sirolimus and Ascites

Beclin1 and mechanistic target of rapamycin (mTOR) can be used as tumor markers of epithelial ovarian cancer. This study aimed to assess the association of Beclin1 and mTOR expression with clinicopathological and prognostic data in epithelial ovarian cancer patients. Serum and tissue samples from 45 epithelial ovarian cancer patients and 20 controls were analyzed by enzyme-linked immunosorbent assay and immunohistochemistry for Beclin1 and mTOR expression. The online datasets from gene expression profiling interactive analysis (n = 426), Kaplan-Meier plotter (n = 398), cBioPortal (n = 585), and UALCAN (n = 302) were also analyzed. Beclin1 expression was associated with low-grade differentiation (P = .003), earlier clinical stage (P = .013), fewer local lymph node metastases (P = .02) and lower serum Beclin1 level (P = .001). mTOR expression was associated with high-grade differentiation (P = .013), advanced clinical stage (P = .021), ascites (P = .028), and higher serum mTOR level (P = .001). The online datasets showed that a high mTOR expression level (HR = 1.44; 95% CI = 1.08-1.92; P = .013) was associated with a poor overall survival of 426 patients. Beclin1 was mutated in 1.8% and mTOR was mutated in 5% of epithelial ovarian cancer patients. Serum Beclin1 and mTOR levels were able to predict tumor differentiation, clinical stage, lymph node metastasis, and ascites in epithelial ovarian cancer patients.

Topics: Ascites; Beclin-1; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Female; Humans; Ovarian Neoplasms; Prognosis; Sirolimus; TOR Serine-Threonine Kinases

Topics: Aged; Ascites; Cough; Drug Therapy, Combination; Erdheim-Chester Disease; Female; Fever; Glucocorticoids; Humans; Immunosuppressive Agents; Middle Aged; Prednisolone; Radionuclide Imaging; Sirolimus; Tomography, X-Ray Computed

Ovarian cancer is the leading cause of death from gynecologic cancer. Often, the disease has spread beyond the ovary to involve the peritoneal cavity and causes ascites. Whereas mammalian target of rapamycin (mTOR) functions to regulate protein translation, cell cycle progression, and metastasis, vascular endothelial growth factor promotes tumor angiogenesis, ascites formation, and metastasis in ovarian cancer. In this study, an i.p. model of human ovarian cancer was used to determine the antitumor activity of rapamycin, bevacizumab, and rapamycin plus bevacizumab (BEV/RAPA). We report that administration of rapamycin, bevacizumab, and BEV/RAPA in mice bearing peritoneal OV-90 ovarian carcinoma resulted in 74.6%, 82.4%, and 93.3% reduction in i.p. tumor burden, respectively. BEV/RAPA-induced reduction in microvessel density and inhibition of cell proliferation were associated with significant reduction in hypoxia-inducible factor-1alpha and cyclin D1 and inactivation of downstream targets of mTOR, p70S6 kinase, S6R, and 4E-binding protein 1. BEV/RAPA treatment was not only able to prolong life of i.p. mice but also more effective than rapamycin and bevacizumab to prevent the development of peritoneal carcinomatosis in adjuvant setting and reverse ascites accumulation in heavy peritoneal disease. Our data indicate that simultaneous inhibition of the vascular endothelial growth factor receptor and mTOR pathways with BEV/RAPA or their analogues may represent a novel approach for prevention of metastasis, recurrence, and treatment of ovarian cancer.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Ascites; Bevacizumab; Body Weight; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Female; Humans; Mice; Mice, SCID; Neoplasm Proteins; Ovarian Neoplasms; Peritoneal Neoplasms; Sirolimus; Tumor Burden

Cell lines and tumors with defined genetic alterations provide ideal systems in which to test the molecular mechanisms of tumor sensitivity to pathway-targeted therapy. We have generated mouse ovarian epithelial tumor cell lines that contain various combinations of genetic alterations in the p53, c-myc, K-ras and Akt genes. Using both in vitro and in vivo approaches, we investigated the effect of rapamycin on cell proliferation, tumor growth, and the accumulation of peritoneal ascites. We demonstrated that rapamycin effectively inhibits the growth of tumors that rely on Akt signaling for proliferation, whereas tumors in which Akt signaling is not the driving force in proliferation are resistant to rapamycin. The introduction of activated Akt to the rapamycin-resistant cells does not render the cells susceptible to rapamycin if they can use alternative pathways for survival and proliferation. Accordingly, the rapamycin-sensitive tumors develop resistance to rapamycin when presented with alternative survival pathways, such as the mitogen-activated extracellular kinase signaling pathway. The combination of rapamycin and the mitogen-activated extracellular kinase inhibitor PD98059 is required to diminish proliferation in these cell lines. Our results indicate that mammalian target of rapamycin inhibitors may be effective in a subset of tumors that depend on Akt activity for survival but not effective in all tumors that exhibit Akt activation. Tumors with alternative survival pathways may require the inactivation of multiple individual pathways for successful treatment.

Topics: Animals; Apoptosis; Ascites; Blotting, Western; Cell Line, Tumor; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; Enzyme Inhibitors; Female; Flavonoids; Mice; Ovarian Neoplasms; Peritoneum; Signal Transduction; Sirolimus; Time Factors; Vascular Endothelial Growth Factor A