A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors
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Published on: July 31, 2016
M Candelaria1, D Gallardo-Rincón, C Arce
1Division de Investigación Clinica, Instituto Nacional de Cancerologia, Mexico City, Mexico.
Background:
Epigenetic aberrations lead to chemotherapy resistance; hence, their reversal by inhibitors of DNA methylation and histone deacetylases may overcome it.
Patients And Methods:
Phase II, single-arm study of hydralazine and magnesium valproate added to the same schedule of chemotherapy on which patients were progressing. Schedules comprised cisplatin, carboplatin, paclitaxel, vinorelbine, gemcitabine, pemetrexed, topotecan, doxorubicin, cyclophosphamide, and anastrozole. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow, acetylators, and magnesium valproate at 40 mg/kg, beginning a week before chemotherapy. Response, toxicity, DNA methylation, histone deacetylase activity, plasma valproic acid, and hydralazine levels were evaluated.
Results:
Seventeen patients were evaluable for toxicity and 15 for response. Primary sites included cervix (3), breast (3), lung (1), testis (1), and ovarian (7) carcinomas. A clinical benefit was observed in 12 (80%) patients: four PR, and eight SD. The most significant toxicity was hematologic. Reduction in global DNA methylation, histone deacetylase activity, and promoter demethylation were observed.
Conclusions:
The clinical benefit noted with the epigenetic agents hydralazine and valproate in this selected patient population progressing to chemotherapy' and re-challenged with the same chemotherapy schedule after initiating hydralazine and valproate' lends support to the epigenetic-driven tumor-cell chemoresistance hypothesis (ClinicalTrials.gov Identifier: NCT00404508).
Insights
This study explored epigenetic agents hydralazine and valproate to overcome chemotherapy resistance. Results showed clinical benefit in 80% of patients, supporting the epigenetic-driven chemoresistance hypothesis.
Area of Science:
- Oncology
- Epigenetics
- Pharmacology
Background:
- Epigenetic alterations are linked to chemotherapy resistance.
- Reversing these epigenetic changes may restore chemotherapy sensitivity.
Purpose of the Study:
- To evaluate the efficacy of hydralazine and magnesium valproate in overcoming chemotherapy resistance.
- To investigate the impact of epigenetic agents on DNA methylation and histone deacetylase activity in patients with advanced cancers.
Main Methods:
- A Phase II, single-arm study involving patients progressing on standard chemotherapy.
- Administration of hydralazine and magnesium valproate prior to and during chemotherapy.
- Monitoring of clinical response, toxicity, and epigenetic markers (DNA methylation, HDAC activity).
Main Results:
- Clinical benefit (PR or SD) observed in 12 out of 15 (80%) evaluable patients.
- Significant reduction in global DNA methylation and histone deacetylase activity.
- Hematologic toxicity was the most prominent adverse event.
Conclusions:
- Hydralazine and valproate demonstrated clinical benefit in patients with chemoresistant tumors.
- Findings support the hypothesis that epigenetic modifications drive tumor cell chemoresistance.
- Epigenetic therapy offers a potential strategy to re-sensitize tumors to chemotherapy.
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