Imaging-Guided Evaluation of the Novel Small-Molecule Benzosuberene Tubulin-Binding Agent KGP265 as a Potential Therapeutic Agent for Cancer Treatment

• Published in: Cancers Vol. 13; no. 19; p. 4769
• Main Authors: Guo, Yihang, Wang, Honghong, Gerberich, Jeni L., Odutola, Samuel O., Charlton-Sevcik, Amanda K., Li, Maoping, Tanpure, Rajendra P., Tidmore, Justin K., Trawick, Mary Lynn, Pinney, Kevin G., Mason, Ralph P., Liu, Li
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 24.09.2021; MDPI
• Subjects: benzosuberene; Bioluminescence; bioluminescence imaging (BLI); Blood vessels; Body weight; Body weight loss; Breast cancer; breast tumors; Cancer therapies; Carboplatin; Cell cycle; combretastatin; Cytotoxicity; FDA approval; Growth factors; Hemorrhage; Kidneys; Life sciences; Oxygen; Oxygenation; Phosphatase; Polymerization; Solid tumors; Syngeneic grafts; Tomography; Toxicity; Tubulin; Tumors; vascular-disrupting agent (VDA); Xenografts; St Louis Missouri; United States > US
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers13194769

The selective disruption of tumor-associated vasculature represents an attractive therapeutic approach. We have undertaken the first in vivo evaluation of KGP265, a water-soluble prodrug of a benzosuberene-based tubulin-binding agent, and found promising vascular-disrupting activity in three distinct tumor types. Dose escalation in orthotopic MDA-MB-231-luc breast tumor xenografts in mice indicated that higher doses produced more effective vascular shutdown, as revealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomography (OE-MSOT) were used to compare vascular shutdown following the administration of KGP265 (7.5 mg/kg). The BLI signal and vascular oxygenation response (ΔsO2) to a gas breathing challenge were both significantly reduced within 2 h, indicating vascular disruption, which continued over 24 h. A correlative histology confirmed increased necrosis and hemorrhage. Twice-weekly doses of KGP265 caused significant growth delay in both MDA-MB-231 and 4T1 breast tumors, with no obvious systemic toxicity. A combination with carboplatin produced significantly greater tumor growth delay than carboplatin alone, though significant carboplatin-associated toxicity was observed (whole-body weight loss). KGP265 was found to be effective at low concentrations, generating long-term vascular shutdown and tumor growth delay, thus providing strong rationale for further development, particularly in combination therapies.