Dual targeting of VEGFR2 and CSF1R with SYHA1813 confers novel strategy for treating both BRAF wild-type and mutant melanoma.

Abstract

Background: Melanoma is notorious for its aggressive growth, metastatic spread, and heterogeneous response to therapy across BRAF (B-Raf proto-oncogene, serine/threonine kinase) genotypes. While BRAF inhibitors improve outcomes in V600E-mutant tumors, their benefit is limited in wild-type melanomas and by transient responses in mutant disease. Vascular endothelial growth factor receptor 2 (VEGFR2) driven angiogenesis and colony-stimulating factor-1 receptor (CSF1R) mediated immunosuppression each sculpt a permissive tumor microenvironment. We hypothesized that simultaneous blockade of both axes with SYHA1813, which currently undergoing Phase II clinical trials in China for solid tumor treatment, would yield a broadly applicable, microenvironment-targeted strategy for melanoma treatment.

Methods: Subcutaneous xenograft models of BRAF wild-type (MeWo) and BRAF V600E-mutant (A375) melanoma were established (NOD-SCID mice), alongside an intracardiac metastasis model (Nude mice) using GFP-Luc-labeled A375 cells. SYHA1813 (2.5 mg/kg or 5 mg/kg), alone or combined with vemurafenib (20 mg/kg), was administered to assess tumor growth, metastatic burden, and microenvironmental modulation. Tumor growth inhibition rates and synergistic effects were quantified. The markers of angiogenesis, macrophage polarization and cell proliferation were analyzed via immunohistochemistry.

Results: SYHA1813 monotherapy exhibited significant antitumor efficacy in BRAF wild-type MeWo and BRAF V600E-mutant A375 melanoma xenograft models at 5 mg/kg, achieving 72.5% and 79.8% tumor growth inhibition, respectively, surpassing vemurafenib in BRAF wild-type tumors. Treatment regimens were well tolerated, with no significant body weight changes observed. Mechanistically, SYHA1813 suppressed angiogenesis, attenuated M2 macrophage infiltration, and inhibited tumor cell proliferation as marked by reduced CD31, CD105, F4/80, CD206 and Ki67 expression. Moreover, we evaluated the combination of SYHA1813 with vemurafenib in BRAF V600E-mutant models and found that 2.5 mg/kg SYHA1813 treatment synergized with vemurafenib, enhancing tumor suppression to 72.9% inhibition compared to each monotherapy (38.9% and 34.7%, respectively). Furthermore, we established a systemic intracardiac metastasis mouse model to assess the impact of SYHA1813 on melanoma metastasis. The results showed that SYHA1813 reduced systemic metastasis by 76.6%, significantly curtailing brain and bone metastases.

Conclusions: Dual targeting of VEGFR2 and CSF1R with SYHA1813 confers a novel microenvironmentcentric strategy for treating both BRAF wildtype and mutant melanoma. By concurrently disrupting angiogenesis and macrophagemediated immunosuppression, SYHA1813 demonstrates strong therapeutic and antimetastatic activity to melanoma, warranting further clinical development as monotherapy or in combination with BRAF V600E inhibitors.