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Targeting acid sphingomyelinase with anti-angiogenic chemotherapy
Jeanna Jacobi1, Mónica García-Barros2, Shyam Rao1
1Department of Radiation Oncology, USA.
Abstract:
Despite great promise, combining anti-angiogenic and conventional anti-cancer drugs has produced limited therapeutic benefit in clinical trials, presumably because mechanisms of anti-angiogenic tissue response remain only partially understood. Here we define a new paradigm, in which anti-angiogenic drugs can be used to chemosensitize tumors by targeting the endothelial acid sphingomyelinase (ASMase) signal transduction pathway. We demonstrate that paclitaxel and etoposide, but not cisplatin, confer ASMase-mediated endothelial injury within minutes. This rapid reaction is required for human HCT-116 colon cancer xenograft complete response and growth delay. Whereas VEGF inhibits ASMase, anti-VEGFR2 antibodies de-repress ASMase, enhancing endothelial apoptosis and drug-induced tumor response in asmase+/+, but not in asmase-/-, hosts. Such chemosensitization occurs only if the anti-angiogenic drug is delivered 1-2h before chemotherapy, but at no other time prior to or post chemotherapy. Our studies suggest that precisely-timed administration of anti-angiogenic drugs in combination with ASMase-targeting anti-cancer drugs is likely to optimize anti-tumor effects of systemic chemotherapy. This strategy warrants evaluation in future clinical trials.
Insights
Combining anti-angiogenic drugs with chemotherapy can enhance anti-tumor effects. Targeting the endothelial acid sphingomyelinase (ASMase) pathway with precise timing sensitizes tumors to chemotherapy, improving treatment outcomes.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Combining anti-angiogenic and conventional anti-cancer drugs has shown limited clinical benefit.
- Understanding anti-angiogenic tissue response mechanisms is crucial for improving cancer therapy.
Purpose of the Study:
- To define a new paradigm for chemosensitizing tumors using anti-angiogenic drugs.
- To investigate the role of the endothelial acid sphingomyelinase (ASMase) pathway in anti-angiogenic therapy.
Main Methods:
- Evaluating the effect of paclitaxel, etoposide, and cisplatin on endothelial ASMase activity.
- Assessing the impact of anti-VEGFR2 antibodies on ASMase and tumor response in asmase+/+ and asmase-/- mice.
- Determining the optimal timing for combining anti-angiogenic drugs with chemotherapy.
Main Results:
- Paclitaxel and etoposide, but not cisplatin, induce rapid ASMase-mediated endothelial injury.
- Anti-VEGFR2 antibodies de-repress ASMase, enhancing chemotherapy response in a host-dependent manner.
- Chemosensitization is achieved only when anti-angiogenic drugs are administered 1-2 hours before chemotherapy.
Conclusions:
- Targeting the endothelial ASMase pathway represents a novel strategy for chemosensitization.
- Precisely timed administration of anti-angiogenic drugs can optimize anti-tumor effects.
- This combination strategy warrants further clinical evaluation for systemic chemotherapy.
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