Institute of Protein Biochemistry, CNR.

Via P. Castellino, 111 - 80131 Napoli

2014 IBP Seminar Series

CNR Conference Room

Friday, May 9th, 2014 at 14:30

Prof. Alfredo Budillon

University of Colorado, School of Medicine, Denver, CO

"Histone deacetylase inhibitors as anticancer agents in solid tumors"

Host: Dr. Daniela Corda

Tel. 081-6132536; e-mail: d.corda@ibp.cnr.it

In cancer treatment it has become evident that agents targeting signaling molecules often exhibit limited clinical activities. Biological redundancies and alternative pathways can often bypass the inhibition of a single target, suggesting that in some cases, broad-specificity compounds or multi-target drug therapies may be more effective than individual high-affinity, high-specificity therapies. Histone deacetylase inhibitors (HDACi), currently in clinical development, represent a new class of antitumor agents able to affect, based on the function of the epigenetic enzymes they regulate, multiple genes and pathways. Several HDACi are currently in clinical development as anticancer agents and two (vorinostat and romidepsin) have been approved by the US FDA for the treatment of cutaneous T-cell lymphoma. However, clinical efficacy of HDACi, particularly in solid tumors, remains not demonstrated, most likely because of lack of understanding of the molecular basis of response to this class of anticancer agents as well as the best context and combination regimen for their clinical use. Several evidences suggested that in solid tumors HDACi are more active in combination with RT and/or chemotherapy rather than as single agent. Budillon's group and many others have demonstrated the synergistic antitumor activity of HDACi in combination with a large number of structurally diverse anticancer agents, including fluoropyrimidines, DNA damaging compounds such as platin-based agents, radiotherapy and recently the aminobiphosphonate zoledronic acid. Valproic acid due to its HDAC inhibiting activity and its safe use as a chronic therapy (for over 40 years) for epileptic disorders and as a mood stabilizer in the treatment of maniac depression (bipolar affective disorder), could be considered a good candidate for anticancer therapy. In details, recent studies from Budillon's group in colorectal, head and neck and breast cancer models showed that VPA, induces synergistic antitumour effects in combination with the fluoropyrimidine capecitabine by up-regulating thymidine phosphorylase (TP), the key enzyme converting of capecitabine  to 5FU, and by downregulating thymidylate synthase (TS), the 5FU target. Radiotherapy further potentiated the antiproliferative effects, DNA damage and apoptosis, induced by capecitabine/VPA combination. On these bases Budillon's group recently launched the V-shoRT-R3 trial (NCT01898104),  a phase 1/2 trial of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer. They are currently recruiting patients in the  phase-I.