A Phase II Trial of Vorinostat (Suberoylanilide Hydroxamic Acid) in Metastatic Breast Cancer: A California Cancer Consortium Study

Abstract

Purpose The primary goal of this trial was to determine the response rate of single-agent vorinostat in patients with metastatic breast cancer. The secondary goals included assessment of time to progression, evaluation of toxicities, and overall survival. Experimental Design From June 2005 to March 2006, fourteen patients received vorinostat, 200 mg orally, twice daily for 14 days of each 21 day cycle. Response and progression were evaluated using RECIST criteria. Results The median age for all patients was 60.5 years (range: 37–88). Eight patients were ER and/or PR positive, four were Her-2 positive. Sites of metastatic disease included brain, liver, lungs, bones, pelvis, pleura, chest wall, and distant lymph nodes. Patients received a median of 1.5 prior (range: 0–2) chemotherapeutic regimens for metastatic disease. Fatigue, nausea, diarrhea, and lymphopenia were the most frequent clinically significant adverse effects. The median number of cycles delivered was two (range: 1–20). There were no complete or partial responses and the study was terminated after the first stage, however 4 patients were observed with stable disease with time to progression of 4,8,9 and 14 months. The median number of months that patients received treatment on this study was 1.7 (range: 0.5–14). Conclusion While not meeting the RECIST response criteria for adequate single-agent activity, the observed tolerable toxicities and the potential for clinical benefit in terms of stable disease suggest that further assessment of vorinostat as a part of combination therapy with either chemotherapeutic or targeted agents in metastatic breast might be undertaken.

S-adenosylhomocysteine hydrolase inhibition by 3-deazaneplanocin A analogues induces anti-cancer effects in breast cancer cell lines and synergy with both histone deacetylase and HER2 inhibition

“…We have also demonstrated synergistic interactions between AHIs and HDAC inhibition mirroring recent description of similar interactions in acute myeloid leukaemia and colorectal cancer models [11,16]. Clinical evidence for efficacy of HDAC inhib ition as a single agent approach in breast cancer has been modest to date and we and others have argued that HDAC inhib ition will require a co mb ination therapeutic strategy for optimal outcomes [19,22,24]. Our results are consistent with a model whereby optimal anti breast cancer effect is dependent on a mo re profound reset of underlying epigenetic abnormalit ies requiring both HDAC and histone methyltransferase inhibit ion.…”

Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells

“…The recognition that the first generation of relatively unspecific or pan-HDAC inhibitors showed limited clinical efficacy with significant side effects 14,15,25 has pushed the development of compounds inhibiting specifically only a single HDAC enzyme. HDAC6 is particularly well suited for specific inhibition by being notably different from other HDACs with regard to protein structure, cellular localization, and its substrates, while still being involved in the regulation of cellular process like proliferation, migration, invasion and especially cellular stress response.…”

“…Since common pan-HDAC inhibitors were shown to have adverse side effects and poor anti-cancer activity against lymphoma and solid tumors, 14,15 efforts have been undertaken to generate enzyme-specific inhibitors. HDAC6 is well-suited for specific inhibition due to its unique domain structure and mode of action and has been suggested to provide an exceptionally suitable target for cancer therapy.…”

Phase I trial of vorinostat and doxorubicin in solid tumours: histone deacetylase 2 expression as a predictive marker

“…Although HDAC inhibitors have shown efficacy in haematological malignancies (Marshall et al, 2002;Sandor et al, 2002;Byrd et al, 2005;Kelly et al, 2005;Garcia-Manero et al, 2008), their singleagent activity in solid tumours has been limited (Reid et al, 2004;Luu et al, 2006;Stadler et al, 2006;Blumenschein et al, 2008). This study describes a sequenced combination with the HDAC inhibitor vorinostat given for 48 h followed by an anthracycline-type topo II inhibitor, doxorubicin (Table 1).…”