CYT997
CYT997 is a novel anti-cancer vascular disrupting agent (VDA). In contrast to most other VDAs, CYT997 may be administered both orally and intravenously. Oral administration may allow for more frequent, convenient, and potentially efficacious dosing schedules either as a single agent or in combination with other anti-cancer drugs.
CYT997 possesses potent vascular disrupting properties against established tumor blood vessels. Studies in several cancer models have demonstrated that the molecule destroys the vasculature which serves growing tumors while sparing normal, healthy blood vessels. By attacking tumor endothelial cells, CYT997 causes tumor blood flow arrest, starvation of rapidly dividing tumor cells and tumor death. The molecule also directly affects tumor cell replication via its inhibition of the cellular structural protein, tubulin.
CYT997: Mechanism of Action
The Oral VDA Advantage
Potential advantages of oral administration of CYT997 include improved patient convenience, combination with other oral molecularly targeted agents and improved efficacy and safety.
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IV administration of most VDAs in clinical development positions them to be administered infrequently and at high doses.
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Such schedules result in rapid tumor revascularization (within days of treatment) and toxicities.
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High doses will likely cause spikes in circulating pro-angiogenic endothelial precursor cells that restore tumor vasculature.[1]
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Oral administration of CYT997 at low, minimally toxic doses at frequent intervals may have safety and efficacy advantages via the continuous disruption of tumor vasculature.
Clinical Progress and Development
CYT997 has completed two Phase I studies in advanced solid tumors and is currently being studied in a Phase II clinical trial in combination with chemotherapy in patients with relapsed glioblastoma multiforme. Results from the intravenous Phase I dose escalation study were published in the British Journal of Cancer (Lickliter et al, 2010), and demonstrated clinically meaningful disease stabilization in the majority of patients treated. Data showed that CYT997 administration was associated with changes in plasma and imaging biomarkers consistent with vascular disruption in tumors. Magnetic resonance imaging showed significant changes in tumor perfusion consistent with vascular disruption in some patients. Data from the Phase I oral study of CYT997 in patients with advanced cancer were reported at ASCO 2009 (Francesconi et al, 2009).
| [1] | Shaked Y, et al. Rapid Chemotherapy-Induced Acute Endothelial Progenitor Cell Mobilization: Implications for Antiangiogenic Drugs as Chemosensitizing Agents. Cancer Cell 2008; 14: 263-273 |