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Faculty Profile Last Modified Time: 02:26:23 PM Thu, 16 Apr 2020   Contact Information William Plunkett Associated Profiles  Director, Therapeutics and Pharmacology Program, Professor, Experimental Therapeutics, UT MD Anderson Cancer Center   MDA 3SCR3.4121, Room No.: Unit 1950    wplunket@mdanderson.org     713-792-3335    Web Link    Cytarabine, Gemcitabine, B-Cell Chronic Lymphocytic Leukemia, Arabinofuranosylcytosine Triphosphate, Leukemia, Vidarabine, Nucleosides, DNA    Associated Profiles Research and Expertise Affiliations Appointments  Research and Expertise Research Interests   My research program melds discovery of mechanisms of drug action and an understanding of cancer cell biology to generate experimental strategies that improve therapeutic efficacy and aim to overcome potential means of tumor resistance. I have concentrated efforts on translational investigations with colleagues in the Leukemia Department. Inhibition of DNA Repair. We have discovered that the mechanism of action of a nucleoside analogue now in early phase clinical trials, sapacitabine, is to generate a single strand break which is difficult to repair, and results in formation of a double-strand DNA break upon subsequent DNA replication. A homologous recombination mechanism is required to repair such lesions. Based on this information, we have initiated investigations of sapacitabine in tumors that lack the homologous recombination repair functions. Cellular context as a basis for specificity. The survival of CLL is dependent upon the sustained expression of anti-apoptotic proteins, some of which (Mcl-1, XIAP) have intrinsic signals for rapid turnover of transcripts and protein. We reasoned that transient inhibition of transcription would decrease these proteins to the point of initiation of apoptosis, an irreversible process. Transcription requires phosphorylation of RNA polymerase II by cyclin-dependent kinase 9. Our investigations in primary CLL samples demonstrated that Cdk9 is potently inhibited by several small molecules, with a resulting decrease in RNA polymerase activity, transcript generation and decreased survival protein levels, that were associated with apoptosis induction within 8 hr. This has provided rationale for the development of this class of novel therapeutics in hematological malignancies.  Publications/Creative Works Click here to search for this faculty member's publications on PubMed.  Affiliations  Research Consortia John S. Dunn GCC for Chemical Genomics  Appointments Title Department / School Institution Professor Experimental Therapeutics MD Anderson Cancer Center Director Therapeutics and Pharmacology Program MD Anderson Cancer Center

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