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Alan Eastman, Ph.D.

Title(s):
Professor of Pharmacology & Toxicology

Department(s):
Pharmacology & Toxicology

Education:
Chester Beatty Research Institute, University of London, Ph.D. 1975

Programs:
Norris Cotton Cancer Center
Pharmacology and Toxicology Graduate Program
Program in Experimental and Molecular Medicine

Websites:
http://dms.dartmouth.edu/pharmtox/
http://cancer.dartmouth.edu/res/molecular_therapeutics.html
http://dms.dartmouth.edu/pemm/

Contact Information:

7936 Rubin 662, One Medical Center Drive
Dept. of Pharmacology and Toxicology
Geisel School of Medicine
Lebanon NH 03756

Office: Rubin 662
Phone: 603-653-9981
Fax: 603-653-9952
Email: alan.r.eastman@dartmouth.edu


Professional Interests:

Research Area:
Molecular Therapeutics of Cancer

Research projects in Dr. Eastmanís laboratory are focused on preclinical development of novel cancer chemotherapeutic strategies, using novel therapeutic agents often as modulators of the response of 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 second generation Chk1 inhibitor MK-8776 that is currently in Phase I clinical trials. Recently we observed that inhibition of Chk1 dramatically sensitizes cells to antimetabolites that inhibit 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 MK-8776 in combination with the antimetabolites hydroxyurea and 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 very variable response of tumors in culture, and are investigating the mechanisms of sensitivity so we can predict which tumors are most likely to respond in a clinical trial.
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 cell 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. Current experiments are directed to understanding the role of JNK and identifying other proteins that are essential for apoptosis. In particular, we are interested in 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. We are screening samples from leukemia patients for their sensitivity to these drug combinations as a prelude to performing a clinical trial.

Rotations and Thesis Projects:

1. Dissect the mechanisms that elicit hypersensitivity to Chk1 inhibitors in a subset of tumor cell lines as a precursor to predicting which tumors will respond to MK-8776
2. Dissect the signaling events that occur on a stalled replication fork and how Chk1 protects the fork from collapase
3. Determine how vinblastine activates JNK and define the downstream pathway by which JNK sensitizes cells to apoptosis.

Grant Information:

Mechanisms of Resistance to Cell Cycle Checkpoint Kinase Inhibitors (NCI/NIH)
Cell Death Induced by Anticancer Agents (NCCC)
Training Grant in Cancer Biology and Carcinogenesis (NCI/NIH)

Courses Taught:

Pharmacology 126: Cancer Biology (Course Director)

Biography:

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.


Selected Publications:

 

  • Levesque AA, Eastman A. p53-based cancer therapies: Is defective p53 the Achilles heel of the tumor? Carcinogenesis. 2007 Jan;28(1):13-20. (view details on MedLine)

  • Levesque AA, Fanous AA, Poh A, Eastman A. Defective p53 signaling in p53 wild-type tumors attenuates p21waf1 induction and cyclin B repression rendering them sensitive to Chk1 inhibitors that abrogate DNA damage-induced S and G2 arrest. Mol Cancer Ther. 2008 Feb;7(2):252-62. (view details on MedLine)

  • Zhang WH, Poh A, Fanous AA, Eastman A. DNA damage-induced S phase arrest in human breast cancer depends on Chk1, but G(2) arrest can occur independently of Chk1, Chk2 or MAPKAPK2. Cell Cycle. 2008 Mar 23;7(11). (view details on MedLine)

  • Garner KM, Pletnev AA, Eastman A. Corrected structure of mirin, a small-molecule inhibitor of the Mre11-Rad50-Nbs1 complex. Nat Chem Biol. 2009 Mar;5(3):129-30. (view details on MedLine)

  • Salerni BL, Bates DJ, Albershardt TC, Lowrey CH, Eastman A. Vinblastine induces acute, cell cycle phase-independent apoptosis in some leukemias and lymphomas and can induce acute apoptosis in others when Mcl-1 is suppressed. Mol Cancer Ther. 2010 Apr;9(4):791-802. (view details on MedLine)

  • Garner KM, Eastman A. Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel. BMC Cancer. 2011 May 27;11:206:1-13. (view details on MedLine)

  • Albershardt TC, Salerni BL, Soderquist RS, Bates DJ, Pletnev AA, Kisselev AF, Eastman A. Multiple BH3 mimetics antagonize antiapoptotic MCL1 protein by inducing the endoplasmic reticulum stress response and up-regulating BH3-only protein NOXA. J Biol Chem. 2011 Jul 15;286(28):24882-95 (view details on MedLine)

  • Bates DJ, Salerni BL, Lowrey CH, Eastman A. Vinblastine sensitizes leukemia cells to cyclin-dependent kinase inhibitors, inducing acute cell cycle phase-independent apoptosis. Cancer Biol Ther. 2011 Aug 15;12(4):314-25. (view details on MedLine)

  • Montano R, Chung I, Garner KM, Parry D, Eastman, A. Preclinical development of the novel Chk1 inhibitor SCH900776 in combination with DNA damaging agents and antimetabolites. Mol Cancer Ther. 2012 Feb;11(2):427-38 (view details on MedLine)

  • Chang LJ, Eastman A. Decreased translation of p21waf1 mRNA causes attenuated p53 signaling in some p53 wild-type tumors. Cell Cycle. 2012 May 1;11(9):1818-26 (view details on MedLine)