Combination therapy using molecular‐targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma

Abstract

Tumor growth and metastasis are determined not by cancer cells alone but also by a variety of stromal cells, various populations of which overexpress platelet‐derived growth factor receptors (PDGF‐Rs). In addition, activation of PI3K‐AKT‐mammalian target of rapamycin (mTOR) signaling is frequently observed in many cancer types as well. mTOR comprises a serine/threonine kinase that increases the production of proteins that stimulate key cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. In this study, we investigated the impact of molecular‐targeting agents including PDGF‐R and mTOR inhibitors on the tumor stroma of human kidney cancer and examined the efficacy of combination therapy with these agents against this disease. Treatment with sunitinib did not suppress tumor growth, but significantly decreased stromal reactivity, microvessel density, and pericyte coverage of tumor microvessels in an orthotopic mouse model. In contrast, treatment with everolimus decreased tumor growth and microvessel density but not stromal reactivity. However, sunitinib and everolimus in combination reduced both the growth rate and stromal reaction. These findings suggest that target molecule‐based inhibition of the cancer–stromal cell interaction appears promising as an effective antitumor therapy.

Targeting Tumor Microenvironment for Cancer Therapy

“…The results suggest that combining these two drugs was a viable strategy leading to the inhibition of growth of ocular melanoma xenografts in mice, including in highly aggressive models where metastases were already developed [ 156 ]. More recently, Kitano and colleagues established a combination therapy regarding renal cell carcinoma [ 157 ]. In this study, Sunitinib was used to inhibit tyrosine kinase activity of VEGF and PDGF receptors, which are overexpressed by stromal cells, and Everolimus inhibits the mTOR pathway, involved in cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis.…”

“…In this study, Sunitinib was used to inhibit tyrosine kinase activity of VEGF and PDGF receptors, which are overexpressed by stromal cells, and Everolimus inhibits the mTOR pathway, involved in cellular processes such as cell growth and proliferation, cell metabolism, and angiogenesis. Although Sunitinib alone only decreased stromal reactivity and Everolimus only decreased tumor growth, when combined they reduced both the growth rate and stromal reaction [ 157 ]. Overall, these results revealed that such combinations were promising approaches for the modulation of the TME, inhibiting both tumor and stromal cells.…”

In vitro and in vivo effects of toceranib phosphate on canine osteosarcoma cell lines and xenograft orthotopic models

“…Interestingly, TOC treatment decreased tumour growth in mice inoculated with Penny cells but not those inoculated with Wall cells. Regarding the selected histological parameters, tumour cell density was reduced in treated mice compared to control mice regardless of the cell line, suggesting that TOC can also act at stromal level to modulate angiogenesis and the microenvironment, which is similar to mechanism of sunitinib …”

Molecular Protein and Expression Profile in the Primary Tumors of Clear Cell Renal Carcinoma and Metastases

“…PI3K/AKT/mTOR is one of the universal signaling pathways characteristic of most cells, the central components of which are the enzymes phosphoinositide-3-kinase (PI3K), AKT and m-TOR kinases [ 19 ]. This intracellular cascade is critical in the life of the cell, determining its growth, proliferation and apoptosis [ 20 , 21 , 22 ]. Our study aimed at investigating the features of the activation of the complex of intracellular signal metabolites in the series of normal renal parenchyma, tumor tissue of localized, disseminated kidney cancer and metastatic tissues.…”