William Plunkett, Ph.D.
Department of Experimental Therapeutics, Division of Cancer Medicine
About Dr. Plunkett
My major research pursuits are related to development of novel therapeutics based on knowledge of cellular responses to DNA damage, and elucidating the mechanisms of drug action, particularly of nucleoside analogs. Investigations by my group demonstrated multiple mechanism of action for both fludarabine and gemcitabine, as well as the mechanisms of other nucleosides. I have enjoyed sustained and dedicated collaborations with his colleagues involved with clinical research, interactions that have resulted in advances in clinical treatments that induce remissions more effectively and are maintained them longer than previously possible in leukemias. I was the recipient of the Service to Mankind Award from the Leukemia Society of America in 1989, the Faculty Achievement Award in Clinical Research in 1996, and the 1 st Potu N. Rao award for Excellence in Basic Research in 2006, and the Waun Ki Hong Achievement Award for Team Research - CLL in 2011. I was elected a Fellow of the American Association for the Advancement of Science in 2012. I was the 2013 recipient of the Charles A. LeMaistre, M.D. Outstanding Acheivement Award in Cancer and received the John Mendelsohn Lifetime Scientific Achievement Award in 2016. Under the title of Associate Vice President, Research Integrity, I have assumed the responsibilities of the Institutional Research Integrity Officer since 2007.
I am particularly interested in education of the next generation of scientists. He has been a member of the University of Texas Graduate School of Biomedical Sciences at Houston since 1976. His activities in graduate education have been recognized by his election to President of the Faculty of The Graduate School of Biomedical Sciences, and the award of the 1 st Sowell-Huggins Professorship in Cancer Research in that school. I was the recipient of the Distinguished Research Faculty Mentor Award in 2013.
Present Title & Affiliation
Primary Appointment
Professor, Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Dual/Joint/Adjunct Appointment
Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
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.
Education & Training
Degree-Granting Education
| 1970 | University of Massachusetts, Amherst, MA, USA, PHD, Biochemistry |
| 1965 | Springfield College, Springfield, MA, USA, BS, Biology, Chemistry |
Postgraduate Training
| 1970-1971 | Postdoctoral Fellow, Therapeutic Research, University of Pennsylvania, Philadelphia, PA |
Experience & Service
Administrative Appointments/Responsibilities
Director, Therapeutics and Pharmacology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, 2017 - Present
Deputy Department Chair, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, 2008 - Present
Associate Vice President, Research Integrity, The University of Texas MD Anderson Cancer Center, Houston, TX, 2008 - Present
Institutional Research Integrity Officer, The University of Texas MD Anderson Cancer Center, Houston, TX, 2007 - Present
Other Appointments/Responsibilities
Chairman, Scientific Advisory Board, Chronic Lymphocytic Leukemia Global Research Foundation, Houston, 2004 - Present
Research Associate, University of Colorado Medical Center, Denver, CO, 1972 - 1975
Endowed Positions
Barnts Family Distinguished Chair for Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, 1999 - Present
Hubert L. and Olive Stringer Professorship in Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, 1989 - 1999
Honors & Awards
| 2018 | Dr. John S. McMurray Lifetime TAP Achievement Award, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences |
| 2016 | John Mendelsohn Lifetime Scientific Achievement Award, Division of Cancer Medicine |
| 2013 | Distinguished Research Faculty Mentor Award, M.D. Anderson Cancer Center |
| 2013 | Charles A. LeMaistre M.D. Outstanding Achievement Award in Cancer, M.D. Anderson Cancer Center |
| 2012 | Co-Leader of CLL Moon Shot Program, M.D.Anderson Cancer Center Moon Shot Program |
| 2012 | Fellow, American Association for the Advancement of Science, American Association for the Advancement of Science |
| 2011 | Waun Ki Hong Achievement Award for Team Science - CLL, Division of Cancer Medicine |
| 2006 | 1st Potu N. Rao Award for Outstanding Achievement in Basic Science, The University of Texas MD Anderson Cancer Center, Division of Cancer Medicine |
| 2001 | 1st Sowell-Huggins Professorship in Cancer Research, University of Texas Graduate School of Biomedical Sciences, Houston |
| 1999 | Barnts Family Distinguished Chair for Cancer Research, The University of Texas M. D. Anderson Cancer Center |
| 1996 | Faculty Achievement Award, Clinical Research, The University of Texas M. D. Anderson Cancer Center |
| 1993 | Chairman, Gordon Research Conference on Purines, Pyrimidines & Related Substances |
| 1991 | Outstanding Faculty Award, University of Texas Graduate School of Biomedical Sciences at Houston |
| 1989 | Service to Mankind Award, Leukemia Society of America, Gulf Coast Chapter |
| 1989 | Hubert L. and Olive Stringer Professorship in Medical Oncology, The University of Texas M. D. Anderson Cancer Center |
| 1988 | President of the Graduate Faculty, University of Texas Graduate School of Biomedical Sciences |
Professional Memberships
Selected Publications
Peer-Reviewed Articles
- Chen R, Chen Y, Xiong P, Zheleva D, Blake D, Keating MJ, Wierda WG, Plunkett W. Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells. Leukemia 36(6):1596-1608, 2022. e-Pub 2022. PMID: 35383271.
- Lai TH, Mitchell S, Wu PJ, Orwick S, Liu C, Ravikrishnan J, Woyach J, Mims A, Plunkett W, Puduvalli VK, Byrd JC, Lapalombella R, Sampath D. HSP90 inhibition depletes DNA repair proteins to sensitize acute myelogenous leukemia to nucleoside analog chemotherapeutics. Leuk Lymphoma 60(9):1-4, 2019. e-Pub 2019. PMID: 30773117.
- Chen R, Zhu M, Chaudhari RR, Robles O, Chen Y, Skillern W, Qin Q, Wierda WG, Zhang S, Hull KG, Romo D, Plunkett W. Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia. Leukemia 33(7):1663-1674, 2019. e-Pub 2019. PMID: 30700841.
- Kantarjian HM, Jabbour EJ, Garcia-Manero G, Kadia TM, DiNardo CD, Daver NG, Borthakur G, Jain N, Waukau JB, Kwari MI, Ravandi F, Anderson BD, Iizuka K, Jin C, Zhang C, Plunkett W. Phase 1/2 study of DFP-10917 administered by continuous intravenous infusion in patients with recurrent or refractory acute myeloid leukemia. Cancer 125(10):1665-1673, 2019. e-Pub 2019. PMID: 30668890.
- Jain N, Keating M, Thompson P, Ferrajoli A, Burger J, Borthakur G, Takahashi K, Estrov Z, Fowler N, Kadia T, Konopleva M, Alvarado Y, Yilmaz M, DiNardo C, Bose P, Ohanian M, Pemmaraju N, Jabbour E, Sasaki K, Kanagal-Shamanna R, Patel K, Jorgensen J, Garg N, Wang X, Sondermann K, Cruz N, Wei C, Ayala A, Plunkett W, Kantarjian H, Gandhi V, Wierda W. Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med 380(22):2095-2103, 2019. PMID: 31141631.
- Elsayed AH, Cao X, Crews KR, Gandhi V, Plunkett W, Rubnitz JE, Ribeiro RC, Pounds SB, Lamba JK. Comprehensive Ara-C SNP score predicts leukemic cell intracellular ara-CTP levels in pediatric acute myeloid leukemia patients. Pharmacogenomics 19(14):1101-1110, 2018. e-Pub 2018. PMID: 30088438.
- Short NJ, Kantarjian H, Ravandi F, Huang X, Xiao L, Garcia-Manero G, Plunkett W, Gandhi V, Sasaki K, Pemmaraju N, Daver NG, Borthakur G, Jain N, Konopleva M, Estrov Z, Kadia TM, Wierda WG, DiNardo CD, Brandt M, O'Brien SM, Cortes JE, Jabbour E. A phase I/II randomized trial of clofarabine or fludarabine added to idarubicin and cytarabine for adults with relapsed or refractory acute myeloid leukemia. Leuk Lymphoma 59(4):1-8, 2018. e-Pub 2017. PMID: 28718728.
- Liu X, Jiang Y, Nowak B, Qiang B, Cheng N, Chen Y, Plunkett W. Targeting BRCA1/2 deficient ovarian cancer with CNDAC-based drug combinations. Cancer Chemother Pharmacol 81(2):255-267, 2018. e-Pub 2017. PMID: 29189915.
- Abo MA, Sasanuma H, Liu X, Rajapakse VN, Huang SY, Kiselev E, Takeda S, Plunkett W, Pommier Y. TDP1 is Critical for the Repair of DNA Breaks Induced by Sapacitabine, a Nucleoside also Targeting ATM- and BRCA-Deficient Tumors. Mol Cancer Ther 16(11):2543-2551, 2017. e-Pub 2017. PMID: 28802254.
- Jabbour E, Short NJ, Ravandi F, Huang X, Xiao L, Garcia-Manero G, Plunkett W, Gandhi V, Sasaki K, Pemmaraju N, Daver NG, Borthakur G, Jain N, Konopleva M, Estrov Z, Kadia TM, Wierda WG, DiNardo CD, Brandt M, O'Brien SM, Cortes JE, Kantarjian H. A randomized phase 2 study of idarubicin and cytarabine with clofarabine or fludarabine in patients with newly diagnosed acute myeloid leukemia. Cancer 123(22):4430-4439, 2017. e-Pub 2017. PMID: 28708931.
- Van Roosbroeck K, Fanini F, Setoyama T, Ivan C, Rodriguez-Aguayo C, Vannini I, Redis RS, D'Abundo L, Zhang X, Xiao L, Nicoloso MS, Rossi S, Gonzalez-Villasana V, Rupaimoole R, Ferracin M, Morabito F, Neri A, Ruvolo PP, Ruvolo VR, Pecot CV, Amadori D, Abruzzo L, Calin S, Wang X, You MJ, Ferrajoli A, Orlowski R, Plunkett W, Davuluri RV, Berindan-Neagoe I, Negrini M, Wistuba II, Kantarjian HM, Sood AK, Lopez-Berestein G, Keating MJ, Fabbri M, Calin GA. Combining anti-miR-155 with chemotherapy for the treatment of lung cancers. Clin Cancer Res 23(11):2891-2904, 2017. e-Pub 2016. PMID: 27903673.
- Bottoni A, Rizzotto L, Lai TH, Liu C, Smith LL, Mantel R, Reiff S, El-Gamal D, Larkin K, Johnson AJ, Lapalombella R, Lehman A, Plunkett W, Byrd JC, Blachly JS, Woyach JA, Sampath D. Targeting BTK through microRNA in chronic lymphocytic leukemia. Blood 128(26):3101-3112, 2016. e-Pub 2016. PMID: 27756747.
- Liu X, Jiang Y, Nowak B, Hargis S, Plunkett W. Mechanism-Based Drug Combinations with the DNA Strand-Breaking Nucleoside Analog CNDAC. Mol Cancer Ther 15(10):2302-2313, 2016. e-Pub 2016. PMID: 27474148.
- Jiang Y, Chen HC, Su X, Thompson PA, Liu X, Do KA, Wierda W, Keating MJ, Plunkett W. ATM function and its relationship with ATM gene mutations in chronic lymphocytic leukemia with the recurrent deletion (11q22.3-23.2). Blood Cancer J 6(9):e465, 2016. e-Pub 2016. PMID: 27588518.
- Lai TH, Ewald B, Zecevic A, Liu C, Sulda M, Papaioannou D, Garzon R, Blachly JS, Plunkett W, Sampath D. HDAC inhibition induces microRNA-182 which targets Rad51 and impairs HR repair to sensitize cells to sapacitabine in acute myelogenous leukemia. Clin Cancer Res 22(14):3537-49, 2016. e-Pub 2016. PMID: 26858310.
- Jouanneau M, McClary B, Reyes JC, Chen R, Chen Y, Plunkett W, Cheng X, Milinichik AZ, Albone EF, Liu JO, Romo D. Derivatization of agelastatin A leading to bioactive analogs and a trifunctional probe. Bioorg Med Chem Lett 26(8):2092-7, 2016. e-Pub 2016. PMID: 26951751.
- Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, Plunkett W, Smith SC, Kantarjian HM, Freireich EJ, Keating MJ. Fludarabine, cyclophosphamide and rituximab achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127(3):303-9, 2016. e-Pub 2015. PMID: 26492934.
- Plunkett W. Arginine addiction in AML. Blood 125(26):3971-2, 2015. PMID: 26113532.
- Yeh YY, Chen R, Hessler J, Mahoney E, Lehman AM, Heerema NA, Grever MR, Plunkett W, Byrd JC, Johnson AJ. Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia. Oncotarget 6(5):2667-79, 2015. PMID: 25596730.
- Tam C, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, Do K-A, Cortes J, Khouri I, Kantarjian H Lerner S, Keating M. Life after FCR: outcomes of patients with chonic lymphocytic leukemia who progress after frontline treatment with fludarabine, cyclophosphamide and rituximab. Blood 124(20):3059-3064, 2014.
- Tam CS, O'Brien S, Plunkett W, Wierda W, Ferrajoli A, Wang X, Do KA, Cortes J, Khouri I, Kantarjian H, Lerner S, Keating MJ. Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 124(20):3059-64, 2014. e-Pub 2014. PMID: 25281606.
- Tsimberidou AM, Keating MJ, Jabbour EJ, Ravandi-Kashani F, O'Brien S, Estey E, Bekele N, Plunkett W, Kantarjian H, Borthakur G. A Phase I Study of Fludarabine, Cytarabine, and Oxaliplatin Therapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia. Clin Lymphoma Myeloma Leuk 14(5):395-400.e1, 2014. e-Pub 2014. PMID: 24637132.
- Faderl S, Balakrishnan K, Thomas DA, Ravandi F, Borthakur G, Burger J, Ferrajoli A, Cortes J, O'Brien S, Kadia T, Feliu J, Plunkett W, Gandhi V, Kantarjian HM. Phase I and Extension Study of Clofarabine Plus Cyclophosphamide in Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Clin Lymphoma Myeloma Leuk 14(3):231-8, 2014. e-Pub 2013. PMID: 24440659.
- Yeh Y-Y, Chen R, Hessler J, Mahoney E, Lehman AM, Heerema NA, Grever MR, Plunkett W, Byrd JC, Johnson AJ. Up-regulation of CDK9 kinase activity and Mcl-1 stability contribures to the acquired resistance to cyclin-dependent kinase inhitors in leukemia. Oncotarget, 2014.
- Koay EJ, Truty MJ, Cristini V, Thomas RM, Chen R, Chatterjee D, Kang Y, Bhosale PR, Tamm EP, Crane CH, Javle M, Katz MH, Gottumukkala VN, Rozner MA, Shen H, Lee JE, Wang H, Chen Y, Plunkett W, Abbruzzese JL, Wolff RA, Varadhachary GR, Ferrari M, Fleming J. Transport properties of pancreatic cancer describe gemcitabine delivery and response. J Clin Invest 124(4):1525-36, 2014. e-Pub 2014. PMID: 24614108.
- Gandhi V, Plunkett W, Cortes JE. Omacetaxine: A Protein Translation Inhibitor for Treatment of Chronic Myelogenous Leukemia. Clin Cancer Res 20(7):1735-40, 2014. e-Pub 2014. PMID: 24501394.
Grant & Contract Support
| Title: | Chronic Lymphocytic Leukemia Research Consortium |
| Funding Source: | NIH |
| Role: | Project Leader |
| Title: | Biochemical Basis for Therapeutic Activity |
| Funding Source: | NIH |
| Role: | Principal Investigator |
| Title: | Creating Novel Translation Inhibitors to Target Pro-Survival Oncoproteins |
| Funding Source: | Cancer Prevention & Research Institute of Texas (CPRIT) |
| Role: | Co-Principal Investigator |
| Title: | Strategies to target the pathophysiology of CLL |
| Funding Source: | CLL Global Research Foundation |
| Role: | Principal Investigator |
| Title: | CLL moon shot - ibrutinib |
| Funding Source: | MDACC Moon Shot Program |
| Role: | Principal Investigator |
| Title: | Cancer Center Support (Core) Grant |
| Funding Source: | NIH/NCI |
| Role: | Program Leader |
| Title: | Single agent and mechanism-based combinations of CYC065 in chronic lymphocytic leukemia |
| Funding Source: | Cyclacel |
| Role: | Principal Investigator |
| Title: | SPORE University of Texas MD Anderson Cancer Center - Career Development Program (CDP) |
| Funding Source: | NIH/NCI |
| Role: | Co-Leader, Career Development Program |
| Title: | SPORE - University of Texas MD Anderson Cancer Center - Development Research Program (DRP) |
| Funding Source: | NIH/NCI |
| Role: | Co-Leader, Development Research Program |
| Title: | Strategies to understand and target Bcl-2 Family Proteins in CLL |
| Funding Source: | CLL Global Research Foundation |
| Role: | Principal Investigator |
| Title: | Evaluation of Biomarkers of CYC065 pharmacodynamics in the Phase 1 trial |
| Funding Source: | Cyclacel Pharmaceuticals |
| Role: | Principal Investigator |
| Title: | Project 3: Targeting CLL Pathophysiology |
| Funding Source: | The University of Texas MD Anderson Cancer Center, Moon Shots Program |
| Role: | Principal Investigator-MDACC |
| Title: | Apoptotic Correlative Analysis of Fadraciclib (MD Anderson CLL Subjects only) in a Phase ½ Trial |
| Funding Source: | Cyclacel Pharmaceuticals |
| Role: | Principal Investigator |
| Title: | Project 2: Curative Targeted Therapy of CLL |
| Funding Source: | The University of Texas MD Anderson Cancer Center, Moon Shots Program |
| Role: | Principal Investigator-MDACC |