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See detailVAC chemotherapy with valproic acid for refractory/relapsing small cell lung cancer: a phase II study
Berghmans, Thierry; Lafitte, Jean-Jacques; Scherpereel, Arnaud et al

in European Respiratory Society Open Research (2015), 1(2),

Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to ... [more ▼]

Salvage chemotherapy (CT) for relapsing or refractory small cell lung cancer (SCLC) remains disappointing. In vitro experiments showed that valproic acid increases apoptosis of SCLC cell lines exposed to doxorubicin, vindesine and bis(2-chloroethyl)amine. The primary objective of this phase II study was to determine whether epigenetic modulation with valproic acid in addition to a doxorubicin, vindesine and cyclophosphamide (VAC) regimen improves 6-month progression-free survival (PFS). Patients with pathologically proven SCLC refractory to prior platinum derivatives and etoposide were eligible. After central registration, patients received VAC plus daily oral valproic acid. 64 patients were registered, of whom six were ineligible. Seven patients did not receive any CT, leaving 51 patients assessable for the primary end-point. The objective response rate was 19.6%. Median PFS was 2.8 months (95% CI 2.5–3.6 months) and 6-month PFS was 6%. Median survival time was 5.9 months (95% CI 4.7–7.5 months). Toxicity was mainly haematological, with 88% and 26% grade 3–4 neutropenia and thrombopenia, respectively. Despite an interesting response rate, the addition of valproic acid to VAC did not translate into adequate PFS in relapsing SCLC or SCLC refractory to platinum–etoposide. [less ▲]

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See detailProspective validation obtained in a similar group of patients and with similar high throughput biological tests failed to confirm signatures for prediction of response to chemotherapy and survival in advanced NSCLC: a prospective study from the European Lung Cancer Working Party
Berghmans, Thierry; Ameye, Lieveke; Lafitte, Jean-Jacques et al

in Frontiers in Oncology (2015), 4

Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aimswere to identify ... [more ▼]

Cisplatin doublets are standard 1st line treatment for advanced non-small cell lung cancer (NSCLC), without accurate predictor for response and survival, but important toxicity. Our aimswere to identify predictive (for response) and prognostic (for survival) biological signatures in patients with NSCLC using messenger RNAs (mRNA) and miRNA expression. [less ▲]

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See detailValproate, in combination with pemetrexed and cisplatin, provides additional efficacy to the treatment of malignant mesothelioma.
Vandermeers, Fabian ULg; Hubert, Pascale ULg; Delvenne, Philippe ULg et al

in Clinical Cancer Research : An Official Journal of the American Association for Cancer Research (2009), 15(8), 2818-28

PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to ... [more ▼]

PURPOSE: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and RESULTS: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. CONCLUSIONS: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma. [less ▲]

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