Bevacizumab, Chemotherapy and Valproic Acid in Advanced Sarcomas

• Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity. [ Time Frame: After one cycle (3 weeks) ] [ Designated as safety issue: Yes ]
  

Drug: Bevacizumab, Gemcitabine, docetaxel and valproic acid
Other Names:
• Avastin
• Gemzar
• Taxotere
• Depakene
• Stavzor

Soft tissue sarcomas (STS) are a heterogeneous group of benign and malignant tumors of various supportive tissues arising from the mesoderm. There are 56 known subtypes classified by the tissue of origin. Soft tissue sarcomas account for 1% of all human malignancies. These tumors share a common mesenchymal origin with the vasculature. Many of the signaling pathways involved in angiogenesis also drive sarcoma tumor cell growth. Autocrine and paracrine vascular endothelial growth factor (VEGF) - and platelet-derived growth factor (PDGF)-mediated growth plays a role in the pathogenesis of several sarcoma subtypes1. Despite promising preclinical data supporting a role for angiogenesis inhibition in sarcoma, relatively few clinical trials have evaluated antiangiogenic therapy in sarcoma.

Most of the studies for the use of anti-angiogenic drugs have been taken from phase I trials of refractory solid tumors showing a lack of response in sarcomas. This may be due to an inadequate dose, wrong sequence of the treatment or lack of studies with combination treatments. Given the heterogeneity of sarcomas there may be a benefit in certain subgroups that can easily be missed. A recent clinical trial has shown improved cytotoxic cell kill and response rates by epigenetically modifying the tumor environment prior to chemotherapy. It is believed that the efficacy of angiogenesis inhibitors has been shown to be greatly improved when they are combined with other anticancer drugs.

Tumor metastasis is highly dependent on angiogenesis progressing through a metastatic cascade that includes primary tumor growth, modification of tumor cell growth and behavior and formation of new blood vessels. This angiogenic switch is believed to be the result of changes in the balance of angiogenesis stimulators, inhibitors and modulators present at the site of the tumor growth. These changes are due to both genetic alterations involving RAS, RAF, MYC, SRC, EGFR and HER-2 and tumor suppressor genes and epigenetic circumstances such as hypoxia, inflammation or hormonal stimulation. It is clear that vascular endothelial growth factor (VEGF) has emerged as the key stimulatory molecule for promoting angiogenesis in a variety of human malignancies. Other pro-angiogenic factors can be induced or amplified in the presence of hypoxia hypoglycemia, inflammatory cytokines and altered cell-cell contact. Thus it would be of interest to combine epigenetic modifiers like Valproic acid, a histone deacetylase inhibitor, with Bevacizumab, an anti-angiogenic agent against VEGF and standard chemotherapy (Gemcitabine /docetaxel) to better modulate the cytotoxic effects against sarcomas.