sirolimus and Carcinoma--Small-Cell

AKT-mTOR pathway is considered as a key actor of the regulation of cell metabolism, interacting in network with multiple pathways implied in immune regulation and carcinogenesis. mTOR inhibitors were initially proposed as immunomodalting agents and are now developed as targeted therapy for non-hematologic solid tumours or lymphomas. This review proposes to synthesize knowledge on the AKT-mTOR pathway and the currently available data for head and neck or pulmonary tumours in order to present the value of these agents in this setting. Rational and preclinic results will then allow us to discuss potential future development of mTOR inhibitors.

Topics: Antibiotics, Antineoplastic; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Head and Neck Neoplasms; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Sirolimus; TOR Serine-Threonine Kinases

Over the last 20 years, progress in the therapy of small cell lung cancer has been painfully slow. Despite dramatic initial responses to chemotherapy, most patients relapse quickly with an overall 5-year survival of about 5%. Recent trials however offer some hope at changing this picture. Combining standard regimens with newer agents has doubled median survival in some cases. The use of novel targeted agents holds the promise of significantly increasing the survival in this disease, with manageable toxicity. This review outlines current treatment strategies, summarizes recent clinical trials and offers a view of what the next 5 years may hold for the treatment of small cell lung cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bridged-Ring Compounds; Carcinoma, Small Cell; Clinical Trials as Topic; Humans; Lung Neoplasms; Palliative Care; Phosphoinositide-3 Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Sirolimus; Taxoids; Topoisomerase I Inhibitors

To study the progression-free survival (PFS) and toxicity with 25- or 250-mg doses of temsirolimus (CCI-779) after induction chemotherapy in patients with extensive small-cell lung cancer.. Patients with either stable or responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan were randomized between 4 and 8 weeks after completion of induction therapy to receive either 25 or 250 mg of temsirolimus intravenously every week until disease progression.. Eighty-seven patients entered between January 2002 and December 2003, of whom 85 were eligible: 44 received 25 mg (arm A), and 41 received 250 mg (arm B). The overall median follow-up time for all eligible patients was 34.6 months. Median age was 59 years (range, 39-80); 42 (49.4%) were male and 43 (50.6%) female; 12.9% had brain metastases. The overall median and 1-year PFS were 2.2 months (95% confidence interval [CI]: 1.8, 2.9) and 4.7% (95% CI: 0.2%, 9.2%), respectively. The median PFS (95% CI) for arm A was 1.9 months (1.6, 2.3); for arm B, it was 2.5 months (1.9, 3.4; p = 0.24). The median overall survival from randomization was 8 months (95% CI: 6.5, 9.5). Among the 86 patients with reported toxicities, 36 (42%) had grade 3 toxicities, the most common of which were thrombocytopenia, hypophosphatemia, and fatigue, and an additional 12 (14%) had grade 4 toxicities, the most common of which was neutropenia. No patients experienced lethal toxicities.. Temsirolimus (CCI 779), given at 25 or 250 mg weekly, seemed not to increase the PFS in this patient population.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Cisplatin; Etoposide; Female; Follow-Up Studies; Humans; Irinotecan; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Protein Kinase Inhibitors; Remission Induction; Sirolimus; Survival Rate; Treatment Outcome

Everolimus has demonstrated antitumor efficacy for various cancers as a result of its inhibition of the mammalian target of rapamycin (mTOR) signaling cascade, which activates cell growth and cell proliferation. However, the low water solubility and low bioavailability of everolimus have prevented its clinical development as an anticancer drug. Therefore, to address the unsuitable characteristic of everolimus, we attempted to prepare liposomal everolimus as a viable drug delivery system, and then evaluated the anticancer efficacy of this system against a medullary thyroid carcinoma cell line (TT cells), a breast cancer cell line (MCF-7 cells) and a small lung carcinoma cell line (NCI-H446 cells). The particle size and entrapment efficacy of liposomal everolimus was ca. 80 nm and more than 90%, respectively. Liposomal everolimus showed higher cytotoxicity against NCI-H446 cells compared with TT cells. Against NCI-H446 tumors, significant suppression of the tumor volume was observed in liposomal everolimus-treated mice by intravenous injection, compared with free everolimus-treated mice by intraperitoneal injection, at a dose of 5 mg/kg without body weight loss. This study showed that liposomal everolimus could be a powerful formulation with anticancer efficacy for some cancers.

Topics: Animals; Antineoplastic Agents; Camptothecin; Carcinoma, Small Cell; Cell Line, Tumor; Cell Survival; Everolimus; Female; Humans; Immunosuppressive Agents; Irinotecan; Liposomes; Lung Neoplasms; Mice; Mice, Inbred BALB C; Sirolimus; Thyroid Neoplasms; Tumor Burden; Xenograft Model Antitumor Assays

The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC.. The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA.. We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor-stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2-specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001.. Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.

Topics: Animals; Antineoplastic Agents; Carcinoma, Small Cell; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p21; Drug Resistance, Neoplasm; Etoposide; Everolimus; Humans; Lung Neoplasms; Mice; Protein Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sirolimus; Stem Cell Factor; TOR Serine-Threonine Kinases

We show that cisplatin resistance in certain lung cancer cell lines can be reversed through inhibition of mTOR (mammalian Target of Rapamycin). These cell lines appear to possess high levels of phospho-mTOR, phospho-AKT and other growth-related proteins, such as hTERT (human telomerase reverse transcriptase), and Cyclin D3 which decrease upon inhibition of mTOR. Interestingly in one cisplatin resistant cell line which expresses BCL2/BCLxL, treatment with mTOR inhibitor (CCI-779) results in decreased levels of these anti-apoptotic proteins and may contribute to increasing apoptosis. Moreover, continuous exposure to CCI-779 was found to increase the expression of the multi-drug resistant P-gp1(P-gycoprotein1) efflux pump and therefore should be taken into consideration when designing clinical trials with this compound.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; bcl-X Protein; Carcinoma, Non-Small-Cell Lung; Carcinoma, Small Cell; Cell Line, Tumor; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Phosphorylation; Protein Kinases; Proto-Oncogene Proteins c-bcl-2; Sirolimus; TOR Serine-Threonine Kinases

Activation of the insulin-like growth factor-1 receptor (IGF-1R) by IGF-1 and IGF-2 plays a prominent role in the growth and survival of small cell lung cancer (SCLC) by potently activating the PI3K-Akt signal transduction pathway, which is also an important factor in the resistance of SCLC to chemotherapy. A12 is a fully human monoclonal antibody directed against the human IGF-1R that does not cross-react with the insulin receptor. In this study we have utilized A12 to determine the effects of selective antibody-mediated blockade of the IGF-1R on SCLC cell lines. Incubation with A12 resulted in a dose-dependent inhibition of IGF-1-stimulated IGF-1R and Akt activity, with maximal inhibition of approximately 75% at a concentration of 10mug/ml in the H526 cell line. Growth of the H526 and H146 cell lines in serum was inhibited by a maximum of 50-70% in a dose-dependent fashion, which correlated well with the extent of Akt inhibition. However, growth of the H69 and WBA cell lines was unaffected by A12. Despite almost complete inhibition of IGF-1R phosphorylation by A12, Akt activity remained constitutively high in these cell lines. H526 transfectants expressing a constitutively active Akt allele also were resistant to A12. Treatment with A12 additively enhanced response to carboplatin in the H526 and H146 cell lines but had no effect on the H69 and WBA cell lines. Treatment of the H526 cell line with a combination of A12 and rapamycin was highly synergistic. These data suggest that growth inhibition and chemosensitization of SCLC by A12 is directly correlated with the ability to inhibit PI3K-Akt signaling, with those cell lines showing constitutive PI3K-Akt signaling displaying a high level of resistance to IGF-1R targeted therapy.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Blotting, Western; Carboplatin; Carcinoma, Small Cell; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Humans; Immunoprecipitation; Insulin-Like Growth Factor I; Lung Neoplasms; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Signal Transduction; Sirolimus

Cisplatin is widely used for the treatment of solid tumors, including small cell lung cancers, but its success is often compromised due to relapse and resistance to further treatment. p70 ribosomal S6 kinase (p70S6K) has been shown to be upregulated in lung cancer cells. In the present study, we investigated whether the p70S6K pathway contributes to cisplatin resistance in human small cell lung cancer H69 cells. The levels of phosphorylated p70S6K and its downstream target S6 but not total p70S6K or S6 were elevated in the H69 cells that acquired resistance to cisplatin (H69/CP) compared to parental H69 cells. Cisplatin treatment resulted in the activation of p70S6K and downregulation of p70S6K was associated with cisplatin-induced PARP cleavage. While the ability of cisplatin to induce apoptosis was attenuated in H69/CP cells, inhibition of p70S6K by rapamycin enhanced cisplatin-induced apoptosis in these cells as evident by the increase in cisplatin-induced poly(ADP-ribose) polymerase (PARP) cleavage. The phosphoinositide 3-kinase (PI3K) inhibitor Ly294002 alone induced PARP cleavage and further augmented cisplatin-induced PARP cleavage. In contrast, inhibition of extracellular signal-regulated kinase (ERK) by U0126 attenuated cisplatin-induced PARP cleavage. Both rapamycin and Ly294002 enhanced cisplatin-induced acti-vation of ERK1/2. Taken together, these results suggest that activation of p70S6K contributes to cisplatin resistance in small cell lung cancer H69 cells, and inhibition/downregulation of p70S6K as well as activation of ERK1/2 could circumvent cisplatin resistance.

Topics: Antineoplastic Agents; Apoptosis; Butadienes; Carcinoma, Small Cell; Cell Line, Tumor; Chromones; Cisplatin; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Lung Neoplasms; Morpholines; Nitriles; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; Sirolimus

The fact that small cell lung cancer (SCLC) is commonly incurable despite being initially responsive to chemotherapy, combined with disappointing results from a recent SCLC clinical trial with imatinib, has intensified efforts to identify mechanisms of SCLC resistance. Adhesion to extracellular matrix (ECM) is one mechanism that can increase therapeutic resistance in SCLC cells. To address whether adhesion to ECM increases resistance through modulation of signaling pathways, a series of SCLC cell lines were plated on various ECM components, and activation of two signaling pathways that promote cellular survival, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway and the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK/ERK) pathway, was assessed. Although differential activation was observed, adhesion to laminin increased Akt activation, increased cellular survival after serum starvation, and caused the cells to assume a flattened, epithelial morphology. Inhibitors of the PI3K/Akt/mTOR pathway (LY294002, rapamycin) but not the MEK/ERK pathway (U0126) abrogated laminin-mediated survival. SCLC cells plated on laminin were not only resistant to serum starvation-induced apoptosis but were also resistant to apoptosis caused by imatinib. Combining imatinib with LY294002 or rapamycin but not U0126 caused greater than additive increases in apoptosis compared with apoptosis caused by the inhibitor or imatinib alone. Similar results were observed when adenoviruses expressing mutant Akt were combined with imatinib, or when LY294002 was combined with cisplatin or etoposide. These studies identify laminin-mediated activation of the PI3K/Akt/mTOR pathway as a mechanism of cellular survival and therapeutic resistance in SCLC cells and suggest that inhibition of the PI3K/Akt/mTOR pathway is one strategy to overcome SCLC resistance mediated by ECM.

Topics: Antineoplastic Agents; Benzamides; Carcinoma, Small Cell; Cell Adhesion; Cell Survival; Chromones; Drug Resistance, Neoplasm; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Humans; Imatinib Mesylate; Laminin; Lung Neoplasms; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperazines; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Pyrimidines; Sirolimus; TOR Serine-Threonine Kinases

The serine/threonine kinase p70s6k was found to be constitutively phosphorylated in H 69, H 345, and H 510 small cell lung cancer cells as judged by the retarded electrophoretic mobility of both isoforms of this kinase. Pretreatment of H 69, H 345, and H 510 cells with the potent immunosuppressant rapamycin led to p70s6k dephosphorylation in a concentration-dependent manner; half-maximum and maximum effects were achieved at 0.3 and 3 nM rapamycin, respectively. Rapamycin inhibited growth of H 69, H 345, and H 510 cells in liquid culture at similar concentrations to those required for inducing dephosphorylation of p70s6k. Furthermore, rapamycin markedly reduced the basal colony forming ability of H 69, H 345, and H 510 cells in semisolid media. Thus, constitutively phosphorylated/active p70s6k plays an important role in promoting the growth of small cell lung cancer cells. Furthermore, the rapamycin-sensitive p70s6k pathway may provide a novel target for therapeutic intervention in small cell lung cancer.

Topics: Antibiotics, Antineoplastic; Carcinoma, Small Cell; Cell Division; Humans; Isomerism; Lung Neoplasms; Neoplastic Stem Cells; Phosphorylation; Polyenes; Protein Serine-Threonine Kinases; Ribosomal Protein S6 Kinases; Sirolimus