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|Ref Type||Journal Article|
|Authors||Wu FT, Man S, Xu P, Chow A, Paez-Ribes M, Lee CR, Pirie-Shepherd SR, Emmenegger U, Kerbel RS|
|Title||Efficacy of Cotargeting Angiopoietin-2 and the VEGF Pathway in the Adjuvant Postsurgical Setting for Early Breast, Colorectal, and Renal Cancers.|
|Date||2016 12 01|
|Abstract Text||Antiangiogenic tyrosine kinase inhibitors (TKI) that target VEGF receptor-2 (VEGFR2) have not been effective as adjuvant treatments for micrometastatic disease in phase III clinical trials. Angiopoietin-2 (Ang2) is a proangiogenic and proinflammatory vascular destabilizer that cooperates with VEGF. The purpose of this study was to test whether CVX-060 (an Ang2-specific CovX-body) can be combined with VEGFR2-targeting TKIs (sunitinib or regorafenib) to successfully treat postsurgical metastatic disease in multiple orthotopically implanted human tumor xenograft and syngeneic murine tumor models. In the MDA-MB-231.LM2-4 human breast cancer model, adjuvant sunitinib was ineffective, whereas adjuvant CVX-060 delayed the progression of pulmonary or distant lymphatic metastases; however, overall survival was only improved with the adjuvant use of a VEGF-A/Ang2-bispecific CovX-body (CVX-241) but not when CVX-060 is combined with sunitinib. Adjuvant CVX-241 also showed promise in the EMT-6/CDDP murine breast cancer model, with or without an immune checkpoint inhibitor (anti-PD-L1). In the RENCA model of mouse renal cancer, however, combining CVX-060 with sunitinib in the adjuvant setting was superior to CVX-241 as treatment for postsurgical lung metastases. In the HCT116 and HT29 xenograft models of colorectal cancer, both CVX-060 and regorafenib inhibited liver metastases. Overall, our preclinical findings suggest differential strategies by which Ang2 blockers can be successfully combined with VEGF pathway targeting in the adjuvant setting to treat micrometastatic disease-particularly, in combination with VEGF-A blockers (but not VEGFR2 TKIs) in resected breast cancer; in combination with VEGFR2 TKIs in resected kidney cancer; and as single agents or with VEGFR2 TKIs in resected colorectal cancer. Cancer Res; 76(23); 6988-7000. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|CVX-060||PF-04856884||CVX-060 (PF-04856884) is a peptide-antibody fusion protein that targets Angiopoeitin-2 (Ang2), resulting in decreased angiogenesis, and potentially leading to decreased tumor growth (PMID: 21233403, PMID: 27651308).|
|CVX-241||PF-05057459||CVX-241 (PF-05057459) is a peptide-antibody fusion protein that targets both Angiopoetin-2 (Ang2) and Vegf, potentially resulted in decreased tumor growth (PMID: 21149738, PMID: 27651308).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||colorectal cancer||not applicable||CVX-060||Preclinical - Cell line xenograft||Actionable||In a preclinical study, CVX-060 did not inhibit primary tumor growth in two colorectal cancer cell line xenograft models, but reduced liver metastases in a xenograft model of colorectal cancer metastasis (PMID: 27651308).||27651308|
|Unknown unknown||kidney cancer||no benefit||CVX-241||Preclinical||Actionable||In a preclinical study, CVX-241 did not improve overall survival in a mouse model of resected renal cancer (PMID: 27651308).||27651308|
|Unknown unknown||breast cancer||not applicable||CVX-241||Preclinical||Actionable||In a preclinical study, CVX-241 treatment resulted in improved overall survival in a breast cancer cell line xenograft model and syngeneic mouse model of breast cancer (PMID: 27651308).||27651308|
|Unknown unknown||kidney cancer||not applicable||CVX-060 + Sunitinib||Preclinical||Actionable||In a preclinical study, the combination of CVX-060 and Sutent (sunitinib) demonstrated a trend improved overall survival compared to single agent Sutent (sunitinib) in mouse models of unresected and resected renal cancer, however, also demonstrated increased toxicity (PMID: 27651308).||27651308|