14735 1,6 6 6 1,6 6 1,6 6 1 1 VX-680/MK-0457 1,2 6 2,6 1,2,6 1,6 1,6 1,6 1,2,6 1,2,4 1,2,4,5 1,2,4,5 1 1,2 1,4 PHA-680632 1 1 1 1 1 1 PHA-739358 1,5,6,7 1,4 1,6 1,6 1,5,6 6,7 1 1,5,6,7 1 1 1,2,4 1,4 CYC-116 1 1 1 1 SNS-314 1 1 1 1,2 AMG-900 1 1 1 1 1 1 1 1 1 1 1 1 1 VE-465 1,2 AS-1404 DMXAA 1 1 1,2 1,2 1,2 1,2 AS-703569/R-763 1 1 1 1 1 1 1 1,4 1,4 1 1 1 Single-drug efficacy, Preclinical�? 2 Combination efficacy, Preclinical�? Expert Opin Drug Discov. Author manuscript, available in PMC 2012 March 1. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript Green et al. Page 26 3 No/minimal efficacy, Preclinical�? 4 Single-drug efficacy, Phase I�? 5 Combination efficacy, Phase I�? 6 No/minimal efficacy, Phase I�? 7 Single-drug efficacy, Phase II�? Where data available/reported, �?Defined as objective response or partial/complete response, �?Defined as stable disease or no objective response Expert Opin Drug Discov.
Author egfr activity manuscript, available in PMC 2012 March 1. Development of an Effective Therapy for CML David W. Woessner, BAa, Carol S. Lim, PhDb, and Michael W. Deininger, MD, PhDc aGraduate Research Assistant, Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah bAssociate Professor, Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, University of Utah cChief of the Division of Hematology and Hematologic Malignancies, M.M. Wintrobe Professor of Medicine, University of Utah Huntsman Cancer Institute Abstract Targeted small molecule drugs have revolutionized treatment of chronic myeloid leukemia over the last decade.
These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with ATP-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today , and discuss treatment modalities which are under development. Recent advances have illuminated the complexity of CML, especially in within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL, since primitive human CML stem cells are not dependent on BCR-ABL.
Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML. Keywords chronic myeloid leukemia, BCR-ABL, tyrosine kinase inhibitors, drug resistance, synthetic lethality Introduction Chronic myeloid leukemia is one of most extensively studied cancers, and a highly treatable disease with overall survival greater than 90% with current therapies.1-3 CML results from a reciprocal translocation between chromosomes 9 and 22 , which is thought to occur in a hematopoietic stem cell. The derivative chromosome 22, originally believed to be a shortened 22, is commonly referred to as Philadelphia chromosome.
As a result of the translocation, fusions are formed between the breakpoint cluster region gene on chromosome 22 and the Abelson oncogene Corresponding author: M.W. Deininger, MD, PhD 2000 Circle of Hope, Room 4280 Salt Lake City, UT 84112-5550 Phone: 801/581-6363 Fax 801/585-0900 Michael.Deiningerhci.utah. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors
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