Effective targeting of the VEGF/VEGFR axis either by knocking down VEGF-A, -C, or -D, or treatment with the pan-VEGFR inhibitor axitinib in a mouse model with constitutive mammalian target of rapamycin (mTOR) activation (develop tumors consistent with lymphangiosarcoma) suggests that targeting the upstream ligand or receptor may be a therapeutic option even in cases when downstream activating mutations are identified.14 Although these alterations do not represent the primary genetic driver events, targeting VEGF/VEGFR signaling is a rational clinical approach in angiosarcoma. Here, VEGFA is linked to lymphangiosarcoma.