title: Optimizing combination therapies with existing and future CML drugs.
abstract: Small-molecule inhibitors imatinib, dasatinib and nilotinib have been developed to treat Chromic Myeloid Leukemia (CML). The existence of a triple-cross-resistant mutation, T315I, has been a challenging problem, which can be overcome by finding new inhibitors. Many new compounds active against T315I mutants are now at different stages of development. In this paper we develop an algorithm which can weigh different combination treatment protocols according to their cross-resistance properties, and find the protocols with the highest probability of treatment success. This algorithm also takes into account drug toxicity by minimizing the number of drugs used, and their concentration. Although our methodology is based on a stochastic model of CML microevolution, the algorithm itself does not require measurements of any parameters (such as mutation rates, or division/death rates of cells), and can be used by medical professionals without a mathematical background. For illustration, we apply this algorithm to the mutation data obtained in [1], [2].
authors.affiliation: Department of Mathematics, University of California Irvine, Irvine, California, United States of America.
authors.forename: Allen A
authors.initials: AA
authors.lastname: Katouli
authors.forename: Natalia L
authors.initials: NL
authors.lastname: Komarova
mesh_terms: D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000628:therapy; D008954:Models, Biological; D009154:Mutation; D011336:Probability; D013269:Stochastic Processes; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
references.citation: Curr Top Med Chem. 2008;8(10):905-21
references.pmid: 18673174
references.citation: J Theor Biol. 2006 Apr 7;239(3):351-66
references.pmid: 16194548
references.citation: Blood. 2007 Dec 1;110(12):4055-63
references.pmid: 17720881
references.citation: Math Biosci. 2007 Sep;209(1):292-315
references.pmid: 17306310
references.citation: J Math Biol. 2004 Apr;48(4):375-422
references.pmid: 15052504
references.citation: Math Biosci. 1992 Apr;109(1):85-97
references.pmid: 1591451
references.citation: J Biol Chem. 2008 Jun 27;283(26):18292-302
references.pmid: 18434310
references.citation: Adv Cancer Res. 2004;91:1-30
references.pmid: 15327887
references.citation: Blood. 2007 Jan 15;109(2):500-2
references.pmid: 16990603
references.citation: Leuk Lymphoma. 2004 Nov;45(11):2197-203
references.pmid: 15512807
references.citation: Nature. 2010 Jan 28;463(7280):501-6
references.pmid: 20072125
references.citation: Leuk Res. 2008 Jun;32(6):980-3
references.pmid: 18191450
references.citation: Nat Rev Drug Discov. 2004 Dec;3(12):1001-10
references.pmid: 15573099
references.citation: Cancer Res. 2007 Sep 1;67(17):7987-90
references.pmid: 17804707
references.citation: Lancet Oncol. 2007 Nov;8(11):1018-29
references.pmid: 17976612
references.citation: Chem Biol Drug Des. 2007 Sep;70(3):171-81
references.pmid: 17718712
references.citation: Adv Exp Med Biol. 1988;233:1-4
references.pmid: 3066148
references.citation: Curr Opin Hematol. 2004 Jan;11(1):35-43
references.pmid: 14676625
references.citation: Recent Results Cancer Res. 2010;184:199-214
references.pmid: 20072840
references.citation: J Clin Oncol. 2009 Jan 20;27(3):469-71
references.pmid: 19075254
references.citation: Mol Cancer Ther. 2003 Oct;2(10):1079-84
references.pmid: 14578473
references.citation: Nat Rev Cancer. 2007 May;7(5):345-56
references.pmid: 17457302
references.citation: Math Biosci. 1995 Dec;130(2):151-81
references.pmid: 8527869
references.citation: Blood. 2007 Jan 15;109(2):497-9
references.pmid: 16990591
references.citation: J Mol Med (Berl). 2008 Jan;86(1):17-27
references.pmid: 17661001
references.citation: Mutat Res. 1993 Aug;292(1):17-24
references.pmid: 7688093
references.citation: Cell Biol Toxicol. 1989 Dec;5(4):445-60
references.pmid: 2560673
references.citation: Blood. 2009 Dec 24;114(27):5426-35
references.pmid: 19880502
references.citation: Blood. 2006 Oct 1;108(7):2332-8
references.pmid: 16772610
references.citation: Exp Hematol. 2007 Apr;35(4 Suppl 1):144-54
references.pmid: 17379100
references.citation: Cancer Treat Rep. 1983 Oct;67(10):923-31
references.pmid: 6627236
references.citation: Theor Popul Biol. 2007 Dec;72(4):523-38
references.pmid: 17915274
references.citation: PLoS One. 2009;4(2):e4423
references.pmid: 19204794
references.citation: Cancer Treat Rep. 1985 Oct;69(10):1041-8
references.pmid: 2412691
references.citation: Cancer. 2003 May 1;97(9):2229-35
references.pmid: 12712476
references.citation: Risk Anal. 1988 Sep;8(3):383-92
references.pmid: 3201016
references.citation: Genetics. 1990 Jul;125(3):633-44
references.pmid: 2379824
references.citation: J Clin Oncol. 2003 Apr 15;21(8):1637-47
references.pmid: 12668652
references.citation: Lancet Oncol. 2003 Feb;4(2):75-85
references.pmid: 12573349
references.citation: J Natl Cancer Inst. 1994 Aug 3;86(15):1152-8
references.pmid: 8028036
references.citation: Hematology Am Soc Hematol Educ Program. 2003;:132-52
references.pmid: 14633780
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 8;105(14):5507-12
references.pmid: 18367669
references.citation: Math Biosci. 2000 Mar;164(1):17-38
references.pmid: 10704636
references.citation: J Natl Cancer Inst. 1981 Jun;66(6):1037-52
references.pmid: 6941039
references.citation: Blood. 2004 Jun 1;103(11):4010-22
references.pmid: 14982876
references.citation: Blood. 1987 Oct;70(4):905-8
references.pmid: 3477299
references.citation: Blood. 2008 Apr 15;111(8):4355-64
references.pmid: 18268096
references.citation: Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9714-9
references.pmid: 15980154
references.citation: Bull Math Biol. 2005 May;67(3):563-611
references.pmid: 15820743
references.citation: PLoS One. 2007 Oct 03;2(10):e990
references.pmid: 17912367
references.citation: Cancer Cell. 2002 Aug;2(2):99-102
references.pmid: 12204529
references.citation: Cancer Treat Rep. 1979 Nov-Dec;63(11-12):1727-33
references.pmid: 526911
references.citation: Blood. 2007 Oct 1;110(7):2242-9
references.pmid: 17496200
references.citation: Int J Hematol. 2004 Jun;79(5):420-33
references.pmid: 15239391
references.citation: N Engl J Med. 2006 Jun 15;354(24):2531-41
references.pmid: 16775234
references.citation: Clin Cancer Res. 2009 Nov 1;15(21):6694-701
references.pmid: 19825950
references.citation: Leuk Lymphoma. 2008 Apr;49(4):615-9
references.pmid: 18398720
references.citation: Mol Cancer Ther. 2003 Mar;2(3):225-6
references.pmid: 12657716
references.citation: Math Biosci. 1991 Feb;103(1):115-38
references.pmid: 1804437
references.citation: Blood. 2007 Mar 1;109(5):2112-20
references.pmid: 17068153
references.citation: N Engl J Med. 2006 Jun 15;354(24):2542-51
references.pmid: 16775235
references.citation: Leukemia. 2002 Aug;16(8):1402-11
references.pmid: 12145676
references.citation: Bull Math Biol. 1994 Mar;56(2):337-57
references.pmid: 8186758
references.citation: Bull Math Biol. 1986;48(3-4):279-92
references.pmid: 3828558
references.citation: Curr Pharm Des. 2006;12(3):261-71
references.pmid: 16454743