RESUMEN
BACKGROUND: There are phase 3 clinical trials underway evaluating anti-PD-L1 antibodies as adjuvant (postoperative) monotherapies for resectable renal cell carcinoma (RCC) and triple-negative breast cancer (TNBC); in combination with antiangiogenic VEGF/VEGFR2 inhibitors (e.g., bevacizumab and sunitinib) for metastatic RCC; and in combination with chemotherapeutics as neoadjuvant (preoperative) therapies for resectable TNBC. METHODS: This study investigated these and similar clinically relevant drug combinations in highly translational preclinical models of micro- and macro-metastatic disease that spontaneously develop after surgical resection of primary kidney or breast tumours derived from orthotopic implantation of murine cancer cell lines (RENCAluc or EMT-6/CDDP, respectively). RESULTS: In the RENCAluc model, adjuvant sunitinib plus anti-PD-L1 improved overall survival compared to either drug alone, while the same combination was ineffective as early therapy for unresected primary tumours or late-stage therapy for advanced metastatic disease. In the EMT-6/CDDP model, anti-PD-L1 was highly effective as an adjuvant monotherapy, while its combination with paclitaxel chemotherapy (with or without anti-VEGF) was most effective as a neoadjuvant therapy. CONCLUSIONS: Our preclinical data suggest that anti-PD-L1 plus sunitinib may warrant further investigation as an adjuvant therapy for RCC, while anti-PD-L1 may be improved by combining with chemotherapy in the neoadjuvant but not the adjuvant setting of treating breast cancer.
Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Neoplasias Renales/terapia , Neoplasias Mamarias Animales/terapia , Neovascularización Patológica/terapia , Animales , Antígeno B7-H1/inmunología , Bevacizumab/administración & dosificación , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Humanos , Inmunoterapia/métodos , Neoplasias Renales/inmunología , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Neoplasias Mamarias Animales/inmunología , Neoplasias Mamarias Animales/patología , Neoplasias Mamarias Animales/cirugía , Ratones , Terapia Neoadyuvante/métodos , Neovascularización Patológica/inmunología , Neovascularización Patológica/patología , Paclitaxel/administración & dosificación , Sunitinib/administración & dosificaciónRESUMEN
BACKGROUND: Progressive loss of podocytes has been documented as an early lesion in the development of glomerular disease. In a variety of glomerular diseases, including diabetic nephropathy the activation of transforming growth factor-beta (TGF-beta) has been demonstrated to promote podocyte death and the development of glomerulosclerosis. In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on TGF-beta1 induced apoptosis in podocytes. METHODS: To accomplish this we generated stable murine PKCalpha deficient podocyte cell lines and examined survival- and pro-apoptotic signaling signatures as well as caspase activation after stimulation with TGF-beta. RESULTS: After stimulation with TGF-beta we can demonstrate an enhanced and prolonged activation of PI3K/AKT and ERK1/2 in PKCalpha-knockout (PKCalpha-/-) podocytes compared to PKCalpha-wildtype (PKCalpha+/ +) podocytes, whereas proapoptotic signaling via p38MAPK is significantly reduced. Interestingly, activation of the Smad-pathway is also prolonged in the PKCalpha-/-podocytes. When we analyzed the underlying mechanisms we found a TGF-beta inducible interaction of PKCalpha with the TGF-beta-type-I-receptor (TGFbetaRI). Moreover, endocytosis assays showed that the TGFbetaRI is less internalized in PKCalpha-/- podocytes. CONCLUSION: Since we can demonstrate a key role for PKCalpha in the signaling response after stimulation with TGF-beta we conclude that PKCalpha might be an interesting target molecule as a "podocyte protective" therapy.