sirolimus and Thymus-Neoplasms

The pathogenesis of thymic epithelial tumors remains poorly elucidated. The PIK3/Akt/mTOR pathway plays a key role in various cancers; interestingly, several phase I/II studies have reported a positive effect of mTOR inhibitors in disease control in thymoma patients. A major limit for deciphering cellular and molecular events leading to the transformation of thymic epithelial cells or for testing drug candidates is the lack of reliable in vitro cell system. We analyzed protein expression and activation of key players of the Akt/ mTOR pathway namely Akt, mTOR, and P70S6K in eleven A, B and AB thymomas as well as in normal thymuses. While only Akt and phospho-Akt were expressed in normal thymuses, both Akt and mTOR were activated in thymomas. Phospho-P70S6K was expressed in all thymic tumors whatever their subtypes, and absent in normal thymus. Interestingly, we report the activation of Akt, mTOR and P70S6 proteins in primary thymic epithelial cells maintained for short period of time after their derivation from seven AB and B thymomas. Finally, we showed that rapamycin (100 nM) significantly reduced proliferation of thymoma- derived epithelial cells without inducing cell death. Our results suggest that the activation of the Akt/ mTOR pathway might participate to the cell proliferation associated with tumor growth. Ultimately, our data enhance the potential role of thymic epithelial cells derived from tissue specimens for in vitro exploration of molecular abnormalities in rare thymic tumors.

Topics: Aged; Aged, 80 and over; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Female; Humans; Male; Middle Aged; Mutation; Neoplasms, Glandular and Epithelial; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Thymoma; Thymus Gland; Thymus Neoplasms; TOR Serine-Threonine Kinases; Transcription Factors, TFII; Tumor Cells, Cultured

The tumor suppressor gene FBXW7 is deleted and mutated in many different types of human cancers. FBXW7 primarily exerts its tumor suppressor activity by ubiquitinating different oncoproteins including mTOR. Here we used gene transcript profiling to gain a deeper understanding of the role of FBXW7 in tumor development and to determine the influence of mTOR inhibition by rapamycin on tumor transcriptome and biological functions. In comparison to tumors from p53 single heterozygous (p53+/-) mice, we find that radiation-induced thymic lymphomas from Fbxw7/p53 double heterozygous (Fbxw7+/-p53+/-) mice show significant deregulation of cholesterol metabolic processes independent of rapamycin treatment, while cell cycle related genes were upregulated in tumors from placebo treated Fbxw7+/-p53+/- mice, but not in tumors from rapamycin treated Fbxw7+/-p53+/- mice. On the other hand, tumors from rapamycin treated Fbxw7+/-p53+/- mice were enriched for genes involved in the integrated stress response, an adaptive mechanism to survive in stressful environments. Finally, we demonstrated that the Fbxw7 gene signatures identified in mouse tumors significantly overlap with FBXW7 co-expressed genes in human cancers. Importantly these common FBXW7 gene signatures between mouse and human are predictive for disease-free survival in human colon, breast and lung adenocarcinoma cancer patients. These results provide novel insights into the role of FBXW7 in tumor development and have identified a number of potential targets for therapeutic intervention.

Topics: Animals; Antineoplastic Agents; Cell Cycle; Cell Cycle Proteins; Cholesterol; Databases, Genetic; Disease Models, Animal; F-Box Proteins; F-Box-WD Repeat-Containing Protein 7; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genotype; Heterozygote; Humans; Lymphoma; Mice, Knockout; Neoplasms, Radiation-Induced; Phenotype; Protein Kinase Inhibitors; Sirolimus; Thymus Neoplasms; TOR Serine-Threonine Kinases; Transcription, Genetic; Tumor Suppressor Protein p53; Ubiquitin-Protein Ligases

Thymomas and thymic carcinomas, although uncommon, constitute a significant proportion of anterior mediastinal tumours. Systemic chemotherapy is the mainstay of treatment for inoperable or recurrent disease, but immunosuppressive therapy may provide an alternative treatment strategy.. We present a series of 18 patients diagnosed with unresectable thymic tumours, of which eight received immunosuppressive therapy following relapse after chemotherapy.. Eight individuals were treated with primary immunotherapy after a median of 3.5 lines of chemotherapy (range 2-6 lines), of which 3 had confirmed myasthenia gravis (MG). After 3 months, 2 patients achieved a radiological partial response and 4 had stable disease. The median time to progression measured 6.8 months (CI 1.4-19.3 months). Two of the 4 patients who progressed on tacrolimus and prednisolone received sirolimus. One of these patients has stable disease (SD) at 21 months, and the other has SD at 3 months.. Although previous case reports have related tacrolimus therapy with tumour shrinkage in patients with MG-associated invasive thymomas, these data are the first to demonstrate the efficacy of such immunosuppressive agents in a larger cohort of heavily pre-treated patients with thymic tumours. Our experience adds to the limited anecdotal evidence in the literature, and suggests that immunosuppressive agents represent a valuable additional treatment for thymic tumours.

Topics: Aged; Combined Modality Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Recurrence, Local; Sirolimus; Tacrolimus; Thymectomy; Thymus Neoplasms

Vaccine strategies aimed at generating CD8(+) T cell memory responses are likely to show augmented efficacy against chronic challenges like tumor. The abundance in variety of memory CD8(+) T cells behooves development of vaccine strategies that generate distinct memory responses and evaluate them for tumor efficacy. In this study, we demonstrate the ability of a variety of rapamycin treatment regimens to regulate virus vaccination-induced CD8(+) T cell memory responses and tumor efficacy. Strikingly, a short course of high-dose, but not low-dose, rapamycin treatment transiently blocks viral vaccination-induced mammalian target of rapamycin activity in CD8(+) T cells favoring persistence and Ag-recall responses over type 1 effector maturation; however, prolonged high-dose rapamycin administration abrogated memory responses. Furthermore, a short course of high-dose rapamycin treatment generated CD8(+) T cell memory responses that were independent of IL-15 and IL-7 and were programmed early for sustenance and greater tumor efficacy. These results demonstrate the impact a regimen of rapamycin treatment has on vaccine-induced CD8(+) T cell responses and indicates that judicious application of rapamycin can augment vaccine efficacy for chronic challenges.

Topics: Adjuvants, Immunologic; Adoptive Transfer; Animals; Antigens, Neoplasm; Canarypox virus; Cancer Vaccines; CD8-Positive T-Lymphocytes; Clonal Selection, Antigen-Mediated; Immunologic Memory; Interleukin-15; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Multiprotein Complexes; Neoplasm Transplantation; Ovalbumin; Proteins; Sirolimus; T-Cell Antigen Receptor Specificity; Thymoma; Thymus Neoplasms; TOR Serine-Threonine Kinases; Vaccination

Abnormal thymocyte development with thymic lymphomagenesis inevitably occurs in Atm-/- mice, indicating that ATM plays a pivotal role in regulating postnatal thymocyte development and preventing thymic lymphomagenesis. The mechanism for ATM controls these processes is unclear. We have shown previously that c-Myc, an oncoprotein regulated by the mammalian target of rapamycin (mTOR), is overexpressed in Atm-/- thymocytes. Here, we show that inhibition of mTOR signaling with its specific inhibitor, rapamycin, suppresses normal thymocyte DNA synthesis by downregulating 4EBP1, but not S6K, and that 4EBP1 phosphorylation and cyclin D1 expression are coordinately increased in Atm-/- thymocytes. Administration of rapamycin to Atm-/- mice attenuates elevated phospho-4EBP1, c-Myc and cyclin D1 in their thymocytes, and delays thymic lymphoma development. These results indicate that mTOR downstream effector 4EBP1 is essential for normal thymocyte proliferation, but deregulation of 4EBP1 in Atm deficiency is a major factor driving thymic lymphomagenesis in the animals.

Topics: Adaptor Proteins, Signal Transducing; Animals; Antibiotics, Antineoplastic; Ataxia Telangiectasia Mutated Proteins; Carrier Proteins; Cell Cycle Proteins; Cyclin D1; DNA Replication; DNA-Binding Proteins; Eukaryotic Initiation Factors; Lymphoma; Mice; Mice, Knockout; Phosphoproteins; Phosphotransferases (Alcohol Group Acceptor); Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Thymus Neoplasms; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins

Rapamycin, a potent immunosuppressive drug that prevents rejection of organ transplants in many animals, caused profound growth inhibition in an immature B cell lymphoma, BKS-2, at very low concentrations (2 ng/ml). Similar growth inhibition was also observed in a series of B cell lymphomas (i.e., L1.2, NFS.1.1, and WEHI-279) as well as in thymoma cells. The cell death induced by rapamycin in BKS-2 lymphoma was found to be via programmed cell death, or apoptosis. In contrast to rapamycin, neither FK506 nor CsA affected the normal growth of these cells. FK506, but not CsA antagonized the effect of rapamycin and rescued the BKS-2 cells from undergoing apoptosis. Further, suboptimal concentrations of anti-IgM antibodies and rapamycin acted synergistically in causing the growth inhibition of BKS-2 cells and this inhibitory effect was also completely reversed by FK506. Thus, rapamycin appeared to inhibit lymphoma growth by binding to FK506 binding protein. These results indicate that rapamycin should be evaluated as an effective immunosuppressive therapeutic agent to prevent the incidence of lymphoma after transplantations.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Apoptosis; B-Lymphocytes; Cell Division; Drug Screening Assays, Antitumor; Immunosuppressive Agents; Lymphoma, B-Cell; Mice; Mice, Inbred CBA; Polyenes; Sirolimus; Tacrolimus; Thymoma; Thymus Neoplasms; Tumor Cells, Cultured