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      A Phase 1 Trial Dose Escalation Study of Tipifarnib on a Week-On, Week-Off Schedule in Relapsed, Refractory or High-Risk Myeloid Leukemia

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          Abstract

          Inhibition of farnesyltransferase (FT) activity has been associated with in vitro and in vivo anti-leukemia activity. We report the results of a phase 1 dose escalation study of tipifarnib, an oral FT inhibitor, in patients with relapsed, refractory, or newly diagnosed (if over age 70) acute myelogenous leukemia (AML), on a week-on, week-off schedule. Forty-four patients were enrolled, 2 patients were newly diagnosed, the rest were relapsed or refractory to previous treatment, with a median age of 61 (range 33–79). The maximum tolerated dose was determined to be 1200 mg given orally twice-daily (bid) on this schedule. Cycle one dose-limiting toxicities were hepatic and renal. There were 3 complete remissions seen, 2 at the 1200 mg bid dose and one at the 1000 mg bid dose, with minor responses seen at the 1400 mg bid dose level. Pharmacokinetic studies performed at doses of 1400 mg bid showed linear behavior with minimal accumulation between days 1–5. Tipifarnib administered on a week-on week-off schedule shows activity at higher doses, and represents an option for future clinical trials in AML.

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          Mechanisms of resistance to 5-aza-2'-deoxycytidine in human cancer cell lines.

          5-aza-2'-deoxycytidine (DAC) is approved for the treatment of myelodysplastic syndromes, but resistance to this agent is common. In search for mechanisms of resistance, we measured the half maximal (50%) inhibitory concentration (IC(50)) of DAC and found it differed 1000-fold among a panel of cancer cell lines. The IC(50) was correlated with the doses of DAC that induced the most hypomethylation of long interspersed nuclear elements (LINE; R = 0.94, P < .001), but not with LINE methylation or DNA methyltransferase 1 (DNMT1), 3a, and 3b expression at baseline. Sensitivity to DAC showed a low correlation (R = 0.44, P = .11) to that of 5-azacytidine (AZA), but a good correlation to that of cytarabine (Ara-C; R = 0.89, P < .001). The 5 cell lines most resistant to DAC had a combination of low dCK, hENT1, and 2 transporters, and high cytosine deaminase. In an HL60 clone, resistance to DAC could be rapidly induced by drug exposure and was related to a switch from heterozygous to homozygous mutation of DCK. Transfection of wild-type DCK restored DAC sensitivity. DAC induced DNA breaks as evidenced by H2AX phosphorylation and increased homologous recombination rates by 7- to 10-fold. These results suggest that in vitro resistance to DAC can be explained by insufficient incorporation into DNA.
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            Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development.

            Ras proteins are guanine nucleotide-binding proteins that play pivotal roles in the control of normal and transformed cell growth and are among the most intensively studied proteins of the past decade. After stimulation by various growth factors and cytokines, Ras activates several downstream effectors, including the Raf-1/mitogen-activated protein kinase pathway and the Rac/Rho pathway. In approximately 30% of human cancers, including a substantial proportion of pancreatic and colon adenocarcinomas, mutated ras genes produce mutated proteins that remain locked in an active state, thereby relaying uncontrolled proliferative signals. Ras undergoes several posttranslational modifications that facilitate its attachment to the inner surface of the plasma membrane. The first-and most critical-modification is the addition of a farnesyl isoprenoid moiety in a reaction catalyzed by the enzyme protein farnesyltransferase (FTase). It follows that inhibiting FTase would prevent Ras from maturing into its biologically active form, and FTase is of considerable interest as a potential therapeutic target. Different classes of FTase inhibitors have been identified that block farnesylation of Ras, reverse Ras-mediated cell transformation in human cell lines, and inhibit the growth of human tumor cells in nude mice. In transgenic mice with established tumors, FTase inhibitors cause regression in some tumors, which appears to be mediated through both apoptosis and cell cycle regulation. FTase inhibitors have been well tolerated in animal studies and do not produce the generalized cytotoxic effects in normal tissues that are a major limitation of most conventional anticancer agents. There are ongoing clinical evaluations of FTase inhibitors to determine the feasibility of administering them on dose schedules like those that portend optimal therapeutic indices in preclinical studies. Because of the unique biologic aspects of FTase, designing disease-directed phase II and III evaluations of their effectiveness presents formidable challenges.
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              A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia.

              At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.
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                Author and article information

                Journal
                8704895
                5536
                Leukemia
                Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
                0887-6924
                1476-5551
                13 May 2011
                31 May 2011
                October 2011
                1 April 2012
                : 25
                : 10
                : 1543-1547
                Affiliations
                [1 ]Department of Hematology/HCT, City of Hope, Duarte, CA, USA
                [2 ]Department of Molecular Pharmacology, City of Hope, Duarte, CA, USA
                [3 ]Division of Hematology and Oncology, University of California, Davis School of Medicine, Sacramento, California, USA
                [4 ]Department of Biostatistics, City of Hope, Duarte, CA, USA
                [5 ]Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
                Author notes
                Corresponding Author: Mark Kirschbaum Current contact information: Director, Experimental Therapeutics, Nevada Cancer Institute, Medical Oncology, One Breakthrough Way, Las Vegas NV 89135 Ph: 702.822.5229 Fax: 702.944.1165 mkirschbaum@ 123456nvcancer.org
                Article
                NIHMS292958
                10.1038/leu.2011.124
                3165084
                21625235
                941b0fa6-36ab-46b7-8f23-78d7bb1fb005

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                Categories
                Article

                Oncology & Radiotherapy
                aml,acute myelogenous leukemia,farnesyltransferase,phase 1 trial,zarnestra®,tipifarnib

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