A Proof-Of-Principle Study of Epigenetic Therapy Added to Neoadjuvant Doxorubicin Cyclophosphamide for Locally Advanced Breast Cancer

Abstract

BackgroundAberrant DNA methylation and histone deacetylation participate in cancer development and progression; hence, their reversal by inhibitors of DNA methylation and histone deacetylases (HDACs) is at present undergoing clinical testing in cancer therapy. As epigenetic alterations are common to breast cancer, in this proof-of-concept study demethylating hydralazine, plus the HDAC inhibitor magnesium valproate, were added to neoadjuvant doxorubicin and cyclophosphamide in locally advanced breast cancer to assess their safety and biological efficacy.MethodologyThis was a single-arm interventional trial on breast cancer patients (ClinicalTrials.gov Identifier: NCT00395655). After signing informed consent, patients were typed for acetylator phenotype and then treated with hydralazine at 182 mg for rapid-, or 83 mg for slow-acetylators, and magnesium valproate at 30 mg/kg, starting from day –7 until chemotherapy ended, the latter consisting of four cycles of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 21 days. Core-needle biopsies were taken from primary breast tumors at diagnosis and at day 8 of treatment with hydralazine and valproate.Main Findings16 patients were included and received treatment as planned. All were evaluated for clinical response and toxicity and 15 for pathological response. Treatment was well-tolerated. The most common toxicity was drowsiness grades 1–2. Five (31%) patients had clinical CR and eight (50%) PR for an ORR of 81%. No patient progressed. One of 15 operated patients (6.6%) had pathological CR and 70% had residual disease <3 cm. There was a statistically significant decrease in global 5mC content and HDAC activity. Hydralazine and magnesium valproate up- and down-regulated at least 3-fold, 1,091 and 89 genes, respectively.ConclusionsHydralazine and magnesium valproate produce DNA demethylation, HDAC inhibition, and gene reactivation in primary tumors. Doxorubicin and cyclophosphamide treatment is safe, well-tolerated, and appears to increase the efficacy of chemotherapy. A randomized phase III study is ongoing to support the efficacy of so-called epigenetic or transcriptional cancer therapy.

Obesity hormone leptin induces growth and interferes with the cytotoxic effects of 5-fluorouracil in colorectal tumor stem cells

“…CSCs have been identified in several human malignancies, and their relative abundance in clinical cancer specimens has been correlated with disease progression (Arce et al 2006, Schatton et al 2008, Zhou et al 2009. Understanding how CSCs interact with tumor environment, including circulating and locally produced cytokines and hormones, might impact clinical management of different cancer types and development of novel therapeutics.…”

Analysis of the genomic response of human prostate cancer cells to histone deacetylase inhibitors

“…4 This combination was successfully added to doxorubicin and cyclophosphamide therapy in breast cancer patients as well. 5 The addition of vorinostat to the mammalian target of rapamycin (mTOR) inhibitor temsirolimus improved anti-cancer activity against renal cell carcinoma in vitro and in vivo. 6 Other recent preclinical studies indicated that HDACis such as VPA may sensitize cancer cells, among others PCa cells, to radiotherapy.…”

Identification of cells initiating human melanomas

“…Broader examination of a larger array of clinical specimen is warranted to establish further ABCB5 as a universal MMIC marker and robust candidate therapeutic target. Whether related ABC members 26,27 might also represent prospective markers of tumour-initiating cells, or whether ABCB5 might represent such a marker in additional malignancies, such as breast cancer, in which it is known to be clinically expressed and specifically downregulated with epigenetic differentiation therapy 28 , requires further study.…”