Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin

Abstract

Purpose Our published preclinical experiments have indicated that romidepsin mediates growth arrest and apoptosis in lung cancer cells (but not cultured normal bronchial epithelia) via chromatin remodeling mechanisms. Also, romidepsin has direct effects on survival and stress signal pathways. A phase II trial was performed to examine clinical and molecular responses mediated by this histone deacetylase (HDAC) inhibitor in patients with lung cancer. Patients and Methods Nineteen patients with neoplasms refractory to standard therapy received 4-hour romidepsin infusions (17.8 mg/m2) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of 2 identical 21-day cycles. Plasma romidepsin levels were evaluated by liquid chromatography/mass spectrometry techniques. A variety of molecular endpoints were assessed in tumor biopsies via immunohistochemistry techniques. Long-oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after romidepsin exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections. Results Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in 1 individual. No significant cardiac toxicities were observed. Maximum steady-state plasma romidepsin concentrations ranged from 384-1114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in 9 patients. Romidepsin enhanced acetylation of histone H3 (H3K9) as well as H4K16 and increased p21 expression in lung cancer cells. No obvious changes in phosho-extracellular signal–regulated kinase, ki67, or cleaved caspase-3 levels were noted. Although romidepsin appeared to induce a relatively small number of genes, this HDAC inhibitor diminished expression of > 1000 genes in laser-captured tumor cells. Interestingly, these genes, which appeared to be induced or repressed by romidepsin, were repressed or induced, respectively, in primary lung cancers relative to adjacent histologically normal bronchial epithelia, suggesting that romidepsin can reverse lung cancer gene expression in vivo. Conclusion Although exhibiting minimal clinical efficacy at this dose and schedule, romidepsin mediates biologic effects that might warrant further evaluation of this HDAC inhibitor in combination with novel agents targeting chromatin remodeling complexes, survival pathways, or death receptors in patients with lung cancer. Our published preclinical experiments have indicated that romidepsin mediates growth arrest and apoptosis in lung cancer cells (but not cultured normal bronchial epithelia) via chromatin remodeling mechanisms. Also, romidepsin has direct effects on survival and stress signal pathways. A phase II trial was performed to examine clinical and molecular responses mediated by this histone deacetylase (HDAC) inhibitor in patients with lung cancer. Nineteen patients with neoplasms refractory to standard therapy received 4-hour romidepsin infusions (17.8 mg/m2) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of 2 identical 21-day cycles. Plasma romidepsin levels were evaluated by liquid chromatography/mass spectrometry techniques. A variety of molecular endpoints were assessed in tumor biopsies via immunohistochemistry techniques. Long-oligo arrays were used to examine gene expression profiles in laser-captured tumor cells before and after romidepsin exposure, relative to lung cancer cells and adjacent normal bronchial epithelia from patients undergoing pulmonary resections. Nineteen patients were evaluable for toxicity assessment; 18 were evaluable for treatment response. Myelosuppression was dose limiting in 1 individual. No significant cardiac toxicities were observed. Maximum steady-state plasma romidepsin concentrations ranged from 384-1114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in 9 patients. Romidepsin enhanced acetylation of histone H3 (H3K9) as well as H4K16 and increased p21 expression in lung cancer cells. No obvious changes in phosho-extracellular signal–regulated kinase, ki67, or cleaved caspase-3 levels were noted. Although romidepsin appeared to induce a relatively small number of genes, this HDAC inhibitor diminished expression of > 1000 genes in laser-captured tumor cells. Interestingly, these genes, which appeared to be induced or repressed by romidepsin, were repressed or induced, respectively, in primary lung cancers relative to adjacent histologically normal bronchial epithelia, suggesting that romidepsin can reverse lung cancer gene expression in vivo. Although exhibiting minimal clinical efficacy at this dose and schedule, romidepsin mediates biologic effects that might warrant further evaluation of this HDAC inhibitor in combination with novel agents targeting chromatin remodeling complexes, survival pathways, or death receptors in patients with lung cancer.