Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura

David S. Schrump, Maria R. Fischette, Dao Nguyen, Ming Zhao, Xinmin Li, Tricia F. Kunst, Ana Hancox, Julie A. Hong, G. Aaron Chen, Vitaliy Pishchik, William D. Figg, Anthony J. Murgo, Seth M. Steinberg

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Purpose: The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2′-deoxycytidine (DAC) in patients with thoracic malignancies. Experimental Design: Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. Results: Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m2 depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. Conclusion: Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.

Original languageEnglish
Pages (from-to)5777-5785
Number of pages9
JournalClinical Cancer Research
Volume12
Issue number19
DOIs
StatePublished - Oct 1 2006
Externally publishedYes

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decitabine
Pleura
Esophagus
Lung Neoplasms
Gene Expression
Neoplasms
Transcriptome
Thorax
Therapeutics
Polymerase Chain Reaction
Chromatin Assembly and Disassembly
Maximum Tolerated Dose
Gene Targeting
Testicular Neoplasms
Neoplasm Antigens
DNA Methylation
Oligonucleotide Array Sequence Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. / Schrump, David S.; Fischette, Maria R.; Nguyen, Dao; Zhao, Ming; Li, Xinmin; Kunst, Tricia F.; Hancox, Ana; Hong, Julie A.; Chen, G. Aaron; Pishchik, Vitaliy; Figg, William D.; Murgo, Anthony J.; Steinberg, Seth M.

In: Clinical Cancer Research, Vol. 12, No. 19, 01.10.2006, p. 5777-5785.

Research output: Contribution to journalArticle

Schrump, DS, Fischette, MR, Nguyen, D, Zhao, M, Li, X, Kunst, TF, Hancox, A, Hong, JA, Chen, GA, Pishchik, V, Figg, WD, Murgo, AJ & Steinberg, SM 2006, 'Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura', Clinical Cancer Research, vol. 12, no. 19, pp. 5777-5785. https://doi.org/10.1158/1078-0432.CCR-06-0669
Schrump, David S. ; Fischette, Maria R. ; Nguyen, Dao ; Zhao, Ming ; Li, Xinmin ; Kunst, Tricia F. ; Hancox, Ana ; Hong, Julie A. ; Chen, G. Aaron ; Pishchik, Vitaliy ; Figg, William D. ; Murgo, Anthony J. ; Steinberg, Seth M. / Phase I study of decitabine-mediated gene expression in patients with cancers involving the lungs, esophagus, or pleura. In: Clinical Cancer Research. 2006 ; Vol. 12, No. 19. pp. 5777-5785.
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AU - Schrump, David S.

AU - Fischette, Maria R.

AU - Nguyen, Dao

AU - Zhao, Ming

AU - Li, Xinmin

AU - Kunst, Tricia F.

AU - Hancox, Ana

AU - Hong, Julie A.

AU - Chen, G. Aaron

AU - Pishchik, Vitaliy

AU - Figg, William D.

AU - Murgo, Anthony J.

AU - Steinberg, Seth M.

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N2 - Purpose: The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2′-deoxycytidine (DAC) in patients with thoracic malignancies. Experimental Design: Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. Results: Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m2 depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. Conclusion: Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.

AB - Purpose: The DNA methylation paradox, manifested as derepression of cancer-testis antigens, and silencing of tumor suppressors during malignant transformation, provides the rationale for the utilization of chromatin remodeling agents for cancer therapy. A phase I trial was done to examine pharmacokinetics, toxicities, and gene expression mediated by 5-aza-2′-deoxycytidine (DAC) in patients with thoracic malignancies. Experimental Design: Thirty-five patients with cancers refractory to standard therapy received continuous 72-hour DAC infusions using a phase I dose-escalation schema. Each full course of therapy consisted of two identical 35-day cycles. Plasma DAC levels were evaluated by liquid chromatography-mass spectrometry techniques. Quantitative reverse transcription-PCR, methylation-specific PCR, and immunohistochemical techniques were used to evaluate NY-ESO-1, MAGE-3, and p16 expression in tumor biopsies. Long oligonucleotide arrays were used to evaluate gene expression profiles in laser-captured tumor cells before and after DAC exposure. Results: Thirty-five patients were evaluable for toxicities; 25 were evaluable for treatment response. Myelosuppression constituted dose-limiting toxicity. The maximum tolerated dose of DAC was 60 to 75 mg/m2 depending on the number of prior cytotoxic chemotherapy regimens. No objective responses were observed. Plasma DAC concentrations approximated thresholds for gene induction in cultured cancer cells. Target gene induction was observed in 36% of patients. Posttreatment antibodies to NY-ESO-1 were detected in three patients exhibiting NY-ESO-1 induction in their tumor tissues. Complex, heterogeneous gene expression profiles were observed in pretreatment and posttreatment tissues. Conclusion: Prolonged DAC infusions can modulate gene expression in primary thoracic malignancies. These findings support further evaluation of DNA-demethylating agents alone or in combination with other regimens targeting induced gene products for the treatment of these neoplasms.

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