Reference Detail

Ref Type

Journal Article

PMID

(27651308)

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	76	23	2016 12 01	6988-7000	Cancer Res

URL

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CVX-060	CVX-060	0	0
CVX-241	CVX-241	0	0

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