sirolimus and Carcinoma--Papillary

Renal cell carcinoma (RCC) encompasses a heterogeneous group of histological subtypes, of which clear cell RCC (CCRCC) is the most common, comprising more than 70% of all cases. Papillary RCC (PRCC) is the next most common, comprising 10-15% of cases. PRCC is refractory to chemotherapy, immunotherapy and hormonal therapy. Recent improvements in our understanding of the molecular biology of CCRCC have identified multiple pathways associated with the development of this cancer. This has led to drug development targeting these pathways, including the small molecule tyrosine kinase inhibitors sunitinib and sorafenib, the monoclonal antibody bevacizumab and the mTOR inhibitor temsirolimus. These drugs have shown significant clinical benefits in randomized trials of advanced CCRCC and have become the standard of care for most patients. However, since these trials were, on the whole, restricted to patients with clear cell histology, their efficacy in patients with non-clear cell RCC, and particularly PRCC, is unclear. This review will focus on the activity of these targeted agents in the treatment of metastatic PRCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Bevacizumab; Carcinoma, Papillary; Carcinoma, Renal Cell; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Indoles; Kidney Neoplasms; Neoadjuvant Therapy; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Protein Kinases; Pyridines; Pyrroles; Quinazolines; Randomized Controlled Trials as Topic; Sirolimus; Sorafenib; Sunitinib; TOR Serine-Threonine Kinases

This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer.. Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety.. Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%).. Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation.. NCT01164176.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Medullary; Carcinoma, Papillary; Disease-Free Survival; Everolimus; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Staging; Sirolimus; Thyroid Neoplasms; Treatment Outcome

We previously reported both in vivo and in vitro effects of rapamycin on urothelial carcinoma. Clinically, the use of rapamycin could not completely prevent the recurrence of urothelial carcinoma. Therefore, we designed this study to compare the difference of efficacy between early and late use of rapamycin in a rat model of urothelial carcinoma.. The rat model of urothelial carcinoma was induced by adding 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to the drinking water for up to 20 weeks in male Fisher-344 rats. Rapamycin was fed orally from the 1st day, 5th week, 9th week, 13th week, and 17th week. The antitumor effects of different periods of rapamycin treatment were assessed grossly and microscopically.. Papillary tumors of urinary bladder were successfully induced in the BBN group. Simultaneous use of rapamycin and BBN from the 1st day of treatment significantly reduced the tumor growth in urinary bladder: 80% of the rats had no tumor and 20% had low-grade tumors. Adding rapamycin from the 5th week was associated with more tumor growth: 20% of the rats had no tumors, 20% had low-grade tumors, and 60% had high-grade tumors. Moreover, in the groups with rapamycin treatment from the 9th week, 13th week, and 17th week, all rats developed high-grade papillary tumors in urinary bladder, as did the control group that received no rapamycin.. The study results suggest that the anticancer effect of rapamycin on urothelial carcinoma is stage dependent. Early use of rapamycin provides better anticancer effect, whereas late use of rapamycin fails to inhibit the cancer growth.

Topics: Animals; Antineoplastic Agents; Butylhydroxybutylnitrosamine; Carcinoma, Papillary; Drug Administration Schedule; Male; Neoplasm Grading; Neoplasms, Experimental; Rats, Inbred F344; Sirolimus; Time Factors; Tumor Burden; Urinary Bladder Neoplasms; Urothelium

Topics: Antineoplastic Agents; Carcinoma; Carcinoma, Papillary; Carcinoma, Renal Cell; Dermatologic Agents; Fatal Outcome; Female; Humans; Hydrocortisone; Keratin-7; Kidney Neoplasms; Lymphatic Metastasis; Middle Aged; Paired Box Transcription Factors; PAX8 Transcription Factor; Sirolimus; Skin Neoplasms; Thyroid Cancer, Papillary; Thyroid Neoplasms

Because mammalian target of rapamycin (mTOR) may be involved in thyroid carcinogenesis, we investigated the expression and activation patterns of mTOR signaling proteins in thyroid carcinoma cells and tumors and their association with tumor histology and aggressiveness.. Tissue specimens from 50 patients with thyroid cancer were analyzed for eIF4E, a critical downstream target of the mTOR pathway, using immunohistochemistry. In addition, fresh-frozen samples from patients, and primary tumor cell cultures were analyzed for expression and activation of mTOR signaling proteins by Western blot. Moreover, pharmacologic studies with rapamycin were performed.. High expression of eIF4E was observed in medullary thyroid carcinomas (MTC) and in aggressive variants of papillary thyroid carcinomas (PTC) as compared with conventional PTC and follicular thyroid carcinomas (P < .0001). The level of eIF4E expression also correlated with tumor stage (P = .002). Using Western blot analysis, p-rpS6, p-4EBP1, 4EBP1, and eIF4E were detected at higher levels in aggressive PTC and MTC cells. Treatment of MTC cells with increasing concentrations of rapamycin resulted in significant cell death and in decreased cell growth associated with deactivation of the mTOR pathway.. mTOR signaling, which controls protein synthesis through regulation of translation initiation, is activated in aggressive PTC and MTC and represents a promising target for investigational therapies in these patients.

Topics: Adult; Blotting, Western; Carcinoma; Carcinoma, Neuroendocrine; Carcinoma, Papillary; Cell Death; Cell Line, Tumor; Eukaryotic Initiation Factor-4E; Female; Humans; Immunohistochemistry; Male; Middle Aged; Neoplasm Staging; Signal Transduction; Sirolimus; Thyroid Cancer, Papillary; Thyroid Neoplasms; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Although autophagy is generally considered a prosurvival mechanism that preserves viability, there is evidence that it could drive an alternative programmed cell death pathway in cells with defects in apoptosis. Because the inhibition of autophagic activity promotes resistance to both chemotherapy and external beam radiation in papillary thyroid cancer (PTC), we determined if RAD001, a potent activator of autophagy, improves the efficacy of either therapy. We found that RAD001 increased the expression level of light chain 3-II, a marker for autophagy, as well as autophagosome formation in cell lines and in human PTC ex vivo. RAD001 sensitized PTC to doxorubicin and external beam radiation in a synergistic fashion, suggesting that combination therapy could improve therapeutic response at less toxic concentrations. The effects of RAD001 were abrogated by RNAi knockdown of the autophagy-related gene 5, suggesting that RAD001 acts, in part, by enhancing autophagy. Because the synergistic activity of RAD001 with doxorubicin and external radiation suggests distinct and complementary mechanisms of action, we characterized how autophagy modulates signaling pathways in PTC. To do so, we performed kinome profiling and discovered that autophagic activation resulted in Src phosphorylation and Met dephosphorylation. Src inhibition did not reverse the effects of RAD001, whereas Met inhibition reversed the effects of autophagy blockade on chemosensitivity. These results suggest that the anticancer effects of autophagic activation are mediated largely through Met. We conclude that RAD001 induces autophagy, which enhances the therapeutic response to cytotoxic chemotherapy and external beam radiation in PTC.

Topics: Autophagy; Autophagy-Related Protein 5; Carcinoma, Papillary; Cell Count; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Everolimus; Humans; Microtubule-Associated Proteins; Phosphorylation; Proto-Oncogene Proteins c-met; Radiation Tolerance; Radiation-Sensitizing Agents; RNA Interference; Sirolimus; src-Family Kinases; Thyroid Neoplasms; Vacuoles

Sirolimus was originally used as an immunosuppressant drug but recent reports have indicated that it may have other potential biological effects as an anticancer drug. The chemopreventive efficacy of sirolimus was evaluated in an experimental model of invasive urinary bladder cancer.. ICR mice received N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in drinking water for a period of twelve weeks. Sirolimus was administered 5 days a week. Animals were sacrificed either one or four weeks after their final treatment. Ki-67 was immunohistochemically analysed in paraffin-embedded tissue.. No evidence of host toxicity was found. The incidence of BBN-induced invasive urothelial carcinoma was significantly reduced in mice treated with sirolimus. Preneoplastic and neoplastic lesions exhibited a significant decrease in cellular proliferation.. Histopathological and immunohistochemical studies showed that sirolimus reduced tumour incidence and proliferation. Sirolimus should be considered for further in vitro and in vivo studies in order to provide evidence of effectiveness.

Topics: Animals; Antibiotics, Antineoplastic; Butylhydroxybutylnitrosamine; Carcinoma in Situ; Carcinoma, Papillary; Hyperplasia; Immunoenzyme Techniques; Male; Mice; Mice, Inbred ICR; Sirolimus; Urinary Bladder Neoplasms