A Pilot Study Targeting Angiogenesis Using Bevacizumab Combined With Chemotherapy and Histone Deacetylase Inhibitor (Valproic Acid) in Advanced Sarcomas
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
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Dose-limiting toxicities per CTCAE 4.0; grade 4 hematologic toxicity; grade 3 or 4 hepatotoxicity.
After one cycle (3 weeks)
Mohammed Milhem, MD
University of Iowa
United States: Institutional Review Board
|University of Iowa Hospitals and Clinics||Iowa City, Iowa 52242|