Network targeting combination therapy of synthetic lethal vulnerabilities in 9p21- deficient glioblastoma: A case report

Background: Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case report describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21.

Methods and results: Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes.

Conclusion: Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.