sirolimus and Pheochromocytoma

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

To assess the activity of mTOR and downstream effector proteins in the mTOR pathway after treatment with a dual mTOR complex 1 and 2 (mTORC1/2) inhibitor (PP242) compared with that of mTOR complex 1 (mTORC1) inhibitor (rapamycin) using a xenograft tumor model.. Pheochromocytoma PC12 cell were xenografted into nude mice. Animals were treated with PP242 and rapamycin. Mean tumor volume was compared across groups. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining was used to detect apoptosis. Immunoblot analysis was performed to assess mTORC1/2 activity using p-Akt, p-S6, and p-4E-BP1. The expression of the antiapoptotic protein Bcl-2, pro-apoptotic protein Bax, and the mediator of angiogenesis vascular endothelial growth factor were also investigated.. The mean tumor volume of PP242 was significantly lower than in other groups. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling results showed that PP242 markedly increased cell apoptosis compared with other groups. Immunoblot analysis of tumor lysates treated with PP242 demonstrated inhibition of activated p-Akt. We also observed that only PP242, but not rapamycin, significantly reduced Bcl-2 expression and markedly increased Bax expression. Rapamycin decreased vascular endothelial growth factor expression, but not nearly as striking as seen in the PP242 group.. Our study showed that PP242 showed strong antitumor activity in a pheochromocytoma PC12 cell tumor model. Based on our study, dual mTORC1/2 kinase inhibitors warrant further investigation as a potential treatment for malignant pheochromocytomas or paragangliomas.

Topics: Adrenal Gland Neoplasms; Animals; Indoles; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred BALB C; Multiprotein Complexes; PC12 Cells; Pheochromocytoma; Purines; Rats; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

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

Pheochromocytomas are benign or malignant neuroendocrine tumours. The unsatisfactory efficacy of the traditional therapeutic methods for patients with metastatic disease results in a continuing search for more effective and targeted agents. Due to the increased vascularisation of these tumours, inhibitors of angiogenesis could be potentially a new group of drugs in pheochromocytoma/paraganglioma therapy.. The aim of this study was to evaluate the influence of angiomodulators: VEGF (vascular endothelial growth factor) and five endogenous and exogenous antiangiogenic compounds (endostatin; IFN-alpha [interferon alpha]; rapamycin - mTOR [mammalian target of rapamycin] inhibitor; JV1-36 and SU5416 (semaxinib]) on the growth of rat pheochromocytoma PC12 cell line.. IFN-alpha (10(5) U/mL) strongly inhibited PC12 growth in a 72 h culture, increasing apoptosis and arresting the cell cycle. Rapamycin in a wide range of concentrations (10(-5) to 10(-8) M) induced a slight inhibitory effect on PC12 viability and decreased cell proliferation at the concentration of 10(-5) M. VEGF, endostatin and JV1-36 did not influence the growth of PC12.. The study has shown for the first time that IFN-a inhibited the growth of pheochromocytoma PC12 line and confirmed the inhibitory action of rapamycin on these cells. The results suggest that IFN-alpha and mTOR inhibitors could be potentially effective in the therapy of malignant pheochromocytoma, and encourage further study in this field.

Topics: Adrenal Gland Neoplasms; Angiogenesis Inhibitors; Animals; Antineoplastic Agents; Cell Proliferation; Endostatins; Growth Hormone-Releasing Hormone; Indoles; Interferon-alpha; Neovascularization, Pathologic; PC12 Cells; Pheochromocytoma; Pyrroles; Rats; Sirolimus; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Phaeochromocytoma and paraganglioma are rare neuroendocrine tumours (NETS). They may be benign or malignant but the pathological distinction is mainly made when metastases are present. Available treatments in the form of surgery, chemotherapy, and radionuclide therapy may improve symptoms and biochemical markers, but the results for the control of tumour bulk are less favourable. Furthermore, responses to treatment are frequently short-lived. This short review outlines the main molecular and histological features of malignant phaeochromocytoma and the difficulties in differentiating between benign and malignant disease. We list current therapies used for malignant pheochromocytoma; however, these generally achieve relatively low success rates. Hence, there is a need for new and more effective therapies. In vitro studies have implicated the PI3/Akt/mTOR pathway in the pathogenesis of malignant NETS, including phaeochromocytoma. Everolimus (RAD001, Novartis UK) is a compound that inhibits mTOR (mammalian Target Of Rapamycin) signalling. We have used RAD001 in four patients with progressive malignant paraganglioma/phaeochromocytoma in addition to other therapies (with institutional approval for compassionate use), and evaluated the effects of this treatment. We outline these four cases and review the theoretical background for this therapy, although the outcomes were relatively disappointing.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Everolimus; Female; Humans; Male; Pheochromocytoma; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Young Adult