sirolimus and Paraganglioma

The current study was conducted to evaluate the efficacy and safety of everolimus in the treatment of patients with nonfunctioning neuroendocrine tumors (NETs) or pheochromocytomas/paragangliomas.. Patients with histologically confirmed nonfunctioning NETs or pheochromocytomas/paragangliomas and with documented disease progression before study enrollment were eligible for the current study. Everolimus was administered daily at a dose of 10 mg for 4 weeks. Response was assessed by Response Evaluation Criteria In Solid Tumors (RECIST; version 1.0) every 8 weeks. The primary endpoint was the 4-month progression-free survival rate (PFSR). The hypothesis of the current study was that the 4-month PFSR would increase from 50% to 65%. Safety was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).. A total of 34 patients were enrolled. Of these, 27 patients had nonfunctioning NETs, 5 had pheochromocytomas, and 2 had paragangliomas. The 4-month PFSR was 78%. Partial response (PR) was observed in 3 patients. Twenty-eight patients had stable disease (SD) and 2 patients developed progressive disease (PD). The response rate (RR) and overall disease control rate (DCR) were 9.0% (95% confidence interval [95% CI], 0%-18.6%) and 93.9% (95% CI, 85.8%-100%), respectively. The PFS was 15.3 months (95% CI, 4.6 months-26.0 months). Of the patients with nonfunctioning NETs, 3 achieved a PR and 23 had SD (RR, 11.1%; DCR, 100%); the PFS was 17.1 months (95% CI, 11.1 months-23.0 months) and the 4-month PFSR was 90.0%. Twenty-one patients (80.8%) demonstrated tumor shrinkage. In 7 patients with pheochromocytomas/paragangliomas, 5 achieved SD, and 2 developed PD. The PFS was 3.8 months (95% CI, 0.5 months-7.0 months) and the 4-month PFSR was 42.9%. Four patients demonstrated tumor shrinkage. The major grade 3/4 adverse events were thrombocytopenia (14.7%), hyperglycemia (5.9%), stomatitis (5.9%), and anemia (5.9%).. Everolimus was associated with high therapeutic efficacy and tolerability in patients with nonfunctioning NETs, and demonstrated modest efficacy in patients with pheochromocytomas/paragangliomas.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Everolimus; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Staging; Neuroendocrine Tumors; Paraganglioma; Pheochromocytoma; Prognosis; Sirolimus; Survival Rate

Recent studies have found that mammalian target of rapamycin complex 2 (mTORC2) is emerging as a potential therapeutic target in the treatment of many human cancers. However, the effects of targeting of mTORC2 on malignant pheochromocytomas (PCC) and paragangliomas (PGL) have not been reported. The aim of the study was to investigate the effects of targeting of mTORC2 on malignant PCC/PGL by comparing the inhibitory effects of targeting of mTORC2 with mTORC1 on pheochromocytoma PC12 cell in vitro and vivo. The expressions of regulatory-associated protein of mTOR (raptor) and rapamycin-insensitive companion of mTOR (rictor) were detected by immunohistochemistry in human tissues of malignant PCC. Targeting of mTORC1, mTORC2, and mTORC1/2 (mTORC1 and mTORC2) were performed by transfected with raptor, rictor, and mammalian target of rapamycin (mTOR) small interfering RNA (siRNA) in pheochromocytoma PC12 cell, respectively. MTT assay, apoptosis analysis, wound healing, and Transwell approach were performed. A tumor model in nude mice bearing PC12 cell xenografts, which were dosed with rapamycin or PP242, was established. The expression of raptor was frequently moderate positive, but the expression of rictor was frequently strong positive in malignant PCC. In vitro, although inhibition of mTORC1 was able to suppress PC12 cell proliferation, inhibition of mTORC2 more effectively suppressed cell proliferation. Inhibition of mTORC2 or mTORC1/2 more effectively prevented cell migration and invasion, and promoted cell apoptosis, while inhibition of mTORC1 only slightly prevented cell migration and invasion, and was not able to promoted apoptosis. Also, we found that mTOR downstream kinases were deregulated by targeting of mTORC2, but not mTORC1. In vivo, we found that PP242 was more potent than rapamycin in inhibiting tumor growth in tumor model. Our data suggest that targeting of mTORC2 may have advantages over selective targeting of mTORC1 in the treatment of malignant PCC/PGL. However, more clinical trials are needed to prove our findings.

Topics: Adaptor Proteins, Signal Transducing; Adrenal Gland Neoplasms; Animals; Carrier Proteins; Humans; Indoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Multiprotein Complexes; Paraganglioma; Pheochromocytoma; Purines; Rapamycin-Insensitive Companion of mTOR Protein; Regulatory-Associated Protein of mTOR; RNA, Small Interfering; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays