Dataset Information

Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.

ABSTRACT:

Introduction

Despite complete surgical resection survival in early-stage non-small-cell lung cancer (NSCLC) remains poor. On the basis of prior preclinical evaluations, we hypothesized that combined induction proteasome and histone deacetylase inhibitor therapy, followed by tumor resection, is feasible.

Methods

A phase I clinical trial using a two-staged multiple-agent design of bortezomib and vorinostat as induction therapy followed by consolidative surgery in patients with NSCLC was performed. Standard toxicity and maximum tolerated dose were examined. Pre- and post-treatment tumor gene-expression arrays were performed and analyzed. Pre- and post-treatment fluorodeoxyglucose-positron emission tomography imaging was used to assess tumor metabolism. Finally, serum 20S proteasome levels were analyzed with enzyme-linked immunosorbent assay, and selected intratumoral proteins were assessed by immunohistochemistry.

Results

Of the 34-four patients providing written consent to participate in the trial, 21 were enrolled. One patient withdrew early because of disease progression. The maximum tolerated dose was bortezomib 1.3 mg/m and vorinostat 300 mg twice daily. There were grade III dose-limiting toxicities of fatigue and hypophosphatemia, which were self-limited. There was no mortality. Thirty percent of patients (6 of 20) had more than 60% histologic necrosis of their tumor after treatment, with two having 90% or more tumor necrosis. Tumor metabolism, 20S proteasome activity, and specific protein expression did not demonstrate consistent results. Gene-expression arrays comparing pre- and post-therapy NSCLC specimens revealed robust intratumoral changes in specific genes.

Conclusions

Induction bortezomib and vorinostat therapy followed by surgery in patients with operable NSCLC is feasible. Correlative gene-expression studies suggest new targets and cell-signaling pathways that may be important in modulating this combined therapy.

SUBMITTER: Jones DR

PROVIDER: S-EPMC3473142 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Publications

Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.

Jones David R DR Moskaluk Christopher A CA Gillenwater Heidi H HH Petroni Gina R GR Burks Sandra G SG Philips Jennifer J Rehm Patrice K PK Olazagasti Juan J Kozower Benjamin D BD Bao Yongde Y

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20121101 11

<h4>Introduction</h4>Despite complete surgical resection survival in early-stage non-small-cell lung cancer (NSCLC) remains poor. On the basis of prior preclinical evaluations, we hypothesized that combined induction proteasome and histone deacetylase inhibitor therapy, followed by tumor resection, is feasible.<h4>Methods</h4>A phase I clinical trial using a two-staged multiple-agent design of bortezomib and vorinostat as induction therapy followed by consolidative surgery in patients with NSCLC ...[more]

PMID: 23059775

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Project description:BackgroundNon-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Pemetrexed, a multi-target folate antagonist, has demonstrated efficacy in NSCLC histological subtypes characterized by low thymidylate synthase (TS) expression. Among many other potential targets, histone deacetylase inhibitors (HDACi) modulate TS expression, potentially sensitizing to the cytotoxic action of anti-cancer drugs that target the folate pathway, such as pemetrexed. Since high levels of TS have been linked to clinical resistance to pemetrexed in NSCLC, herein we investigated the molecular and functional effects of combined pemetrexed and ITF2357, a pan-HDACi currently in clinical trials as an anti-cancer agent.ResultsIn NSCLC cell lines, HDAC inhibition by ITF2357 induced histone and tubulin acetylation and downregulated TS expression at the mRNA and protein level. In combination experiments in vitro ITF2357 and pemetrexed demonstrated sequence-dependent synergistic growth-inhibitory effects, with the sequence pemetrexed followed by ITF2357 inducing a strikingly synergistic reduction in cell viability and induction of both apoptosis and autophagy in all cell line models tested, encompassing both adenocarcinoma and squamous cell carcinoma. Conversely, simultaneous administration of both drugs achieved frankly antagonistic effects, while the sequence of ITF2357 followed by pemetrexed had additive to slightly synergistic growth-inhibitory effects only in certain cell lines. Similarly, highly synergistic growth inhibition was also observed in patient-derived lung cancer stem cells (LCSC) exposed to pemetrexed followed by ITF2357. In terms of molecular mechanisms of interaction, the synergistic growth-inhibitory effects observed were only partially related to TS modulation by ITF2357, as genetic silencing of TS expression potentiated growth inhibition by either pemetrexed or ITF2357 and, to a lesser extent, by their sequential combination. Genetic and pharmacological approaches provided an interesting link between the autophagic and apoptotic pathways, and showed that sequential pemetrexed/ITF2357 causes a toxic form of autophagy with consequent activation of a caspase-dependent apoptotic program. In vivo experiments in NSCLC xenografts confirmed that sequential pemetrexed/ITF2357 is feasible and results in increased inhibition of tumor growth and increased mice survival.ConclusionsOverall, these data provide a strong rationale for the clinical development of sequential schedules employing pemetrexed followed by HDACi in NSCLC.

Project description:BackgroundThe optimal treatment for patients with resectable non-small cell lung cancer (NSCLC) involving adjacent organs (T3 or T4) and/or cN2 remains unclear. We investigated whether or not induction chemoradiotherapy (ICRT) followed by surgery improves the survival.MethodsWe retrospectively analyzed 84 patients with NSCLC involving the adjacent organs and/or cN2 who underwent ICRT followed by surgery at our hospital from 2006 to 2018. Presurgical treatment consisted of 2 courses of platinum-doublet and concurrent radiotherapy (40–50 Gy) to the tumor and involved field.ResultsAll 84 patients completed ICRT. One patient died after completion of ICRT due to bacterial pneumonia. Radiological responses to ICRT were a complete response (CR), n=1; partial response (PR), n=48; stable disease (SD), n=32; and progressive disease (PD), n=2 (overall response rate: 58.3%). Eighty-one patients underwent radical surgery. The procedures included lobectomy, n=66; bilobectomy, n=7; pneumonectomy, n=6; and segmentectomy, n=2 (including 49 extended resections). Seventy-three patients (90%) underwent complete resection. The postoperative morbidity rate was 30%. The 30- and 90-day mortality rates were 1.2% and 2.4%, respectively. A pathological CR (Ef3) and major response (Ef2) were achieved in 17 (21.0%) and 38 (46.9%) patients, respectively; a minor response (Ef1) was observed in 26 (32%). The 5-year overall survival (OS) and recurrence-free survival (RFS) rates were 58.0% and 45.6%, respectively. The median survival time was 73.2 months. Based on the response to ICRT, patients with radiological CR or PR showed better 5-year OS than those with SD (63.7% vs. 40.0%, P=0.020). Patients with Ef3 or Ef2 demonstrated a much better 5-year OS than those with Ef1 (65.0% vs. 24.4%, P=0.005).ConclusionsICRT followed by surgery for patients with NSCLC involving the adjacent organs and/or cN2 was feasible and improved the survival. A CR/PR or Ef2/Ef3 after ICRT led to a better prognosis.

Dataset Information

Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.

Introduction

Methods

Results

Conclusions

Publications

Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.

Similar Datasets

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