Geoffrey Shapiro, MD, PhD
Clinical Director, Center for DNA Damage and Repair
Associate Professor of Medicine, Harvard Medical School
Center/ProgramEarly Drug Development Center
Office phone: 617-632-4942
Preferred contact method: office phone
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Developmental therapeutics, Phase 1 clinical trials, Solid tumors
Area of ResearchCell-Cycle-Related Targets for Antitumor Drug Development
Dana-Farber Cancer Institute
450 Brookline Avenue
Boston, MA 02215
BiographyDr. Shapiro received his PhD in 1987 and his MD in 1988 from Cornell University, followed by postgraduate training in internal medicine at Beth Israel Hospital, Boston, where he served as chief medical resident.
He completed a fellowship in medical oncology at Dana-Farber Cancer Institute, during which he investigated the role of cell-cycle-related proteins in lung cancer. He joined the Dana-Farber faculty in 1994.
ResearchCell-Cycle-Related Targets for Antitumor Drug Development
Cyclin-dependent kinases (cdks) are critical regulators of cell cycle progression and RNA transcription. A variety of genetic and epigenetic events cause universal overactivity of the cdks in human cancer, and their inhibition frequently leads to cell cycle arrest, depletion of transcripts with short half-lives, and apoptosis. Using siRNA technology, we have recently shown that depletion of both cell cycle and transcriptional cdk activities induces apoptosis in transformed cells. A primary focus of our laboratory is the characterization of cdk inhibitor drugs that mimic these effects.
We are investigating both pan-cdk inhibitors, including flavopiridol, as well as inhibitors more selective for cdks 1 and 2. These compounds induce p53-independent apoptosis in transformed cells and modulate phosphorylation of Rb, p27(Kip1) and E2F-1. We are designing pharmacodynamic assays to assess their biologic effects in tumors as early-phase trials begin.
In addition, we have found that cdk inhibition is synergistic with DNA damage in inducing cancer cell death. Cdk inhibition following cell-cycle disruption by chemotherapy drugs may alter the activity of the transcription factor E2F-1, thereby activating apoptosis pathways. Clinical trials exploiting this biology are under way, including a combination of gemcitabine and flavopiridol.
We have also investigated the geldanamaycins, small-molecule inhibitors of hsp90, a cellular chaperone required for the proper folding of multiple kinases, including cdk4. We have demonstrated the depletion of cdk4 in lung cancer cell lines treated with geldanamycins, an effect that induces retinoblastoma-dependent G1 arrest. During the course of this work, we discovered that lung cancer cell lines harboring kinase domain mutations of epidermal growth factor receptor (EGFR) were the most sensitive to hsp90 inhibition, and we have defined mutant EGFR as a novel hsp90 client protein that is rapidly depleted following geldanamycin treatment. Hsp90 inhibition may represent a promising strategy for EGFR mutant lung cancers that have acquired resistance to standard tyrosine kinase inhibitors.
Another active area of investigation is in regulation of Aurora kinases, mitotic kinases that are frequently dysregulated in cancer. We have shown that the Aurora kinase inhibitor VX-680 induces endoreduplication and eventual cell death in cancer cells. This effect is markedly enhanced in cells with a compromised p53-p21-dependent post-mitotic checkpoint. Transformed cells lacking the post-mitotic checkpoint are most likely to die in response to VX-680, while cells with intact checkpoint function are more likely to arrest. This work represents a first step toward defining tumors that are more likely to respond to Aurora kinase inhibition.
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