sirolimus and Carcinoma--Ovarian-Epithelial

Several 'lines of therapy' that utilize cytotoxic agents and are driven by platinum-free intervals are the current standard of care for patients with recurrent ovarian cancer. For patients with platinum-resistant disease, single agent chemotherapy (pegylated liposomal doxorubicin, topotecan, gemcitabine or weekly paclitaxel) is the standard of care. For patients with platinum-sensitive disease, combination chemotherapy (carboplatin plus paclitaxel, pegylated liposomal doxorubicin or gemcitabine) is the standard of care. In addition, antiangiogenic therapy using bevacizumab is an established option. Future directions could include 'lines of therapy' with biologic agents driven by specific biologic targets. Data from antiangiogenic agents (trebananib, pazopanib and cediranib), antifolate drugs (farletuzumab and vintafolide), poly(ADP-ribose) polymerase inhibitors (olaparib and veliparib), mTOR inhibitors (everolimus and temsirolimus) and immune editing agents (nivolumab) have been summarized in this review.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Carboplatin; Carcinoma, Ovarian Epithelial; Deoxycytidine; Doxorubicin; Everolimus; Female; Folic Acid; Gemcitabine; Humans; Indazoles; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Nivolumab; Ovarian Neoplasms; Paclitaxel; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Polyethylene Glycols; Pyrimidines; Quinazolines; Recombinant Fusion Proteins; Sirolimus; Sulfonamides; Topotecan; TOR Serine-Threonine Kinases; Vinca Alkaloids

The mammalian target of rapamycin (mTOR) is frequently activated in epithelial ovarian cancer, and is regarded as an attractive therapeutic target for therapy. Preclinical investigations using rapamycin and its analogs have demonstrated significant growthinhibitory effects on the growth of ovarian cancer both in the setting of monotherapy and in combination with cytotoxic agents. Based on promising preclinical data, mTOR inhibitors are currently being evaluated in several phase I/II trials in patients with ovarian cancer. In an effort to overcome resistance to rapamycin and its analogs, the novel ATP-competitive mTOR inhibitors have recently been developed. In this report, we review the scientific rationale and evidence for the potential clinical benefits provided by mTOR inhibitor therapy for patients with epithelial ovarian cancer.

Topics: Animals; Antineoplastic Agents; Carcinoma, Ovarian Epithelial; Catalytic Domain; Female; Humans; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Preclinical data suggest that combining the mTOR/hypoxia-inducible factor (HIF) inhibitor temsirolimus and the antiangiogenesis antibody bevacizumab may augment antitumor activity as well as resensitize cells to anthracyclines.. We initiated a phase I study of bevacizumab and temsirolimus plus liposomal doxorubicin in patients with advanced malignancies. Patients (N = 136) were enrolled according to a modified 3 + 3 design plus dose expansion in responsive tumor types.. The most common cancers were breast (n = 29), epithelial ovarian (n = 23), and colorectal cancer (n = 17). The median number of prior chemotherapy regimens was four (range: 0-16). Grade 3 or higher adverse events (> 5%) included pancytopenia, mucositis, hand-foot syndrome, hypertension, and fistula. This regimen led to a 21% (n = 28) stable disease (SD) ≥ 6 months and 21% (n = 29) rate of partial or complete remission [PR/CR; (total SD ≥ 6 months/PR/CR = 42% (n = 57)]. PR/CR was most common in parotid gland adenocarcinoma (4/6, 67%), metaplastic breast cancer (5/12, 42%), endometrial endometrioid carcinoma (6/15, 40%), and in patients with a PIK3CA mutation and/or a PTEN mutation/loss (11/28, 39%). The maximum tolerated dose was liposomal doxorubicin 30 mg/m(2) and bevacizumab 15 mg/kg every three weeks with temsirolimus 25 mg weekly.. Patients tolerated bevacizumab and temsirolimus together with liposomal doxorubicin. Further evaluation, especially in patients with parotid, metaplastic breast, and endometrial endometrioid cancer, and in patients with PIK3CA and/or PTEN aberrations is warranted.

Topics: Adolescent; Adult; Aged; Angiogenesis Inhibitors; Antibiotics, Antineoplastic; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Breast Neoplasms; Carcinoma, Ovarian Epithelial; Colorectal Neoplasms; Disease-Free Survival; Doxorubicin; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Maximum Tolerated Dose; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Protein Kinase Inhibitors; Sirolimus

Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers.. Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1-3 prior regimens were treated with 25mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall's tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome.. Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90% CI 14.9%-38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90% CI 3.7%-23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic (8), gastrointestinal (8), pain (6), constitutional (5) and pulmonary (4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS.. Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Ovarian Epithelial; Cyclin D1; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasms, Glandular and Epithelial; Neoplastic Cells, Circulating; Ovarian Neoplasms; Peritoneal Neoplasms; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases; Young Adult

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

Genomic instability and chemoresistance can arise in cancer due to a unique form of plasticity: that of polyploid giant cancer cells (PGCCs). These cells form under the stress of chemotherapy and have higher than diploid chromosome content. PGCCs are able to then repopulate tumors through an asymmetric daughter cell budding process. PGCCs have been observed in ovarian cancer histology, including the deadly and common form high-grade serous ovarian carcinoma (HGSC). We previously discovered that drugs which disrupt the cellular recycling process of autophagy are uniquely efficacious in pre-clinical HGSC models. While autophagy induction has been associated with PGCCs, it has never been previously investigated if autophagy modulation interacts with the PGCC life cycle and this form of tumor cell plasticity.. CAOV3 and OVCAR3 ovarian cancer cell lines were treated with carboplatin or docetaxel to induce PGCC formation. Microscopy was used to characterize and quantify PGCCs formed by chemotherapy. Two clinically available drugs that inhibit autophagy, hydroxychloroquine and nelfinavir, and a clinically available activator of autophagy, rapamycin, were employed to test the effect of these autophagy modulators on PGCC induction and subsequent colony formation from PGCCs. Crystal violet-stained colony formation assays were used to quantify the tumor-repopulating stage of the PGCC life cycle.. Autophagy inhibitors did not prevent PGCC formation in OVCAR3 or CAOV3 cells. Rapamycin did not induce PGCC formation on its own nor did it exacerbate PGCC formation by chemotherapy. However, hydroxychloroquine prevented efficient colony formation in CAOV3 PGCCs induced by carboplatin (27% inhibition) or docetaxel (41% inhibition), as well as in OVCAR3 cells (95% and 77%, respectively). Nelfinavir similarly prevented colony formation in CAOV3 PGCCs induced by carboplatin (64% inhibition) or docetaxel (94% inhibition) as well as in OVCAR3 cells (89% and 80%, respectively). Rapamycin surprisingly also prevented PGCC colony outgrowth (52-84% inhibition).. While the autophagy previously observed to correlate with PGCC formation is unlikely necessary for PGCCs to form, autophagy modulating drugs severely impair the ability of HGSC PGCCs to form colonies. Clinical trials which utilize hydroxychloroquine, nelfinavir, and/or rapamycin after chemotherapy may be of future interest.

Topics: Apoptosis; Autophagy; Carboplatin; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Docetaxel; Female; Giant Cells; Humans; Hydroxychloroquine; Nelfinavir; Ovarian Neoplasms; Polyploidy; Sirolimus

Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers.

Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinogenesis; Carcinoma, Ovarian Epithelial; Cell Adhesion; Cell Cycle; Cell Movement; Cell Proliferation; Disease Models, Animal; Female; Humans; Mice; Neoplasms, Glandular and Epithelial; Obesity; Ovarian Neoplasms; Phosphorylation; Prognosis; Signal Transduction; Sirolimus; Tumor Cells, Cultured