Part II: Imatinib Resistance and Other Diseases Targeted by Imatinib
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Imatinib (Gleevec) has become a paradigm for targeted cancer therapies. The first part of this lecture will describe the clinical features and the molecular pathogenesis of the disease for which imatinib was developed, chronic myeloid leukemia (CML). This overview will trace the history of the identification of the target of imatinib, BCR-ABL. The preclinical development of the BCR-ABL kinase inhibitor, imatinib and highly successful clinical trials of this agent for patients with CML will be reviewed along with the most up-to-date follow-up on these studies.
Although the majority of patients with CML respond well to imatinib, a minority of patients have relapsed. This part of the lecture will cover what has been learned about mechanisms of relapse and how this information has been translated into new therapies for patients with imatinib resistance. Although imatinib is a relatively specific inhibitor of the ABL kinase, a couple of other kinases, KIT and the platelet derived growth factor receptor are also inhibited by imatinib. This use of this information to treat successfully treat other malignant diseases driven by these kinases will be reviewed.
The lessons learned from the clinical trials of imatinib will be reviewed in this section. This will include examples of where imatinib has or has not worked, analysis of target expression versus activation and a discussion of how the success of imatinib can be translated to other malignancies. The section concludes with what this means for research to control or cure cancer in the coming decades.
Dr. Brian Druker is an Investigator of the Howard Hughes Medical Institute, Director of the Oregon Health & Science University (OHSU) Cancer Institute, and JELD-WEN Chair of Leukemia Research at OHSU. Upon graduating from the University of California, San Diego School of Medicine in 1981, Dr. Druker completed his internship and residency in internal medicine at Barnes Hospital, Washington School of Medicine in St. Louis, Missouri. He then trained in oncology at Harvard's Dana-Farber Cancer Institute.
Dr. Druker then returned to the lab to begin his research career studying the regulation of the growth of cancer cells and the practical application to cancer therapies. His work was instrumental in the development of Gleevec (imatinib), a drug that targets the molecular defect in chronic myeloid leukemia (CML). After completing a series of preclinical studies, Dr. Druker spearheaded the highly successful clinical trials of imatinib for CML. Imatinib is currently FDA approved for CML and gastrointestinal stromal tumors (GIST). His role in the development of imatinib and its application in the clinic have resulted in numerous awards for Dr. Druker, including Warren Alpert Prize from Harvard Medical School, the American Society of Hematology’s Dameshek Prize, the American Cancer Society’s Medal of Honor, the Kettering Prize from General Motors Cancer Research Foundation, and the David A. Karnofsky Award from the American Society of Clinical Oncology. He was elected to the Institute of Medicine of the National Academies in 2003, the American Association of Physicians in 2006, and the National Academy of Sciences in 2007.
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Druker BJ. Imatinib as a paradigm of targeted therapies. In: Vande Woude GF, Klein G, eds. Advances in Cancer Research. San Diego: Elsevier Academic Press, 2004, vol 91:1-30.
Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000 Nov 15;96(10):3343-56.
O'Hare T, Corbin AS, Druker BJ. Targeted CML therapy: controlling drug resistance, seeking cure. Curr Opin Genet Dev 16:92-99, 2006.
Rubin BP, Heinrich MC, Corless CL.Gastrointestinal stromal tumour. Lancet. 2007 May 19;369(9574):1731-41.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J, Lydon NB. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nature Medicine 2:561-566, 1996.
Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, Deininger MWN, Silver RT, Goldman JM, Stone RM, Cervantes F, Hochhaus A, Powell BL, Gabrilove JL, Rousselot P, Reiffers J, Cornelissen JJ, Hughes T, Agis H, Fischer T, Verhoef G, Shepherd J, Saglio G, Gratwohl A, Nielsen JL, Radich JP, Simonsson B, Taylor K, Baccarani M, So C, Letvak L, Larson R, for the IRIS Investigators. Five-year follow- up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355:2408-2417, 2006.
Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003.
Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, Blackwood-Chirchir MA, Iyer V, Chen TT, Huang F, Decillis AP, Sawyers CL. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006 Jun 15;354(24):2531-41.
Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51.