Enhancement of Soft Tissue Sarcoma Response to Gemcitabine through Timed Administration of a Short-Acting Anti-Angiogenic Agent.

BACKGROUND/AIMS

Despite enormous effort, anti-angiogenic drugs have not lived up to the promise of globally-enhancing anti-cancer therapies. Clinically, anti-angiogenic drugs have been used to persistently suppress vascular endothelial growth factor (VEGF) in order to "normalize" dysfunctional neo-angiogenic microvasculature and prevent recruitment of endothelial progenitors. Recently, we showed that a 1h pre-treatment with anti-angiogenic drugs prior to ultra-high single dose radiotherapy and specific chemotherapies transiently de-represses acid sphingomyelinase (ASMase), leading to enhanced cancer therapy-induced, ceramide-mediated vascular injury and tumor response. Here we formally decipher parameters of chemotherapy induction of endothelial sphingolipid signaling events and define principles for optimizing anti-angiogenic chemosensitization.

METHODS

These studies examine the antimetabolite chemotherapeutic gemcitabine in soft tissue sarcoma (STS), a clinically-relevant combination.

RESULTS

Initial studies address the theoretic problem that anti-angiogenic drugs such as bevacizumab, an IgG with a 3-week half-life, have the potential for accumulating during the 3-week chemotherapeutic cycles currently standard-of-care for STS treatment. We show that anti-angiogenic ASMase-dependent enhancement of the response of MCA/129 fibrosarcomas in sv129/BL6 mice to gemcitabine progressively diminishes as the level of the VEGFR2 inhibitor DC101, an IgG, accumulates, suggesting a short-acting anti-angiogenic drug might be preferable in multi-cycle chemotherapeutic regimens. Further, we show lenvatinib, a VEGFR2 tyrosine kinase inhibitor with a short half-life, to be superior to DC101, enhancing gemcitabine-induced endothelial cell apoptosis and tumor response in a multi-cycle treatment schedule.

CONCLUSION

We posit that a single delivery of a short-acting anti-angiogenic agent at 1h preceding each dose of gemcitabine and other chemotherapies may be more efficacious for repeated sensitization of the ASMase pathway in multi-cycle chemotherapy regimens than current treatment strategies.

Informations de copyright

© Copyright by the Author(s). Published by Cell Physiol Biochem Press.

Déclaration de conflit d'intérêts

Patents unrelated to this work: RK (US7195775B1, US7850984B2, US10052387B2, US8562993B2, US9592238B2, US20150216971A1, and US20170335014A1, US20170333413A1, US20180015183A1, US10414533B2, US10450385B2), ZF (US 10413533B2, US20170333413A1, and US20180015183A1).Richard Kolesnick and Zvi Fuks are co-funders of Ceramedix Holding L.L.C. The remaining authors have declared that no conflicts of interest exist.