sirolimus and Leiomyosarcoma

Advanced sarcoma has a poor prognosis. Dysregulation of the mammalian target of rapamycin (mTOR) occurs in various types of cancer. We aimed to determine the safety and efficacy of mTOR inhibitor nab-sirolimus when combined with the immune checkpoint inhibitor nivolumab.. Previously treated patients ≥18 years with confirmed diagnosis of advanced sarcoma or tumor with mutations in the mTOR pathway were treated with 3 mg/kg nivolumab intravenously every 3 weeks; escalating doses of nab-sirolimus at 56, 75 or 100 mg/m. The maximum-tolerated dose was 100 mg/m. The data indicate that (i) treatment with nivolumab plus nab-sirolimus is safe with no unexpected adverse events; (ii) treatment outcome parameters were not improved by combining nivolumab with nab-sirolimus; and (iii) best responders were patients with undifferentiated pleomorphic sarcoma with PTEN loss and TSC2 mutation and estrogen receptor-positive leiomyosarcoma. Future direction in sarcoma research with nab-sirolimus will be biomarker-based (TSC1/2/mTOR, tumor mutational burden/mismatch repair deficiency etc.).

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Humans; Leiomyosarcoma; Mutation; Nivolumab; Receptors, Estrogen; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases

A probable case of bowel perforation associated with temsirolimus use in a patient with uterine leiomyosarcoma is reported.. A 45-year-old Hispanic woman reported acute abdominal pain one day after receiving her third weekly i.v. infusion of temsirolimus, a mammalian target of rapamycin inhibitor increasingly used against a variety of cancers, including renal cell carcinoma and soft tissue sarcomas. Temsirolimus had been initiated three weeks previously in an attempt to control retroperitoneal metastases of uterine leiomyosarcoma, which had progressed despite surgical resection, six cycles of adjuvant chemotherapy, and pelvic irradiation. A computed tomography scan revealed a large pelvic mass with foci of gas, fluid collection, and other findings highly suggestive of an abscess due to bowel perforation. Application of the adverse drug reaction probability scale of Naranjo et al. in this case indicated a probable relationship between the bowel perforation and temsirolimus use; a literature search identified no other reported cases of temsirolimus-associated bowel perforation in association with uterine leiomyosarcoma. It is suspected that the patient's recent course of pelvic radiotherapy may have played a role in predisposing her to bowel perforation during temsirolimus use. While the mechanism of bowel perforations associated with temsirolimus therapy remains unclear, it is possible that due to its inhibitory effects on vascular endothelial growth factor (VEGF), temsirolimus use may result in gastrointestinal stresses and weaknesses similar to those attributed to bevacizumab, a VEGF-targeted angiogenesis inhibitor that has been linked to chemotherapy-induced bowel perforation.. A woman who recently received pelvic radiation experienced a bowel perforation after three infusions of temsirolimus for the treatment of metastatic leiomyosarcoma.

Topics: Antineoplastic Agents; Female; Humans; Intestinal Perforation; Leiomyosarcoma; Middle Aged; Pelvis; Sirolimus; TOR Serine-Threonine Kinases; Uterine Neoplasms

The significance of mTOR activation in uterine leiomyosarcoma (ULMS) and its potential as a therapeutic target were investigated. Furthermore, given that effective therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora-A kinase (Aurk-A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated.. Immunohistochemical staining was used to evaluate expression of activated mTOR components in a large (>200 samples) ULMS tissue microarray. Effects of mTOR blockade (using rapamycin) and Aurk-A inhibition (using MLN8237) alone and in combination on human ULMS cell growth, cell-cycle progression, and apoptosis were assessed in cellular assays. Drug interactions were determined via combination index analyses. The antitumor effects of inhibitors alone or in combination were evaluated in vivo.. Enhanced mTOR activation was seen in human ULMS samples. Increased pS6RP and p4EBP1 expression correlated with disease progression; p4EBP1 was found to be an independent prognosticator of patient outcome. Rapamycin inhibited growth and cell-cycle progression of ULMS cell strains/lines in culture. However, only a cytostatic effect on tumor growth was found in vivo. Combining rapamycin with MLN8237 profoundly (and synergistically) abrogated ULMS cells' growth in culture; interestingly, these effects were seen only when MLN8237 was preadministered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo.. mTOR and Aurk-A pathways are commonly deregulated in ULMS. Preclinical data support further exploration of dual mTOR and Aurk-A therapeutic blockade for human ULMS.

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinases; Azepines; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; Leiomyosarcoma; Mice; Protein Serine-Threonine Kinases; Pyrimidines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Transplantation, Heterologous; Uterine Neoplasms

Preclinical data have indicated that alteration of PTEN and activation of the mammalian target of rapamycin (mTOR) pathway play a crucial role in the oncogenesis of leiomyosarcoma. The objective of this exploratory study was to assess the clinical role of mTOR inhibition in patients with advanced leiomyosarcoma refractory to standard chemotherapy. Patients with advanced leiomyosarcoma were treated with temsirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined according to the response evaluation criteria in solid tumor (RECIST) and Choi criteria. Tumors were assessed for immunohistochemical evidence of PTEN loss of expression and mTOR activation. Six patients participated in the study. According to the RECIST, three patients had stable disease and three patients had progressive disease. The three patients with RECIST stable disease had partial response according to the Choi criteria. Partial response according to the Choi criteria was associated with clinical improvement and biological signs of temsirolimus antitumor activity. The immunohistochemical status of PTEN and phosphorylated S6 ribosomal protein was not predictive of the outcome. This exploratory study indicates antitumor activity of temsirolimus in leiomyosarcoma, possibly through a mechanism involving aberration of the PTEN gene. Further investigations of the phosphoinositide 3-kinases/PTEN/Akt/mTOR pathway are needed to explore the role of mTOR inhibitors, either alone or in combination, in patients with advanced sarcoma.

Topics: Adult; Antineoplastic Agents; Female; Humans; Leiomyosarcoma; Male; Middle Aged; Protein Kinase Inhibitors; PTEN Phosphohydrolase; Ribosomal Protein S6; Signal Transduction; Sirolimus; Statistics as Topic; TOR Serine-Threonine Kinases; Treatment Outcome

Uterine leiomyosarcoma generally has an unfavorable response to standard chemotherapy. The loss of PTEN which results in constitutive AKT-mTOR activation causes an increase in leiomyosarcoma formation in mice. The active ingredient derived from the herb Curcuma longa, curcumin, shows antitumor properties in a variety of cancer cell lines by altering a number of oncogenic pathways. To explore the possibility of curcumin as an alternative to standard chemotherapy, we decided to investigate curcumin's antitumor effect on uterine leiomyosarcoma cells.. Human leiomyosarcoma cell lines, SKN and SK-UT-1, were cultured for in vitro experiments. Rapamycin or curcumin was added in different doses and their effect on cell growth was detected by MTS assay. The influence of rapamycin or curcumin on AKT, mTOR, p70S6 and S6 phosphorylation and protein expression was detected by Western Blotting. The ability of rapamycin or curcumin to induce apoptosis was determined by Western blotting using cleaved-PARP specific antibody, Caspase-3 activity assay and TUNEL assay.. Both rapamycin and curcumin significantly reduced SKN cell proliferation. Curcumin inhibited mTOR, p70S6 and S6 phosphorylation similar with rapamycin. Cleaved PARP, caspase-3 activity and DNA fragmentation increased proportional with curcumin concentration. At a high concentration, curcumin significantly induced apoptosis in SKN cells, but not rapamycin.. Curcumin inhibited uterine leiomyosarcoma cells' growth by targeting the AKT-mTOR pathway for inhibition. However, rapamycin, a specific mTOR inhibitor, did not induce apoptosis in SKN cells unlike curcumin that also has a pro-apoptotic potential in SKN cells.

Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Enzyme Activation; Female; Humans; Leiomyosarcoma; Oncogene Protein v-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Uterine Neoplasms

Drug combinations may provide a therapeutic benefit in treating cancer patients. However when considering a drug combination, it is important to assess how the molecular impact of the combination relates to the effects manifested by each drug alone and whether or not it varies depending on the tumor type. In this study, we have analyzed the molecular impact on a human leiomyosarcoma cell line (SK-LMS-1) of a combination consisting of the mTOR inhibitor rapamycin and either the anti-metabolite drug gemcitabine (Gemzar) or the protein tyrosine kinase inhibitor imatinib mesylate (Gleevec, STI571). We show that imatinib mesylate depolarizes the mitochondrial membrane potential (DeltaPhim) and inhibits protein tyrosine phosphorylation, but displays only minor effects on cell proliferation when added alone or in combin-ation with rapamycin. Gemcitabine or rapamycin, when added alone, inhibit protein tyrosine phosphorylation as well as phosphorylation of the MAP kinases ERK1/2. Both drugs also affect the cell cycle, arresting the cells at the S or G1 phase respectively. Rapamycin elevates significantly DeltaPhim but produces only a moderate effect on cell growth. Gemcitabine inhibits considerably cell growth but exerts no effect on DeltaPhim. Combining gemcitabine and rapamycin produces a major effect on the cell cycle, elevates the DeltaPhim even further and maintains the molecular impacts exerted by each single drug. Therefore, consistent with our clinical observation, these results suggest that combining gemcitabine and rapamycin may be beneficial in treating leiomyosarcoma patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; Gemcitabine; Humans; Imatinib Mesylate; Leiomyosarcoma; Membrane Potential, Mitochondrial; Mitogen-Activated Protein Kinase Kinases; Models, Biological; Piperazines; Pyrimidines; Signal Transduction; Sirolimus

The emerging anti-cancer approach is based on combining a 'traditional' cytotoxic drug with a 'signaling' blocking agent. Such combination, if designed and applied properly, may increase selectivity towards tumor cells. The use of such combinations requires smart planning and choice of the drugs to be combined, their proper dosing as well as correct sequence and schedule of application. The combination of the anti-metabolite gemcitabine and the mTOR blocker, rapamycin, has achieved an impressive response in a patient with metastatic leiomyosarcoma.

Topics: Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Diabetic Nephropathies; Gemcitabine; Humans; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Leiomyosarcoma; Liver Neoplasms; Male; Middle Aged; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome