Inhibition of mTOR Radiosensitizes Soft Tissue Sarcoma and Tumor Vasculature

Abstract

Purpose: The PI3K/Akt/mTOR prosurvival pathway is frequently up-regulated in soft tissue sarcoma. Mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, have recently shown clinical benefit in soft tissue sarcoma, and mTOR inhibition has also been associated with radiosensitization of carcinoma and endothelial cells. This study tested the hypothesis that rapamycin radiosensitizes soft tissue sarcoma and endothelial cells in vitro and in vivo through the inhibition of mTOR. Experimental Design: Colony formation assays were done to determine the radiosensitizing properties of rapamycin on three human soft tissue sarcoma cell lines (SK-LMS-1, SW-872, and HT-1080) and human dermal microvascular endothelial cells (HDMEC). The functional effects of rapamycin and radiation on the endothelial compartment were evaluated with microvascular sprouting assays. The in vivo radiosensitizing activity of rapamycin was assessed with s.c. SK-LMS-1 nude mice xenografts treated with concurrent daily rapamycin, radiation, or both for three weeks. Results: In vitro radiosensitization was shown in all three soft tissue sarcoma cell lines with minimally cytotoxic doses of rapamycin. SK-LMS-1 xenografts displayed significant tumor growth delay with rapamycin and radiation compared with either treatment alone. Radiation resulted in transient increased mTOR function, whereas rapamycin abolished this signaling in irradiated and unirradiated samples. In HDMEC, rapamycin and radiation reduced microvessel sprouting, but did not alter colony formation. Conclusions: Minimally cytotoxic concentrations of rapamycin inhibited the mTOR cascade in culture and in vivo while radiosensitizing soft tissue sarcoma, and produced synergistic effects with radiation on HDMEC microvessel formation. By targeting both tumor and endothelial compartments, rapamycin produced potent radiosensitization of soft tissue sarcoma xenografts. Clinical trials combining rapamycin and radiotherapy in soft tissue sarcoma are warranted.

HSP90 inhibition as a means of radiosensitizing resistant, aggressive soft tissue sarcomas

“…Whereas for heavy ion irradiation and hyperthermia in combination with photon irradiation the clinical results are promising [33,36], the efficacy of combined radiochemotherapy is controversially discussed and comes at the costs of accumulating side effects [37,38]. Additionally, molecularly targeted approaches of radiosensitization with protein kinase, mammalian target of rapamycin (mTOR), and histone deacetylase (HDAC) inhibitors have been developed in preclinical studies and are currently undergoing clinical evaluation [39][40][41][42][43][44]. HSP90 inhibition in general appears as a very attractive means of radiosensitization, since it can target multiple HSP90 client proteins orchestrating radioresistance and other characteristics of the malignant phenotype, including angiogenesis, invasiveness and metastasis, at the same time [28,30,45,46].…”

Réirradiation de métastases ganglionnaires d’un adénocarcinome œsogastrique par une technique de tomothérapie associée à de l’évérolimus

“…Théoriquement, l'inhibition de mTor peut perturber les mécanismes de radiorésistance en diminuant l'expression de facteurs pro-angiogéniques induits par l'irradiation et en interrompant la voie de signalisation du VEGF, conduisant à une inhibition de la prolifération des cellules endothéliales [13]. Les inhibiteurs de mTor ont un effet anti-angiogénique, en sensibilisant l'endothélium vasculaire à l'irradiation assurant ainsi un meilleur contrôle tumoral dans des modèles de gliomes [10], de sarcomes [6], de cancers coliques et de cancers pancréatiques [13] ; • la promotion de l'autophagie. L'autophagie est un processus vacuolaire cellulaire de dégradation du contenu du cytoplasme dans les lysosomes.…”

“…À ce jour, aucune donnée clinique n'existe sur une association concomitante d'évérolimus et de radiothérapie dans le cancer gastrique évolué. Des études précliniques suggèrent, néanmoins, une radiosensibilisation par l'évérolimus [6][7][8]. L'association de l'évérolimus et de la tomothérapie a déjà été rapportée dans un cas clinique chez un patient atteint d'un adénocarcinome rénal en progression péri-tonéale sans augmentation particulière de la toxicité aiguë [9].…”

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors

“…Synergistic antitumor effects have been observed when rapalogs are combined with multiple cytotoxics and targeted agents, as well as with radiation therapy [198][199][200]. For example, it has been published that lack of response to EGFR and HER2 inhibitors is associated with deregulation of downstream signaling elements and mTOR activation [201,202], and that this resistance could be bypassed by rapalogs [166,203].…”