Clinical and Molecular Responses in Lung Cancer Patients Receiving Romidepsin

Abstract

Purpose: Our preclinical experiments indicated that Romidepsin (Depsipeptide FK228; DP) mediates growth arrest and apoptosis in cultured lung cancer cells. A phase II trial was done to examine clinical and molecular responses mediated by this histone deacetylase inhibitor in lung cancer patients. Experimental Design: Nineteen patients with neoplasms refractory to standard therapy received 4-h DP infusions (17.8 mg/m 2 ) on days 1 and 7 of a 21-day cycle. Each full course of therapy consisted of two identical 21-day cycles. Plasma DP levels were evaluated by liquid chromatography^mass spectrometry techniques. A variety of molecular end points 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 DP 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 one individual. No significant cardiac toxicities were observed. Maximum steady-state plasma DP concentrations ranged from 384 to 1,114 ng/mL. No objective responses were observed. Transient stabilization of disease was noted in nine patients. DP enhanced acetylation of histone H4, increased p21expression in lung cancer cells, and seemed to shift global gene expression profiles in these cells toward those detected in normal bronchial epithelia. Conclusion: Although exhibiting minimal clinical efficacy at this dose and schedule, DP mediates biological effects that may warrant further evaluation of this histone deacetylase inhibitor in combination with novel-targeted agents in lung cancer patients.Dynamic patterns of gene expression during embryonic development and cellular homeostasis, as well as stable repression of gene expression associated with X chromosome inactivation and imprinting, are mediated via DNA methylation in conjunction with acetylation, methylation, and phosphorylation of core histone proteins (H2a, H2b, H3, and H4; refs. 1, 2). Perturbation of these tightly linked epigenetic processes during multistep pulmonary carcinogenesis results in global DNA demethylation, derepression of endogenous retroviruses and germ cell -restricted genes, such as BORIS, NY-ESO-1, and MAGE-3, and paradoxical silencing of a variety of tumor suppressor genes, including p16, p14/ARF, TFPI-2, and RASSF1A (3 -5).Whereas considerable literature pertains to mechanisms contributing to aberrant DNA methylation in cancer cells (6), less information is available regarding specific histone modifications that arise during malignant transformation. However, recent studies indicate that unique changes in the histone code occur early during multistep carcinogenesis and contribute significantly to altered chromatin structure and gene expression in cancer cells (7). For example, leukemia and breast cancer cells exhibit loss of monoacetylati...

Multiple roles of class I HDACs in proliferation, differentiation, and development

“…This classic pan-HDACi can induce apoptosis as well as autophagy in cancer cells. Romidepsin (FK-228 2), one of the more selective inhibitors, has also been approved since 2009 to treat CTCL [93][94][95][96]. It belongs to the cyclic peptides that strongly inhibit HDAC1 and 2, and inhibits HDAC class II enzymes at higher concentrations [97][98][99].…”

Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research

“…Based on the currently available information, the most common HDACi-induced cardiac side effects are ST-depression/T-wave inversion, more prevalent after Romidepsin treatment and hardly ever of high grade [17,20,23]. These abnormalities are followed, in terms of incidence in the analyzed series, by QTc-prolongation, most frequently in patients receiving Valproate [70] or Belinostat [61,62].…”

Epigenetic therapy in non-small-cell lung cancer: targeting DNA methyltransferases and histone deacetylases

“…In general, the results in advanced, solid tumors have been disappointing. While well tolerated, these agents typically produce only stable disease as the best response, with rates varying from 15 --75% depending on the clinical context and the HDI tested [94][95][96][97][98][99][100][101][102]. In a small Phase II study of vorinostat in patients with relapsed NSCLC, stable disease ranging from 1.4 --19.4 months was achieved in 8 of 14 patients [101].…”