A novel strategy for treating oncogene-mutated tumors by targeting tumor microenvironment and synergistically enhancing anti-PD-1 immunotherapy

Oncogenes are critical factors in tumorigenesis of diverse cancer types and play essential roles in tumor immune escape.Mutations in Kirsten rat sarcoma viral oncogene homolog(KRAS)and epidermal growth factor receptor(EGFR)are among the most frequent gain-of-function alterations[1].After many years of in-depth research,inhibitors targeting EGFR or KRAS mutations have been successfully developed,however,their clinical benefit is relatively limited,and they will inevitably encounter the challenge of drug resistance.The emergence of resistance is attributed to secondary mutations in driver genes and other complicated factors.

Preclinical and early clinical studies of a novel compound SYHA1813 that efficiently crosses the blood-brain barrier and exhibits potent activity against glioblastoma

Glioblastoma(GBM)is the most common and aggressive malignant brain tumor in adults and is poorly controlled.Previous studies have shown that both macrophages and angiogenesis play significant roles in GBM progression,and co-targeting of CSF1R and VEGFR is likely to be an effective strategy for GBM treatment.Therefore,this study developed a novel and selective inhibitor of CSFIR and VEGFR,SYHA1813,possessing potent antitumor activity against GBM.SYHA1813 inhibited VEGFR and CSFIR kinase activities with high potency and selectivity and thus blocked the cell viability of HUVECs and macrophages and exhibited anti-angiogenetic effects both in vitro and in vivo.SYHA1813 also displayed potent in vivo antitumor activity against GBM in immune-competent and immune-deficient mouse models,including temozolomide(TMZ)insensitive tumors.Notably,SYHA1813 could penetrate the blood-brain barrier(BBB)and prolong the survival time of mice bearing intracranial GBM xenografts.Moreover,SYHA1813 treatment resulted in a synergistic antitumor efficacy in combination with the PD-1 antibody.As a clinical proof of concept,SYHA1813 achieved confirmed responses in patients with recurrent GBM in an ongoing first-in-human phase I trial.The data of this study support the rationale for an ongoing phase I clinical study(ChiCTR2100045380).