Deciphering the effects of ANG-2, VEGFR and PD-1 blockade in small cell lung cancer
Among the various lung cancer subtypes, small cell lung cancer (SCLC) accounts for about 15% of diagnoses. This subtype is characterized by an extraordinarily rapid progression and early metastasis formation and is thus associated with a particularly poor prognosis. SCLC is treated with platinum-based chemotherapy as a standard which can be extended by immunotherapy in the form of Atezolizumab, a PD-L1 blocking antibody, since 2018. The molecular pathways driving the early tumor-cell invasion and metastasis formation are still widely uncertain. To gain further insights into SCLC-biology concerning metastasis, we studied both an inducible autochthonous SCLC mouse model as well as matched SCLC patient samples in order to pursue a translational approach.
We identified a signaling-pathway that triggers SCLC metastasis formation via the angiopoietin-2 (ANG-2) ligand CD29 (integrin-β1) and downstream activation of the focal adhesion (FAK) and c-SRC kinases. Further, we showed that pharmacological blockade of ANG-2 in SCLC-bearing mice significantly reduced the liver metastasis formation in vivo. Our analysis of matched tumor samples from SCLC patients further revealed a strong increase of integrin-β1 levels in liver metastases compared to the matched primary lung tumor.
Based on these recently gained insights, we have extended the previously evaluated combination therapy consisting of VEGFR- and PD-1/PD-L1 blockade (Meder et al. 2018) with additional antibody-mediated blockade of ANG-2. We demonstrated the triple combination therapy to significantly suppress metastasis formation in vivo and to display synergistic treatment effects concerning overall and progression-free survival of mice suffering from SCLC. In summary, our study provides a rationale that therapeutic blockade of ANG-2 may inhibit SCLC metastasis formation and that the combination therapy of ANG-2/VEGFR/PD-1 blockade serves as a potential new therapy approach in the treatment of patients suffering from SCLC.