivity and develop clinical trials targeted to patients with sensitive tumors.
Current 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 and then through a lethal mitosis. We previously performed a clinical trial with the Chk1 inhibitor UCN-01 in combination with cisplatin but the drug exhibited unfavorable pharmacokinetics. We are now focused on a third generation Chk1 inhibitor SRA737 that has just completed Phase I clinical trials. Recently we observed that inhibition of Chk1 dramatically sensitizes cells to the antimetabolite gemcitabine that inhibits DNA synthesis. Stalled replication forks are dependent on Chk1 for stability such that inhibition of Chk1 results in fork collapse, DNA double-strand breaks and cell death.
Current experiments are directed to further preclinical development of SRA737 in combination with the antimetabolite gemcitabine with the goal of performing a clinical trial of these combinations. Critical to these clinical trials will be analysis of tumor biopsies to confirm cell cycle perturbation and inhibition of Chk1 at doses that are tolerated by the patient. We have also observed that a small subset of tumors are very sensitive to Chk1 inhibitors as single agents suggesting a potential chemical synthetic lethal interaction. Current experiments are directed to determining the underlying mechanisms so we can predict which patients might be most susceptible to this therapy.
Other studies are directed toward enhancing apoptotic cell death of tumors. 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 cells die within 4 h. Various leukemia 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. We are interested in drug combinations with small molecule inhibitors of Bcl-2 proteins, and have shown that many activate the endoplasmic reticulum stress response leading to up-regulation of pro-apoptotic Noxa. These experiments have catalyzed a Phase I clinical trial with a novel microtubule-targeting drug, BNC105P, that like vinblastine, also induces NOXA.
Mechanisms of Sensitivity to Cell Cycle Checkpoint Kinase Inhibitors (NCI/NIH)
Enhancing the Efficacy of BCL2 Inhibitors in Chronic Lymphocytic Leukemia (Leukemia and Lymphoma Society)
PEMM102, Scientific Basis of Disease (Lecturer)
PEMM 126: Cancer Biology (former Course Director)
PEMM 133: Pharmacology of Drug Development (Course Director)
Dr. Eastman received his B. Tech. from Brunel University, 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 where is has been a Professor since 1992.
Comparison of the different mechanisms of cytotoxicity induced by checkpoint kinase I inhibitors when used as single agents or in combination with DNA damage.
Inhibition of checkpoint kinase 1 following gemcitabine-mediated S phase arrest results in CDC7- and CDK2-dependent replication catastrophe.
Synthetic nat- or ent-steroids in as few as five chemical steps from epichlorohydrin.
Cell cycle perturbation induced by gemcitabine in human tumor cells in cell culture, xenografts and bladder cancer patients: implications for clinical trial designs combining gemcitabine with a Chk1 inhibitor.
Stereoselective Synthesis and Biological Evaluation of C1-Epimeric and Desmethyl Monomeric Nuphar Analogues.
Microtubule destabilising agents: far more than just antimitotic anticancer drugs.
Improving anticancer drug development begins with cell culture: misinformation perpetrated by the misuse of cytotoxicity assays.
BCL2 Inhibitors as Anticancer Drugs: A Plethora of Misleading BH3 Mimetics.
Critical reanalysis of the methods that discriminate the activity of CDK2 from CDK1.
Rapid induction of apoptosis in chronic lymphocytic leukemia cells by the microtubule disrupting agent BNC105.