Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide

Karp, Judith E.; Flatten, Karen S.; Feldman, Eric J.; Greer, Jacqueline M.; Loegering, David A.; Ricklis, Rebecca M.; Morris, Lawrence E.; Ritchie, Ellen K.; Smith, B. Douglas; Ironside, Valerie; Talbott, Timothy M.; Roboz, Gail J.; Le, Son; Meng, Xue; Schneider, Paula A.; Dai, Nga T.; Adjei, Alex A.; Gore, Steven D.; Levis, Mark J.; Wright, John J.; Garrett‐Mayer, Elizabeth; Kaufmann, Scott H.

doi:10.1182/blood-2008-08-172726

Cited by 51 publications

(59 citation statements)

References 67 publications

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Section: Tipifarnib Induces Apoptosis Through the Mitochondrial Pathwaymentioning

confidence: 94%

“…31,37,38 Briefly, cells were fixed in 3:1 (vol:vol) methanol:acetic acid and dropped onto glass slides. After staining with 1 g/ml Hoechst 33258 in 50% (wt:vol) glycerol containing 100mM Tris-HC1 (pH 7.4 at 21°C), samples were examined on a Zeiss Axioplan microscope using a 63ϫ (NA 1.4) lens, photographed with a Hamamatsu C4742-95 digital camera using QED Image Version 1.7.12 software (QED Imaging), and imported as PICT files into Canvas 8.0.…”

Section: Detection Of Apoptosismentioning

confidence: 99%

“…Previous studies demonstrated that tipifarnib elicits little cytotoxicity in Jurkat cells over 24 hours. 38 In contrast, after a 48-to 72-hour exposure to tipifarnib, increasing numbers of cells displayed the typical morphologic characteristics of apoptosis ( Figure 1A) as well as phosphatidylserine externalization ( Figure 1B) and DNA fragmentation ( Figure 1C).In type II cells such as Jurkat cells, the mitochondrial pathway can be activated either downstream of death receptor ligation through the effects of cleaved Bid or by changes that affect other Bcl-2 family members (reviewed in Taylor et al 39 ). Jurkat variants lacking procaspase-8 (I9.2; Figure 1D) or FADD (I2.1) were resistant to death ligands such as agonistic anti-Fas antibody CH.11 ( Figure 1E) 38 but were at least as sensitive as parental Jurkat cells to tipifarnib (Figure 1E-F).…”

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Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation

Ding¹,

Hackbarth²,

Schneider³

et al. 2011

Blood

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The mechanism of cytotoxicity of farnesyltransferase inhibitors is incompletely understood and seems to vary depending on the cell type. To identify potential determinants of sensitivity or resistance for study in the accompanying clinical trial ( IntroductionFarnesyltransferase inhibitors (FTIs) are currently undergoing extensive clinical testing in various hematologic malignancies. [1][2][3] These agents inhibit farnesyltransferase, an enzyme that transfers the 15-carbon farnesyl group from farnesyl pyrophosphate to a variety of polypeptide acceptors, including the chaperone heat shock protein 40/HDJ-2; the nuclear intermediate filament proteins prelamin A and lamin B; the centromere protein CENP E; and small GTP-binding proteins of the Ras, Rho, and Rheb families. 4,5 Collectively, inhibition of farnesylation of these polypeptides leads to diminished cell proliferation. In addition, FTIs induce cell death in some model systems under certain conditions. These cytotoxic effects have been attributed to FTI-induced inhibition of prosurvival signaling by Akt,6,7 signal transducers and activators of transcription, [8][9][10] mitogen-activated protein kinases (MAPKs), 9,[11][12][13] or the Rheb target mammalian target of rapamycin. 14 Recent work has especially emphasized the role of Rheb inhibition as a mechanism of FTI-induced antilymphoma effects in murine lymphomas and leukemia. 15 Alternatively, it has been suggested that FTIs induce apoptosis by causing up-regulation of the proapoptotic Bcl-2 family members Bax, 16 Bak, 17 or Puma. 18 Although FTIs were initially developed based on the premise that inhibition of farnesylation would abrogate signaling by mutant Ras proteins, 19 these agents have demonstrated little efficacy in solid tumors. [20][21][22] In contrast, tantalizing activity was observed in several hematologic malignancies. [1][2][3] In particular, the orally bioavailable nonpeptidimimetic FTI tipifarnib 23 demonstrated activity in adults with acute leukemia. The initial phase 1 trial not only established a maximum tolerated dose in patients with relapsed and refractory acute leukemias but also determined that tipifarnib levels in bone marrow were 1.6-8 nmol/mg of tissue at this dose, demonstrated FT inhibition in leukemia cells in situ, and provided evidence of activity in relapsed AML. 24 Subsequent phase 2 and phase 3 studies have demonstrated response rates of 11%-23% in elderly patients with previously untreated poor risk acute myeloid leukemia (AML). 25,26 In an effort to select the subset of AML patients most likely to respond, Raponi et al empirically identified a 2-transcript signature, characterized by a high ratio of mRNA encoding the Ras guanine nucleotide exchange factor RasGRP1 27 relative to mRNA encoding the repair protein aprataxin, that had a 92% negative predictive value and a 28% positive predictive value in 2 single-agent phase 2 tipifarnib AML trials. 28 Based on these results, gene signature-guided trials of tipifarnib in acute leukemia are being initiated.Tipifarnib also has...

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Section: Tipifarnib Induces Apoptosis Through the Mitochondrial Pathwaymentioning

confidence: 94%

Section: Detection Of Apoptosismentioning

confidence: 99%

mentioning

confidence: 99%

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Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation

Ding¹,

Hackbarth²,

Schneider³

et al. 2011

Blood

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“…[1][2][3][4][5] Whereas many groups have speculated that FTIs induce their effect via ras signaling, [6][7][8] others have suggested alternative pathways by which FTIs exert their anticancer effects. [9][10][11] Marcus et al first reported that FTIs inhibit histone deacetylase 6 expression, resulting in destabilization of the microtubule assembly structure, and impaired cell survival in nonsmall cell lung cancer cell lines. 12 Based on published preclinical data demonstrating that histone deacetylase inhibitors synergize with proteasome inhibition via inhibition of aggresome formation, we sought to determine whether the in vitro synergy we have previously observed using the combination of an FTI with bortezomib was a result of dual blockade of the proteasome and aggresome pathways of protein catabolism.…”

Section: Introductionmentioning

confidence: 99%

Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes

David

Kaufman

Flowers

et al. 2010

Blood

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In this report, we investigated the mechanism responsible for synergistic induction of myeloma cell apoptosis induced by the combination of tipifarnib and bortezomib. Immunofluorescence studies revealed that bortezomib alone resulted in an accumulation of puncta of ubiquitinated proteins that was further enhanced by the addition of tipifarnib. These data suggest inhibition of the degradation of bortezomib-induced aggresomes; and consistent with this possibility, we also observed an increase in p62SQSTM1 in cells treated with the combination. However, autophagy in these cells appears to be normal as LC3BII is present, and auto- IntroductionWe have previously reported that the farnesyl transferase inhibitor (FTI) lonafarnib (SCH66336) combined with the proteasome inhibitor bortezomib induced synergistic apoptosis in myeloma cell lines and primary patient cells; however, the mechanism responsible for this synergy was unclear. 1-5 Whereas many groups have speculated that FTIs induce their effect via ras signaling, 6-8 others have suggested alternative pathways by which FTIs exert their anticancer effects. 9-11 Marcus et al first reported that FTIs inhibit histone deacetylase 6 expression, resulting in destabilization of the microtubule assembly structure, and impaired cell survival in nonsmall cell lung cancer cell lines. 12 Based on published preclinical data demonstrating that histone deacetylase inhibitors synergize with proteasome inhibition via inhibition of aggresome formation, we sought to determine whether the in vitro synergy we have previously observed using the combination of an FTI with bortezomib was a result of dual blockade of the proteasome and aggresome pathways of protein catabolism. MethodsThe MM.1S (provided by S. Rosen, Chicago, IL) and RPMI8226 (ATCC) cell lines were used in this study. Tipifarnib (R115777) was provided by Johnson & Johnson Pharmaceuticals, and bortezomib was provided by Millennium Pharmaceuticals. Methyl-thiazol-tetrazolium assays, annexin V staining, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis were performed according to previously published methods. 1,5,13 The antibodies used included antiubiquitin, anticaspase-8, anticaspase-9, anticaspase-3, and anti-poly-adenosine diphosphate or PARP ribose polymerase (Cell Signaling). p62SQSTM1 antibody (MBL International), bafilomycin A 1 , and LC3B antibody (Sigma-Aldrich) were used to assess autophagy. Confocal microscopy was performed using standard methods with minor modifications to assess aggresome formation. 12,13 Vimentin (SigmaAldrich) and ␥-tubulin (Abcam) antibodies were used in the evaluation of aggresome formation by confocal immunofluorescence microscopy. Results and discussionConsistent with our previous findings using lonafarnib in myeloma cells, the combination of tipifarnib and bortezomib resulted in greater growth inhibition than when either agent was used separately in both MM.1S as well as in RPMI8826 with concentrations up to 10nM of bortezomib and 5M of tipifarnib (Figure 1). Combination therapy...

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“…A number of drugs targeting AML-related genes have been tested for their efficacy in treating AML, including TNF-related apoptosis inducing ligand (TRAIL) and tipifarnib, an inhibitor of farnesyltransferase (FTase), alone or in combination with other anti-leukemia drugs (10,11). Inhibitors of histone deacetylase, proteasome and Bcl-2 antisense oligonucleotides have also been used as targeted drugs in the clinical treatment of AML (12).…”

Section: Introductionmentioning

confidence: 99%

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Huang

Chen

et al. 2013

Oncology Reports

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Abstract. The present study was designed to evaluate the expression and subcellular distribution of the familial acute myelogenous leukemia-related factor (FAMLF). A 14-amino acid epitope of the predicted open reading frame of the FAMLF gene was identified using bioinformatics. This polypeptide was synthesized, conjugated to keyhole limpet hemocyanin and was subsequently used to produce antibodies. The antibody titer and specificity were characterized using ELISA and western blot assays, respectively. The antibody detected FAMLF protein expression in several human leukemia cell lines, bone marrow cells derived from one acute myeloid leukemia patient and one chronic myeloid leukemia patient, but not in bone marrow cells of healthy subjects. The FAMLF/ GFP fusion protein was expressed in both the nucleus and the cytoplasm of transfected NIH3T3 cells. Our results demonstrate that the FAMLF gene is expressed in an AML patient but not in healthy controls, suggesting its association with AML. IntroductionAcute myeloid leukemia (AML) is the most common hematological malignancy in adults, with a worldwide incidence of ~3.6 cases in 100,000 individuals (National Cancer Institute. SEER Stat Fact Sheets: Acute Myeloid Leukemia; http://seer. cancer.gov/statfacts/html/amyl.html). A number of AMLrelated chromosomal abnormalities and gene mutations have been identified, and their involvement in the regulation of DNA methylation, signal transduction, energy synthesis, and cellular structure has been reported (1).The identification of new AML-related genes may provide insight into disease prognosis, treatment response, and new therapeutic regimens for patients with AML. Mutations in CCAAT enhancer binding factor α (CEBPA) have been associated with prolonged recurrence-free survival in AML patients (2). Mutations in nucleophosmin-1 (NPM1) and the internal tandem duplications in FLT3 predict positive AML prognosis (3), and mutations in several genes such as MLL-PTD, FLT3/ITD, WT1, and C-KIT predict negative AML prognosis (4-7). Thus, screening for mutations in CEBPA, NPM1, FLT3, and KIT is part of the routine workup for AML (8,9).A number of drugs targeting AML-related genes have been tested for their efficacy in treating AML, including TNF-related apoptosis inducing ligand (TRAIL) and tipifarnib, an inhibitor of farnesyltransferase (FTase), alone or in combination with other anti-leukemia drugs (10,11). Inhibitors of histone deacetylase, proteasome and Bcl-2 antisense oligonucleotides have also been used as targeted drugs in the clinical treatment of AML (12). Furthermore, inhibitors of Fms-like tyrosine kinase 2 (FLT-2), such as lestaurtinib (CEP701), tandutinib (MLN518) and PKC412 have shown benefit in treating FLT3-associated AML (13).Previously, we identified a large family with a high incidence of AML in Fujian China (14). A total of 11 family members in 4 generations were diagnosed with AML; two patients developed acute erythroleukemia (M6), one suffered from minimally differentiated acute myeloblastic leukemia (M1), one ha...

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Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide

Abstract: The farnesyltransferase inhibitor tipifarnib exhibits modest activity against acute myelogenous leukemia. To build on these results, we examined the effect of combining tipifarnib with other agents.

Cited by 51 publications

References 67 publications

Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation

Cytotoxicity of farnesyltransferase inhibitors in lymphoid cells mediated by MAPK pathway inhibition and Bim up-regulation

Tipifarnib sensitizes cells to proteasome inhibition by blocking degradation of bortezomib-induced aggresomes

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

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