Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors

Papadimitrakopoulou, Vali; Agelaki, Sofia; Tran, Hai T.; Kies, Merrill S.; Gagel, Robert F.; Zinner, Ralph; Kim, Edward; Ayers, Gregory D.; Wright, John J.; Khuri, Fadlo R.

doi:10.1158/1078-0432.ccr-04-1659

Cited by 13 publications

(14 citation statements)

References 44 publications

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“…Some effect against normal LTC-IC is not unexpected as, in clinical trials, myelosuppression has been a recognized but manageable side effect of treatment with BMS-214662. 21,38 These results confirm that BMS-214662 is targeting primitive CML stem/progenitor cells and provide further evidence of selectivity for CML over normal cells.…”

Section: Bms-214662 Induces Apoptosis Of CML Stem Cells 2847supporting

confidence: 66%

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Copland

Pellicano

Richmond

et al. 2008

Blood

112

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IntroductionChronic myeloid leukemia (CML) is a clonal myeloproliferative disorder originating in a hematopoietic stem cell. It is characterized by the Philadelphia (Ph) chromosome, 1 arising from a reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in fusion of the BCR gene on chromosome 22 with the ABL oncogene on chromosome 9, with expression of its fusion gene product, BCR-ABL, a constitutively active tyrosine kinase. 2 The deregulated BCR-ABL tyrosine kinase activity is essential for its transforming ability, 3 resulting in phosphorylation of cellular substrates and activation of signal transduction pathways, including the RAS-ERK cascade, JAK-STAT, PI3-kinase, c-Myc, c-CBL, and CrKL, affecting cell growth, stromal interaction, and apoptosis. [4][5][6] Imatinib mesylate (IM; Novartis Pharma, Basel, Switzerland) is a tyrosine kinase inhibitor (TKI) active against ABL, c-KIT, and PDGFR, acting by competitive inhibition of adenosine triphosphate binding to the tyrosine kinase. 7 Despite an impressive rate of durable complete cytogenetic response in chronic phase CML patients treated with IM, 8 only a minority of patients achieve complete molecular remission. 9 At least 2 mechanisms of resistance appear to account for residual disease in these patients: the innate insensitivity of primitive quiescent CML stem/progenitor cells, which greatly overexpress BCR-ABL, to IM 10,11 and BCR-ABL kinase mutations, 12 which are present before IM therapy in a subgroup of patients and result in IM resistance. 13,14 However, there is currently no direct evidence that these resistance mechanisms, observed in vitro, are responsible for residual disease in IM-treated patients.Two main strategies to overcome IM resistance have emerged. These are the development of second generation TKIs 15,16 and the use of IM in drug combinations. 17 Dasatinib (Sprycel, formerly BMS-354825; Bristol-Myers Squibb, Stamford, CT) is an oral, multitargeted inhibitor of BCR-ABL and SRC kinases, with greatly improved potency against wild-type (WT) BCR-ABL, capable of binding all known BCR-ABL kinase mutants resistant to IM except T315I. 15 In our previous work, although dasatinib induced durable inhibition of BCR-ABL in primitive progenitor cells from CML patients compared with either IM or nilotinib, which were ineffective, 11,18 none of these TKIs targeted the most primitive, quiescent CML stem/progenitor cells. Of a wide range of rational drug combinations, 17 the only agent to synergize with IM against these cells was the cytostatic farnesyltransferase inhibitor (FTI) lonafarnib (Schering-Plough). 17 FTIs inhibit oncogenic RAS and have entered clinical trials in solid tumors and acute leukemias. [19][20][21] However, the observed antitumor effects of FTIs are not solely the result of RAS inhibition 22,23 ; they may also act by inhibiting farnesylation of other proteins. 24,25 BMS-214662 is a cytotoxic FTI 26 that produces potent tumor regression and curative responses in human tumor xenografts and transgenic tumor mode...

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Section: Bms-214662 Induces Apoptosis Of CML Stem Cells 2847supporting

confidence: 66%

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Copland

Pellicano

Richmond

et al. 2008

Blood

112

View full text Add to dashboard Cite

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“…An additional phase I study exploring weekly dosing demonstrated activity in 5 patients with acute leukemia or high-risk MDS (among 30 patients), including two complete responses (213). Phase I studies exploring weekly 1 h infusions and weekly 24 h infusions in solid tumor patients have also been reported (214,215). The toxicity profiles for the two regimens differed significantly.…”

Section: Clinical Activity Of Bms-214662mentioning

confidence: 99%

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

Basso¹,

Kirschmeier²,

Bishop³

2006

Journal of Lipid Research

282

246

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Some proteins undergo posttranslational modification by the addition of an isoprenyl lipid (farnesyl-or geranylgeranyl-isoprenoid) to a cysteine residue proximal to the C terminus. Protein isoprenylation promotes membrane association and contributes to protein-protein interactions. Farnesylated proteins include small GTPases, tyrosine phosphatases, nuclear lamina, cochaperones, and centromereassociated proteins. Prenylation is required for the transforming activity of Ras. Because of the high frequency of Ras mutations in cancer, farnesyl transferase inhibitors (FTIs) were investigated as a means to antagonize Ras function. Evaluation of FTIs led to the finding that both K-and N-Ras are alternatively modified by geranylgeranyl prenyltransferase-1 in FTI-treated cells. Geranylgeranylated forms of Ras retain the ability to associate with the plasma membrane and activate substrates. Despite this, FTIs are effective at inhibiting the growth of human tumor cells in vitro, suggesting that activity is dependent on blocking the farnesylation of other proteins. FTIs also inhibit the in vivo growth of human tumor xenografts and sensitize these models to chemotherapeutics, most notably taxanes. Several FTIs have entered clinical trials for various cancer indications. In some clinical settings, primarily hematologic malignancies, FTIs have displayed evidence of single-agent activity. Clinical studies in progress are exploring the antitumor activity of FTIs as single agents and in combination. This review will summarize the basic biology of FTIs, their antitumor activity in preclinical models, and the current status of clinical studies with these agents.-Basso, A. D., P. Kirschmeier, and W. R. Bishop. Farnesyl transferase inhibitors. J. Lipid Res. 2006. 47: 15-31.

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“…The predominate DLTs were secondary to BMS-214662 and were either an acute (starting within 24 h of receiving BMS-214662) syndrome of a sudden leukopenia/ neutropenia and elevation in serum transaminases or gastrointestinal toxicity (both acute nausea/vomiting and diarrhea occurring days after drug infusion). These have been the DLTs or commonly observed toxicities in other phase I dose escalation studies of BMS-214662 (3,12,14,16,17). Unlike some of the prior studies, renal insufficiency was not observed.…”

Section: Discussionmentioning

confidence: 69%

Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors

Bailey

Alberti

Thomas

et al. 2007

Clinical Cancer Research

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Objective partial responses were observed in patients with pretreated head and neck, ovarian, and hormone-refractory prostate carcinomas, and leiomyosarcoma. The observed pharmacokinetics of paclitaxel and BMS-214662 imply no interaction between the two. Significant inhibition (>80%) of farnesyl transferase activity in peripheral mononuclear cells was observed at the end of BMS-214662 infusion. Conclusions: Pretreated patients with advanced malignancies can tolerate weekly paclitaxel and BMS-214662 at doses that achieve objective clinical benefit. Due to multiple DLTs occurring at the expanded MTD, the recommended phase 2 dose and schedule is paclitaxel (80 mg/m 2 over 1h) and BMS-214662 (160 mg/m 2 over 1h) administered weekly.

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Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors

Cited by 13 publications

References 44 publications

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors

Thematic review series: Lipid Posttranslational Modifications. Farnesyl transferase inhibitors

Phase I Trial of Weekly Paclitaxel and BMS-214662 in Patients with Advanced Solid Tumors

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