Imaging-guided evaluation of the novel small-molecule benzosuberene tubulin-binding agent kgp265 as a potential therapeutic agent for cancer treatment

Yihang Guo, Honghong Wang, Jeni L. Gerberich, Samuel O. Odutola, Amanda K. Charlton-Sevcik, Maoping Li, Rajendra P. Tanpure, Justin K. Tidmore, Mary Lynn Trawick, Kevin G. Pinney, Ralph P. Mason, Li Liu

Research output: Contribution to journalArticlepeer-review

Abstract

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 pro-drug 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 re-vealed by dynamic bioluminescence imaging (BLI). In syngeneic orthotopic 4T1-luc breast and RENCA-luc kidney tumors, dynamic BLI and oxygen enhanced multispectral optoacoustic tomog-raphy (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 contin-ued 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, generat-ing long-term vascular shutdown and tumor growth delay, thus providing strong rationale for fur-ther development, particularly in combination therapies.

Original languageEnglish (US)
Article number4769
JournalCancers
Volume13
Issue number19
DOIs
StatePublished - Oct 1 2021

Keywords

  • Benzosuberene
  • Bioluminescence imaging (BLI)
  • Breast tumors
  • Carboplatin
  • Com-bretastatin
  • Kidney tumors
  • Multispectral optoacoustic tomography (MSOT)
  • Photoacoustics
  • Vascular-disrupting agent (VDA)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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