A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer

A phase II clinical study with proteomic profiling

Edwin M. Posadas, Virginia Kwitkowski, Herbert L. Kotz, Virginia Espina, Lori Minasian, Nana Tchabo, Ahalya Premkumar, Mahrukh M. Hussain, Richard Chang, Seth M. Steinberg, Elise C. Kohn

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS. Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS. Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade ≥2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P < .005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P < .01). CONCLUSIONS. The results of this study indicated imatinib had minimal activity as a single agent in EOC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy.

Original languageEnglish (US)
Pages (from-to)309-317
Number of pages9
JournalCancer
Volume110
Issue number2
DOIs
StatePublished - Jul 15 2007
Externally publishedYes

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Proteomics
Ovarian Neoplasms
Platelet-Derived Growth Factor Receptors
Epidermal Growth Factor Receptor
Ascites
Fatigue
Edema
Neoplasms
Protein Array Analysis
Clinical Studies
Imatinib Mesylate
Receptor Protein-Tyrosine Kinases
Pleural Effusion
Disease Progression
Interleukin-6
Phosphotransferases
Cytokines
Biopsy
Ovarian epithelial cancer
Therapeutics

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Posadas, Edwin M. ; Kwitkowski, Virginia ; Kotz, Herbert L. ; Espina, Virginia ; Minasian, Lori ; Tchabo, Nana ; Premkumar, Ahalya ; Hussain, Mahrukh M. ; Chang, Richard ; Steinberg, Seth M. ; Kohn, Elise C. / A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer : A phase II clinical study with proteomic profiling. In: Cancer. 2007 ; Vol. 110, No. 2. pp. 309-317.
@article{be3c26ad18e6466580618b32b629c06c,
title = "A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer: A phase II clinical study with proteomic profiling",
abstract = "BACKGROUND. c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS. Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS. Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48{\%}), GI complaints in 8 patients (35{\%}), fatigue in 3 patients (13{\%}), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43{\%} and 13{\%}), respectively. Increased circulating levels of interleukin 6 were associated with grade ≥2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P < .005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P < .01). CONCLUSIONS. The results of this study indicated imatinib had minimal activity as a single agent in EOC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy.",
author = "Posadas, {Edwin M.} and Virginia Kwitkowski and Kotz, {Herbert L.} and Virginia Espina and Lori Minasian and Nana Tchabo and Ahalya Premkumar and Hussain, {Mahrukh M.} and Richard Chang and Steinberg, {Seth M.} and Kohn, {Elise C.}",
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Posadas, EM, Kwitkowski, V, Kotz, HL, Espina, V, Minasian, L, Tchabo, N, Premkumar, A, Hussain, MM, Chang, R, Steinberg, SM & Kohn, EC 2007, 'A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer: A phase II clinical study with proteomic profiling', Cancer, vol. 110, no. 2, pp. 309-317. https://doi.org/10.1002/cncr.22757

A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer : A phase II clinical study with proteomic profiling. / Posadas, Edwin M.; Kwitkowski, Virginia; Kotz, Herbert L.; Espina, Virginia; Minasian, Lori; Tchabo, Nana; Premkumar, Ahalya; Hussain, Mahrukh M.; Chang, Richard; Steinberg, Seth M.; Kohn, Elise C.

In: Cancer, Vol. 110, No. 2, 15.07.2007, p. 309-317.

Research output: Contribution to journalArticle

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T1 - A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer

T2 - A phase II clinical study with proteomic profiling

AU - Posadas, Edwin M.

AU - Kwitkowski, Virginia

AU - Kotz, Herbert L.

AU - Espina, Virginia

AU - Minasian, Lori

AU - Tchabo, Nana

AU - Premkumar, Ahalya

AU - Hussain, Mahrukh M.

AU - Chang, Richard

AU - Steinberg, Seth M.

AU - Kohn, Elise C.

PY - 2007/7/15

Y1 - 2007/7/15

N2 - BACKGROUND. c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS. Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS. Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade ≥2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P < .005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P < .01). CONCLUSIONS. The results of this study indicated imatinib had minimal activity as a single agent in EOC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy.

AB - BACKGROUND. c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatinib inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS. Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatinib was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS. Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade ≥2 fluid collection (P = .02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P < .01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P < .005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P < .01). CONCLUSIONS. The results of this study indicated imatinib had minimal activity as a single agent in EOC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy.

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