Dll4 blockade potentiates the anti-tumor effects of VEGF inhibition in renal cell carcinoma patient-derived xenografts.

[severe combined immunodeficiency]

The Notch ligand Delta -like 4 (Dll 4 ) is highly expressed in vascular endothelium and has been shown to play a pivotal role in regulating tumor angiogenesis . Blockade of the Dll 4 -Notch pathway in preclinical cancer models has been associated with non-productive angiogenesis and reduced tumor growth . Given the cross-talk between the vascular endothelial growth factor (VEGF ) and Delta -Notch pathways in tumor angiogenesis , we examined the activity of a function-blocking Dll 4 antibody , REGN 1035 , alone and in combination with anti-VEGF therapy in renal cell carcinoma (RCC ).Severe combined immunodeficiency (SCID ) mice bearing patient-derived clear cell RCC xenografts were treated with REGN 1035 and in combination with the multi-targeted tyrosine kinase inhibitor sunitinib or the VEGF blocker ziv -aflibercept . Immunohistochemical and immunofluorescent analyses were carried out , as well as magnetic resonance imaging (MRI ) examinations pre and 24 hours and 2 weeks post treatment . Single agent treatment with REGN 1035 resulted in significant tumor growth inhibition (36 -62 %) that was equivalent to or exceeded the single agent anti-tumor activity of the VEGF pathway inhibitors sunitinib (38 -54 %) and ziv -aflibercept (46 %). Importantly , combination treatments with REGN 1035 plus VEGF inhibitors resulted in enhanced anti-tumor effects (72 -80 % growth inhibition ), including some tumor regression . Magnetic resonance imaging showed a marked decrease in tumor perfusion in all treatment groups . Interestingly , anti-tumor efficacy of the combination of REGN 1035 and ziv -aflibercept was also observed in a sunitinib resistant ccRCC model .Overall , these findings demonstrate the potent anti-tumor activity of Dll 4 blockade in RCC patient-derived tumors and a combination benefit for the simultaneous targeting of the Dll 4 and VEGF signaling pathways , highlighting the therapeutic potential of this treatment modality in RCC .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated