sirolimus and Peritoneal-Neoplasms

Perivascular epithelioid cell tumors (PEComas) include different morphological entities originating from perivascular epithelioid cells. Their clinical behavior is not predictable, and there are no strict histologic criteria for malignancy, although larger tumors with infiltrative growth, hypercellularity, cellular atypia, atypical mitoses, and necrosis generally have a malignant course. Pediatric PEComas are rare, with less than 40 cases reported, mostly in children older than 5 years. We describe a case of malignant PEComa of the ligamentum teres in a 2-year-old girl, characterized by the occurrence of local relapse after primary treatment with chemotherapy and surgery and poor response to imatinib mesilate and temsirolimus used after further analyses confirmed p70S6K expression involved in the mTOR pathway. The girl was eventually treated with a debulking surgical procedure and is now alive with disease 6 years after diagnosis. Literature data of children affected by PEComas were also analyzed, trying to identify pathologic characteristics that could predict their course and therapeutic options. Histologically, they may be differentiated in 3 prognostic categories: (1) benign, lacking unfavorable morphological markers; (2) with uncertain malignant potential, carrying 1 unfavorable marker; and (3) malignant, with at least 2 unfavorable markers. In the literature, 9% of cases occurred as a second malignancy probably because of genomic instability related to treatment. Their different biology and the potential value of targeted therapies remain to be explored. The indolent evolution in our patient was similar to that reported in some other cases in the literature. In terms of treatment, the present case suggests a minor response to temsirolimus compared with the adult population.

Topics: Abdominal Neoplasms; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Biopsy; Child, Preschool; Combined Modality Therapy; Diagnostic Errors; Etoposide; Female; Humans; Imatinib Mesylate; Intestinal Obstruction; Ligaments; Liver Neoplasms; Neoplasm Recurrence, Local; Peritoneal Neoplasms; Perivascular Epithelioid Cell Neoplasms; Piperazines; Protein Kinase Inhibitors; Pyrimidines; Radiography; Sarcoma, Clear Cell; Sirolimus; X Chromosome Inactivation

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

Topics: Antineoplastic Agents; Child; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Lymphangioma, Cystic; Male; Mesentery; Peritoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Treatment Outcome

BACKGROUND Benign multicystic peritoneal mesothelioma (BMPM) is a rare intra-abdominal tumor. Although considered by many to be benign, this tumor has a high local recurrence rate. Because of its rarity, preoperative diagnosis is difficult and its origin and pathogenesis are uncertain. There are no evidence-based treatment strategies for BMPM. It is agreed that the best treatment strategy for BMPM is the combination of surgical cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC). An increasing body of evidence supports a pivotal role of the cytoplasmic serine/threonine kinase mTOR in the development and progression of several neoplastic diseases and specific mTOR inhibitors, including rapamycin, have been suggested as potential therapeutic options for different cancers. CASE REPORT A 65-year-old male with end-stage renal disease on hemodialysis for seven years presented with BMPM. He underwent surgery to remove multiple peritoneal cysts, but four months later he experienced a recurrence of the disease. Immunohistochemistry of the cysts demonstrated a high level of phosphorylation of p70S6 kinase, a downstream mTOR target, and since a target therapy that blocks PI3K/Akt/mTOR pathway has been shown to have a scientific and logical rationale to treat this rare intra-abdominal neoplasia, we started the patient on low dose rapamycin therapy, an mTOR inhibitor. Long-term mTOR inhibition resulted in a complete and stable remission of BMPM. CONCLUSIONS The current case is the first report of BMPM successfully treated with rapamycin, which resulted in a long-lasting response to mTOR inhibition.

Topics: Aged; Antibiotics, Antineoplastic; Humans; Male; Mesothelioma, Cystic; Peritoneal Neoplasms; Rare Diseases; Remission Induction; Sirolimus

The purpose of this study is to investigate a sol-gel transition property and content release profiles for thermosensitive poly-(D,L-lactide-co-glycolide)-block-poly-(ethylene glycol)-block-poly-(D,L-lactide-co-glycolide) (PLGA-b-PEG-b-PLGA) hydrogels carrying paclitaxel, rapamycin, and LS301, and to present a proof-of-concept that PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, called TheranoGel, exhibit excellent theranostic activity in peritoneal ES-2-luc ovarian cancer xenograft mice.. Thermosensitive PLGA-b-PEG-b-PLGA hydrogels carrying paclitaxel, rapamycin, and LS301, individually or in combination, were prepared via a lyophilization method, characterized with content release kinetics, and assessed with theranostic activity in ES-2-luc xenograft mice.. A thermosensitive PLGA-b-PEG-b-PLGA sol-gel system was able to entrain 3 poorly water-soluble payloads, paclitaxel, rapamycin, and LS301 (TheranoGel). TheranoGel made a sol-to-gel transition at 37°C and slowly released 3 drugs at a simultaneous release rate in response to the physical dissociation of hydrogels in vitro. TheranoGel enabled loco-regional delivery of multi-drugs by forming a gel-depot in the peritoneal cavity of ES-2-luc xenograft mice. An intraperitoneal (IP) administration of TheranoGel resulted in excellent therapeutic and diagnostic activities, leading to the improved peritoneal surgery in ES-2-luc xenograft mice.. TheranoGel prepared via a facile lyophiliation method enabled successful IP delivery of multi-drugs and exhibited excellent theranostic activity in vivo.

Topics: Animals; Drug Carriers; Drug Delivery Systems; Female; Hydrogels; Injections, Intraperitoneal; Mice; Mice, Nude; Ovarian Neoplasms; Paclitaxel; Peritoneal Neoplasms; Polyesters; Polyethylene Glycols; Polymers; Sirolimus; Surgery, Computer-Assisted

Focal adhesion kinase (FAK) mediates survival of normal pancreatic islets through activation of AKT. Upon malignant transformation of islet cells into pancreatic neuroendocrine tumors (PanNETs), AKT is frequently overexpressed and mutations in the AKT/mTOR pathway are detected. Because mTOR inhibitors rarely induce PanNET tumor regression, partly because of feedback activation of AKT, novel combination strategies are needed to target FAK/AKT/mTOR signaling.. We characterized the activation of FAK in PanNETs using immunohistochemistry and Western blot analysis and tested the FAK inhibitor PF-04554878 in human PanNET cells in vitro and in vivo (at least three mice per group). In addition, we evaluated the effect of combined FAK and mTOR inhibition on PanNET viability and apoptosis. All statistical tests were two-sided.. We found that FAK is overexpressed and hyperphosphorylated in human PanNETs and that PF-04554878 strongly inhibited FAK (Tyr397) autophosphorylation in a dose-dependent manner. We found that PF-04554878 inhibited cell proliferation and clonogenicity and induced apoptosis in PanNET cells. Moreover, oral administration of PF-04554878 statistically significantly reduced tumor growth in a patient-derived xenograft model of PanNET (P = .02) and in a human PanNET xenograft model of peritoneal carcinomatosis (P = .03). Importantly, PF-04554878 synergized with the mTOR inhibitor everolimus by preventing feedback AKT activation.. We demonstrate for the first time that FAK is overexpressed in PanNETs and that inhibition of FAK activity induces apoptosis and inhibits PanNET proliferation. We found that the novel FAK inhibitor PF-04554878 synergizes with everolimus, a US Food and Drug Administration-approved agent for PanNETs. Our findings warrant the clinical investigation of combined FAK and mTOR inhibition in PanNETs.

Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Carcinoma; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; Drug Synergism; Everolimus; Female; Focal Adhesion Kinase 1; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neuroendocrine Tumors; Organic Chemicals; Pancreatic Neoplasms; Peritoneal Neoplasms; Protein Kinase Inhibitors; Pyrazines; Signal Transduction; Sirolimus; Sulfonamides; TOR Serine-Threonine Kinases; Up-Regulation; Xenograft Model Antitumor Assays

Peritoneal carcinomatosis (PC) is the most common secondary cancerous disease, and more effective novel regimens are needed. In this study, we identified a novel combination treatment for PC, chemotherapeutic agent mitomycin C in combination with mTOR (mammalian target of rapamycin) inhibitor rapamycin. We observed that the combination of mitomycin C and rapamycin induced synergistic cytotoxicity and apoptosis, which was mediated through an increase in caspase activation. The combination of mitomycin C and rapamycin inactivated p70 S6 ribosomal kinase (S6K1) and dephosphorylated Bad, leading to dissociation of Bcl-xL from Bak, which resulted in Bak oligomerization, mitochondria dysfunction and cytochrome c release. PF-4708671, a S6K1-specific inhibitor, enhanced the combination treatment-induced apoptosis, whereas S6K1 E389 DeltaCT-HA (S6K1 active form) dramatically decreased the induction of apoptosis. In addition, the combination treatment significantly inhibited LS174T intraperitoneal tumor growth in vivo. This study provides a preclinical rationale for apoptosis induction linked with the mTOR pathway through a combination of chemotherapeutic agents and mTOR inhibitor, and will support this combinatorial strategy to PC patients.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; Apoptosis; bcl-2 Homologous Antagonist-Killer Protein; bcl-Associated Death Protein; Cell Line, Tumor; Humans; Mice; Mice, Nude; Mitomycin; Peritoneal Neoplasms; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus

Cholangiocarcinoma (CC) is a malignant epithelium neoplasm that originates from the bile epithelium and for which there are few therapeutic strategies. The mTOR pathway involved in many cellular processes was reported to be up-regulated in various cancers. We investigated the activation of the AKT/mTOR pathway in CC cell lines with different degrees of dedifferentiation and found that rapamycin could suppress the motility and the peritoneal dissemination of sarcomatoid SCK cells. Inhibition of the mTOR pathway with rapamycin decreased significantly the number of tumor nodules and prolonged the survival rates of nude mice inoculated with sarcomatoid CC cells. Prolonged treatments with rapamycin were found to disrupt the mTORC2 assembly and to reduce the phosphorylation of STAT3 at Ser 727. Rapamycin decreased both mRNA and protein levels of MMP2 and Twist1, which are regulated by STAT3 and associated with cancer metastasis. The overexpression of STAT3 S727A lacking the phosphorylation site resulted in significantly less sensitivity to rapamycin than the overexpression of STAT3 WT. Taken together, our results suggest that rapamycin could suppress the motility of sarcomatoid CC by down-regulating p-STAT3 (S727) through the impairment of mTORC2 assembly.

Topics: Animals; Apoptosis; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Blotting, Western; Cell Adhesion; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Down-Regulation; Humans; Immunoenzyme Techniques; Immunoprecipitation; Male; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; Multiprotein Complexes; Peritoneal Neoplasms; Phosphorylation; Proto-Oncogene Proteins c-akt; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sirolimus; STAT3 Transcription Factor; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

Few targeted therapies have been developed for ovarian granulosa cell tumor (GCT), even though it represents 5% of all malignant ovarian tumors in women. As misregulation of PI3K/AKT signaling has been implicated in GCT development, we hypothesized that the AKT signaling effector mammalian target of rapamycin (mTOR) may play a role in the pathogenesis of GCT and could represent a therapeutic target. Analyses of human GCT samples showed an increase in protein levels of mTOR and its downstream effectors RPS6KB1, RPS6, eIF4B and PPARG relative to normal granulosa cells, suggestive of an increase in mTOR pathway activity and increased translational activity and/or protein stability. We next sought to evaluate mTOR as a GCT therapeutic target using the Pten (tm1Hwu/tmiHwu);Ctnnb1 (tm1Mmt/+);Amhr2 (tm3(cre)Bhr/+) (PCA) mouse model, in which mTOR, RPS6KB1, eIF4B and PPARG are upregulated in tumor cells in a manner similar to human GCT. Treatment of PCA mice with the mTOR-specific inhibitor everolimus reduced tumor growth rate (1.5-fold; P < 0.05) and also reduced total tumor burden (4.7-fold; P < 0.05) and increased survival rate (78 versus 44% in the vehicle group) in a PCA surgical model of GCT peritoneal carcinomatosis. Everolimus decreased tumor cell proliferation and tumor cell volume relative to controls (P < 0.05), whereas apoptosis was unaffected. Phosphorylation of RPS6KB1 and RPS6 were decreased (P < 0.05) by everolimus, but RPS6KB1, RPS6, eIF4B and PPARG expressions were not affected. These results suggest that mTOR is a valid and clinically useful pharmacological target for the treatment of GCT, although its inhibition does not reverse all consequences of aberrant PI3K/AKT signaling in the PCA model.

Topics: Adult; Animals; Apoptosis; beta Catenin; Blotting, Western; Cell Proliferation; Eukaryotic Initiation Factors; Everolimus; Female; Granulosa Cell Tumor; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; Mice; Mice, Transgenic; Peritoneal Neoplasms; Phosphorylation; PTEN Phosphohydrolase; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 70-kDa; RNA, Messenger; Signal Transduction; Sirolimus; Survival Rate; TOR Serine-Threonine Kinases

Peritoneal dissemination occurs frequently in patients with unresectable advanced-stage gastric cancer. In this study, we tested the efficacy of the mTOR inhibitor RAD001 (everolimus) against advanced gastric cancer with peritoneal dissemination. Using the two cell lines, 58As1, a cell line exhibiting a high propensity for peritoneal metastasis, and its parental cell line, HSC-58, a human scirrhous gastric cancer cell line, we first examined the growth-inhibitory activity of everolimus in vitro. Methylene blue assay demonstrated a moderate inhibitory effect of the drug on both cell lines under normal culture conditions (maximal inhibitory effect: 50.5% at 1 μM, HSC-58, 65.3%, 58As1). However, under the hypoxic condition (1% O(2)), while the growth-inhibitory activity of everolimus was greatly reduced in the HSC-58 cell line, the degree of reduction of the inhibitory activity was much smaller in the 58As1 cell line. Western blotting revealed that the degree of phosphorylation of mTOR and its downstream signaling molecules, p70S6K and 4E-BP1, was decreased under hypoxic conditions in HSC-58. On the other hand, phospho-p70S6K and phospho-4E-BP1 remained active under hypoxic conditions in 58As1, the molecular activity was suppressed by everolimus. Cell-cycle analysis showed that hypoxia-induced G1 arrest was not manifested in the 58As1 cells, unlike in the HSC-58 cells. Separately, an in vivo orthotopic mouse model of 58As1 revealed that everolimus significantly reduced peritoneal dissemination as evaluated by the quantitative photon counting method. Taken together, our results suggest that everolimus may have favorable activity against gastric cancer, particularly in cases with peritoneal dissemination.

Topics: Adenocarcinoma, Scirrhous; Animals; Antineoplastic Agents; Cell Cycle; Cell Hypoxia; Cell Line, Tumor; Everolimus; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Peritoneal Neoplasms; Phosphorylation; Sirolimus; Stomach Neoplasms; TOR Serine-Threonine Kinases

The mTOR-inhibitor rapamycin has shown antitumor activity in various tumors. Bedside observations have suggested that rapamycin may be effective as a treatment for colorectal carcinomatosis.. We established an orthotopic syngenic model by transplanting CT26 peritoneal tumors in Balb/C mice and an orthotopic xenograft model by transplanting SW620 peritoneal tumors in nu/nu mice. Expression levels of tissue inhibitor of matrix-metalloproteinases 1 (TIMP-1) in the tumor and serum was determined by enzyme-linked immunosorbent assay.. Rapamycin significantly suppressed growth of syngenic and xenografted peritoneal tumors. The effect was similar with intraperitoneal or oral rapamycin administration. Tumor suppression was further enhanced when rapamycin was combined with 5-fluorouracil and/or oxaliplatin. The combination treatment showed no acute toxicity. TIMP-1 serum levels correlated well (CC = 0.75; P < 0.01) with rapamycin treatment.. Rapamycin suppressed advanced stage colorectal cancer, even with oral administration. Combining rapamycin with current chemotherapy regimens significantly increased antitumor efficacy without apparent toxicity. The treatment efficacy correlated with serum TIMP-1 levels, suggesting its potential as a surrogate marker in future clinical trials.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Colorectal Neoplasms; Fluorouracil; Humans; Mice; Organoplatinum Compounds; Oxaliplatin; Peritoneal Neoplasms; Sirolimus; Tissue Inhibitor of Metalloproteinase-1; Treatment Outcome; Xenograft Model Antitumor Assays

Surgeons will increasingly have to address the development of gastrointestinal disease in transplant patients or deal with extended bowel resection and bowel anastomosis in advanced cancer patients. Immunosuppressants as well as intraoperative hyperthermic peritoneal chemoperfusion (IHPC) may alter intestinal anastomotic healing. We evaluated the effects of the immunosuppressant sirolimus and of IHPC on healing and stability of bowel anastomoses in pigs. Twenty-four pigs were divided into four groups (SIR: sirolimus was administered orally; IHPC: animals received IHPC with mitomycin-C; COMP: combination of sirolimus and IHPC was administered; CON: sham-treated control group). Animals underwent hand-sutured small bowel and left colon anastomoses and were killed on postoperative day 4. Anastomoses were evaluated by morphometric analysis and immunohistochemistry (IHC) and by measuring the bursting pressure (BP). In all experimental groups (SIR, IHPC, COMP), anastomotic BPs remained unaltered and were not statistically different compared with control (CON). In addition, ileum villous height and colonic crypt depth analysis revealed no significant difference in mucosal thickness, and IHC showed no difference among groups in proliferation, as assessed by the number of KI-67- and bromodeoxyuridine-labeled cells. Immunosuppression with sirolimus as well as IHPC with mitomycin-C do not alter healing of intestinal anastomosis in pigs.

Topics: Anastomosis, Surgical; Animals; Antibiotics, Antineoplastic; Cell Proliferation; Digestive System Neoplasms; Female; Humans; Hyperthermia, Induced; Immunosuppressive Agents; Intestinal Mucosa; Intestines; Mitomycin; Models, Animal; Perfusion; Peritoneal Cavity; Peritoneal Neoplasms; Sirolimus; Sus scrofa; Wound Healing

The Akt/mammalian target of the rapamycin (mTOR) signaling pathway represents a promising target for cancer therapy. The phosphorylation status of Akt and of mTOR's phosphorylation target eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) is often used to assess the activity of Akt and mTOR signaling. The purpose of this study was to determine whether primary tumors differ from their metastasis in their expression of pAkt and p4E-BP1.. Primary breast tumors and their distant metastases surgically resected from the same patients were evaluated with immunohistochemical analysis (IHC) for pAkt (Ser473) and p4E-BP1 (Ser65). The agreement between the IHC results for the primary tumor and metastases was evaluated with Cohen kappa (kappa).. Most primary breast tumors and metastatic tumors expressed pAkt (76% of each). Of the 23 matched evaluable pairs, however, 11 (47.8%) had discordant IHC results (kappa -0.31; 95% confidence interval [CI], -0.49 to -0.13). Similarly, although most of the primary and metastatic tumors were positive for p4E-BP1 (75% and 74%), of the 23 matched evaluable pairs, 8 (47.8%) were discordant (kappa 0.10; 95% CI, -0.33-0.52).. In this series, most primary breast tumors and metastases expressed pAkt and p4E-BP1 by IHC. Concordance between IHC findings in primary tumors and metastases was poor, however. Further work is needed to determine whether this reflects true biological heterogeneity or poor reproducibility of IHC with phosphospecific antibodies, and to identify which biomarkers can be assessed most reproducibly in primary tumors to predict activity of Akt/mTOR signaling and sensitivity to pathway inhibitors.

Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Breast Neoplasms; Cell Cycle Proteins; Cytoplasm; Female; Humans; Immunoenzyme Techniques; Liver Neoplasms; Lung Neoplasms; Middle Aged; Peritoneal Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Lymphatic complications are common side effects of mammalian target of rapamycin (mTOR) inhibitor-based immunosuppression in kidney transplantation. Therefore, we investigated whether the mTOR inhibitor rapamycin, besides its known antihemangiogenic effect, also impedes regenerative lymphangiogenesis. In a murine skin flap model, rapamycin impaired recovery of lymphatic flow across surgical incisions resulting in prolonged wound edema in these animals. Importantly, the antilymphangiogenic effect of rapamycin was not related to a general inhibition of wound healing as demonstrated an in vivo Matrigeltrade mark lymphangiogenesis assay and a model of lymphangioma. Rapamycin concentrations as low as 1 ng/ml potently inhibited vascular endothelial growth factor (VEGF)-C driven proliferation and migration, respectively, of isolated human lymphatic endothelial cells (LECs) in vitro. Mechanistically, mTOR inhibition impairs downstream signaling of VEGF-A as well as VEGF-C via mTOR to the p70S6 kinase in LECs. In conclusion, we provide extensive experimental evidence for an antilymphangiogenic activity of mTOR inhibition suggesting that the early use of mTOR inhibitor following tissue injury should be avoided. Conversely, the antilymphangiogenic properties of rapamycin and its derivates may provide therapeutic value for the prevention and treatment of malignancies, respectively.

Topics: Animals; Cell Movement; Cell Proliferation; Collagen; Drug Combinations; Endothelial Cells; Endothelium, Lymphatic; Immunosuppressive Agents; Laminin; Lymphangiogenesis; Lymphangioma; Mice; Mice, Inbred C57BL; Peritoneal Neoplasms; Phosphorylation; Protein Kinases; Proteoglycans; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus; TOR Serine-Threonine Kinases; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C

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