Sarcoma Clinical Trial
Official title:
A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas
The purpose of this study is to test the combination of the chemotherapy drugs Gemcitabine, bevacizumab, and docetaxel with valproic acid to treat patients with metastatic sarcoma. Valproic acid is used by people who have seizures to prevent seizures from happening; however, its use in cancer is investigational. This study will help define the proper dosing of this valproic acid. We will assess the safety of valproic acid with the combination of the above chemotherapy drugs and check for possible side effects. Valproic acid may improve the function of the chemotherapy drugs against the cancer.
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.
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