Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma

Melissa Alsina, Rafael Fonseca, Edward F. Wilson, A. Nelida Belle, Elvira Gerbino, Tammy Price-Troska, Rose M. Overton, Gregory Ahmann, Laura M. Bruzek, Alex A. Adjei, Scott H. Kaufmann, John J. Wright, Daniel Sullivan, Benjamin Djulbegovic, Alan B. Cantor, Philip R. Greipp, William S. Dalton, Saïd M. Sebti

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Abstract

Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.

Original languageEnglish
Pages (from-to)3271-3277
Number of pages7
JournalBlood
Volume103
Issue number9
DOIs
Publication statusPublished - May 1 2004

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tipifarnib
Farnesyltranstransferase
Prenylation
Multiple Myeloma
Tumors
Stabilization
Survival
Neoplasms
Chemotherapy
Toxicity
Bone
Protein Prenylation
Drug Therapy
STAT3 Transcription Factor
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase 1
Bone Marrow Cells
Thrombocytopenia
Nausea
Fatigue

ASJC Scopus subject areas

  • Hematology

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Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. / Alsina, Melissa; Fonseca, Rafael; Wilson, Edward F.; Belle, A. Nelida; Gerbino, Elvira; Price-Troska, Tammy; Overton, Rose M.; Ahmann, Gregory; Bruzek, Laura M.; Adjei, Alex A.; Kaufmann, Scott H.; Wright, John J.; Sullivan, Daniel; Djulbegovic, Benjamin; Cantor, Alan B.; Greipp, Philip R.; Dalton, William S.; Sebti, Saïd M.

In: Blood, Vol. 103, No. 9, 01.05.2004, p. 3271-3277.

Research output: Contribution to journalArticle

Alsina, M, Fonseca, R, Wilson, EF, Belle, AN, Gerbino, E, Price-Troska, T, Overton, RM, Ahmann, G, Bruzek, LM, Adjei, AA, Kaufmann, SH, Wright, JJ, Sullivan, D, Djulbegovic, B, Cantor, AB, Greipp, PR, Dalton, WS & Sebti, SM 2004, 'Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma', Blood, vol. 103, no. 9, pp. 3271-3277. https://doi.org/10.1182/blood-2003-08-2764
Alsina, Melissa ; Fonseca, Rafael ; Wilson, Edward F. ; Belle, A. Nelida ; Gerbino, Elvira ; Price-Troska, Tammy ; Overton, Rose M. ; Ahmann, Gregory ; Bruzek, Laura M. ; Adjei, Alex A. ; Kaufmann, Scott H. ; Wright, John J. ; Sullivan, Daniel ; Djulbegovic, Benjamin ; Cantor, Alan B. ; Greipp, Philip R. ; Dalton, William S. ; Sebti, Saïd M. / Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma. In: Blood. 2004 ; Vol. 103, No. 9. pp. 3271-3277.
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abstract = "Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66{\%} of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.",
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T1 - Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma

AU - Alsina, Melissa

AU - Fonseca, Rafael

AU - Wilson, Edward F.

AU - Belle, A. Nelida

AU - Gerbino, Elvira

AU - Price-Troska, Tammy

AU - Overton, Rose M.

AU - Ahmann, Gregory

AU - Bruzek, Laura M.

AU - Adjei, Alex A.

AU - Kaufmann, Scott H.

AU - Wright, John J.

AU - Sullivan, Daniel

AU - Djulbegovic, Benjamin

AU - Cantor, Alan B.

AU - Greipp, Philip R.

AU - Dalton, William S.

AU - Sebti, Saïd M.

PY - 2004/5/1

Y1 - 2004/5/1

N2 - Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.

AB - Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase I) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/tumor survival pathways.

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