Role Of mTOR Inhibitors Research Articles

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

The Role of Mtor Inhibitors in Endocrine Resistance Therapy of Breast Cancer Type ER+

Breast cancer is the leading cause of death in women. Although hormonal therapy has produced positive results in HR+ breast cancer, resistance to this therapy remains a challenge in the treatment of breast cancer. Various mechanisms have been proposed as an explanation of resistance in breast cancer, one of which is the activation of the PI3K/AKT/mTOR pathway. The PI3K/AKT/mTOR pathway is a transduction pathway that regulates many important aspects in both normal cells and cancer cells, including cell proliferation, apoptosis, cell morphology and migration, protein synthesis, and integrase metabolism. Preclinical dan clinical data show inhibition of this pathway can improve survival, especially in resistant hormonal therapy models. The use of mTOR inhibitors (everolismus) has been approved by the FDA as a combination therapy with exemestane for postmenopausal women with HR+/HER2-breast cancer. 

Abstract 3209: Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC

Abstract Head and neck squamous cell carcinoma (HNSCC) constitutes the eighth most common cancer globally, with the eighth highest mortality rate amongst all cancer types. TP53 is the most frequently mutated gene in HPV -negative HNSCC. HPV-negative HNSCC harboring p53 mutations have the worst clinical outcomes with 50-60% local regional and distant recurrences causing increased morbidity and mortality. TP53 mutations are associated with shorter recurrence-free and overall survival. Angiogenesis and lymphangiogenesis play a causal role in tumor recurrence and lymph node metastasis. Therefore, inhibiting tumor angiogenesis and lymphangiogenesis is important in to preventing tumor recurrence and metastasis of TP53 mutant HNSCC. Previous studies demonstrated that mTOR activates STAT3 to upregulate HIF-1α and its target proteins, VEGF-A and VEGF-C, key molecules involved in angiogenesis and lymphangiogenesis, respectively. Further, mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing the VEGF-C/VEGF-3 axis and releasing soluble VEGFR-2. Accordingly, our objective was to investigate the effect of an mTOR inhibitor, everolimus, on angiogenesis and lymphangiogenesis of HPV-negative TP53 mutant HNSCC. Everolimus treatment of HPV-negative HNSCC cell lines harboring a variety of TP53 mutations, significantly downregulated protein and mRNA levels of VEGF-A and VEGF-C. Moreover, everolimus downregulated HIF-1α protein levels suggesting a HIF-1alpha-dependent VEGF modulation. Interestingly, treatment of human microvascular and lymphatic endothelial cells (HMEC-1 and HMEC-1A, respectively) with everolimus was also associated with a significant reduction in cell proliferation, in vitro tube formation, and migration. Protein and mRNA levels of HIF-1α, VEGF-A, and VEGF-C were downregulated by everolimus treatment in both HMEC-1 and HMEC-1A cell lines. Taken together, our data suggest that everolimus prevents angiogenesis and lymphangiogenesis through the inhibition of HIF-1α, indicating a promising role for mTOR inhibitors in treating HPV-negative TP53 mutant HNSCC patients at high risk for recurrence. Citation Format: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Emily K. Daniel, Tara Moore-Medlin, Xiaohua Rong, Alok R. Khandelwal, Cherie-Ann O. Nathan. Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3209.

Mammalian Target of Rapamycin (mTOR) Inhibitor Improves Local Immune Microenvironment and Reduces Seizures via Increasing miR-211 Level in Rat Brain

This study aims to analyze the role of mTOR inhibitor on the expression of miR-211 in rat brain tissue and the biological effect of miR-211 in attenuating seizure. Rats were randomly divided into four groups, and the number of seizures and the duration of single seizure were observed within 24 hours after intervention. The level of miR-211 in brain tissue was detected by RT qPCR, the apoptosis of nerve cells was assessed by TUNEL staining, the level of immune cells was detected by flow cytometry, and the level of serum inflammatory factors was determined by ELISA. The number of seizures and the duration of single seizure in the three groups treated by rapamycin within 24 hours were lower than those in the control group, and the symptom relief in group C was the best. After treatment, the expression level of miR-211 in the brain tissue of epileptic rats increased. TUNEL staining showed that neuronal apoptosis was obvious in epileptic rats. The anti apoptotic ability of group C was the most significant, followed by group D and group B. Compared with group A, the levels of CD3+ cells, CD8+ cells and CD4+/CD25+ cells in brain tissue of group C were decreased, while the levels of IL-2 and IFN-γ were lower in group C than those in control. In group C (n = 5), the levels of CD3+ cells, CD8+ cells and CD4+/CD25+ cells were elevated, and the levels of immune related cytokines IL-2 and IFN-γ were higher than those of rats without miR-211 inhibition. mTOR inhibitors can improve the local immune microenvironment, reduce the release of inflammatory factors, and finally decrease the frequency and duration of seizures by up regulating the level of miR-211 in rat brain tissue.

MTOR Inhibitors Induce Erythropoietin Resistance in Renal Transplant Recipients.

AimTo elucidate the role of mTOR inhibitors on iron, hepcidin and erythropoietin-mediated regulation of hemopoiesis in stable renal transplant recipients (RTR).BackgroundImpaired hemopoiesis is common following renal transplantation managed using mTOR inhibitors. The mechanisms responsible are uncertain but include direct effects on iron, hepcidin or erythropoietin-mediated hemopoiesis.MethodsWe conducted a single center prospective case-control study of 26 adult RTR with stable allograft function. RTR received stable mTOR dosing (cases, 11/26 [42%]) or stable tacrolimus dosing (controls, 15/26 [58%]). Baseline demographics, full blood count, renal function, iron studies, hepcidin-25, Interleukin-6 (IL-6) and erythropoietin (EPO) levels were determined.ResultsThere were no differences in age, gender or allograft function. Mean daily sirolimus dose for cases was 1.72 mg, with mean trough level of 8.46 ng/mL. Mean daily tacrolimus dose for controls was 4.3 mg, with mean trough level of 5.8 ng/mL. There were no differences in mean hemoglobin (143 vs. 147 g/L; p = 0.59), MCV (88 vs. 90 fL; p = 0.35), serum ferritin (150 vs. 85.7 μg/L; p = 0.06), transferrin saturation (26 vs. 23.3%; p = 0.46), IL-6 (11 vs. 7.02 pg/ml; p = 0.14) or hepcidin-25 (3.62 vs. 3.26 nM; p = 0.76) between the groups. EPO levels were significantly higher in the group receiving mTOR therapy (16.8 vs. 8.49 IU/L; p = 0.028). On logistic regression analysis EPO level was the only variable that had a significant impact providing an odds ratio of 0.84 (95%CI 0.66–0.98). The area under the receiver operator characteristic curve (ROC) for the analysis was 0.77 (95%CI 0.54–0.94) with p = 0.04.Conclusion: Higher levels of EPO in the absence of deranged iron biochemistry or hepcidin-25 levels suggest that EPO resistance rather than impaired iron metabolism may contribute to the impaired hemopoiesis previously demonstrated in RTR on mTOR therapy.

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside.

The mTOR pathway plays a central role in many cellular processes, such as cellular growth, protein synthesis, glucose, and lipid metabolism. Aberrant regulation of mTOR is a hallmark of many cancers, including hematological malignancies. mTOR inhibitors, such as Rapamycin and Rapamycin analogs (Rapalogs), have become a promising class of agents to treat malignant blood diseases—either alone or in combination with other treatment regimens. This review highlights experimental evidence underlying the molecular mechanisms of mTOR inhibitors and summarizes their evolving role in the treatment of hematologic disease, including leukemia, lymphoma, myeloma, immune hemocytopenia, and graft-versus-host disease (GVHD). Based on data presented in this review, we believe that mTOR inhibitors are becoming a trusted therapeutic in the clinical hematologist’s toolbelt and should be considered more routinely in combination therapy for the management of hematologic disease.

TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

Idiopathic pulmonary fibrosis is a fatal interstitial lung disease characterized by the TGF-β (transforming growth factor-β)-dependent differentiation of lung fibroblasts into myofibroblasts, which leads to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine-glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here, we demonstrate that TGF-β promotes accumulation of ATF4 (activating transcription factor 4), which is required for increased expression of the serine-glycine synthesis pathway enzymes in response to TGF-β. We found that induction of the integrated stress response (ISR) contributes to TGF-β-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-β is activation of mTORC1 (mTOR Complex 1). TGF-β activates the PI3K-Akt-mTOR pathway, and inhibition of PI3K prevents activation of downstream signaling and induction of ATF4. Using a panel of mTOR inhibitors, we found that ATF4 activation is dependent on mTORC1, independent of mTORC2. Rapamycin, which incompletely and allosterically inhibits mTORC1, had no effect on TGF-β-mediated induction of ATF4; however, Rapalink-1, which specifically targets the kinase domain of mTORC1, completely inhibited ATF4 induction and metabolic reprogramming downstream of TGF-β. Our results provide insight into the mechanisms of metabolic reprogramming in myofibroblasts and clarify contradictory published findings on the role of mTOR inhibition in myofibroblast differentiation.

PTEN Hamartoma tumor syndrome in childhood: A review of the clinical literature.

PTEN hamartoma tumor syndrome (PHTS) is a highly variable autosomal dominant condition associated with intellectual disability, overgrowth, and tumor predisposition phenotypes, which often overlap. PHTS incorporates a number of historical clinical presentations including Bannayan-Riley-Ruvalcaba syndrome, Cowden syndrome, and a macrocephaly-autism/developmental delay syndrome. Many reviews in the literature focus on PHTS as an adult hamartoma and malignancy predisposition condition. Here, we review the current literature with a focus on pediatric presentations. The review starts with a summary of the main conditions encompassed within PHTS. We then discuss PHTS diagnostic criteria, and clinical features. We briefly address rarer PTEN associations, and the possible role of mTOR inhibitors in treatment. We acknowledge the limited understanding of the natural history of childhood-onset PHTS as a cancer predisposition syndrome and present a summary of important management considerations.

Non-CMV Viral Infections Following Solid-Organ Transplantation – Focus on Human T-Cell Lymphotropic Virus Type-1 and Human Herpesviruses-6,-7 and -8

In non-endemic areas, HTLV-1 is an uncommon pathogen in the transplant host but can be associated with significant morbidity and mortality. Careful assessment of risk factors, targeted screening and heightened awareness of the clinical presentation of HTLV-1 associated disease is necessary for timely recognition and management in the transplant host. The use of antiretroviral agents in the management of symptomatic disease due to HTLV-1 remains controversial. HHV-6 has long been recognized as a pathogen in the transplant host however, establishing pathogenicity remains a challenge in clinical situations due to its ubiquitous nature, overlapping clinical manifestations and clustering of infection with other beta-herpesviruses. HHV-6 has the unique ability to undergo integration into the host chromosome and has been reported in ~1% of solid-organ and allogeneic stem cell transplant population. Increased recognition of this entity is needed as it can be mistaken for active viral infection and can lead to unnecessary use of antiviral medications. Current guidelines recommend against screening and treatment of asymptomatic HHV-6 infection in the solid-organ transplant host. HHV-7 is often diagnosed as co-infection with other beta-herpesviruses but pathogenicity is less clear. No clinical syndrome solely attributable to HHV-7 has been identified. HHV-8 infection following organ transplantation can be due to primary acquisition from donor or non-donor derived exposures; or secondary to reactivation of latent infection in a seropositive recipient. Kaposi sarcoma is the most common HHV-8 associated post-transplant complication however, there is increasing recognition of non-neoplastic syndromes of febrile illness with bone marrow suppression and hemophagocytic syndrome. Lack of standardized laboratory assays remains an impediment to targeted screening and diagnosis of HHV-8 associated complications. There is accumulating data on the role of mTOR inhibitors and HIV protease inhibitors particularly nelfinavir in the treatment of KS however, data in the transplant host is sparse. Multi-disciplinary approach is needed for management of HHV-8 associated complications.

Pyomyositis in a Patient with IgA Nephropathy and Kidney Transplant

Infections are among the most common complications transplant physicians face when dealing with solid organ transplant recipients. We present a case of pyomyositis caused by Staphylococcus aureus in a patient with IgA nephropathy and a kidney transplant, under treatment with mTOR inhibitors and prednisone. This entity is a rare intramuscular infection, given the resistance of healthy muscle to colonization. We review the most frequent agents, the diagnostic algorithm, and therapeutic alternatives. We also comment on the role of mTOR inhibitors in this case as possible predisposing factor for the infection.

MTOR Inhibitors in Advanced Biliary Tract Cancers.

Patients with advanced biliary tract cancers (BTCs), including cholangiocarcinoma (CCA), have poor prognosis so novel treatment is warranted for advanced BTC. In current review, we discuss the limitations of current treatment in BTC, the importance of mTOR signalling in BTC, and the possible role of mTOR inhibitors as a future treatment in BTC. Chemotherapy with gemcitabine-based chemotherapy is still the standard of care and no targeted therapy has been established in advanced BTC. PI3K/AKT/mTOR signaling pathway linking to several other pathways and networks regulates cancer proliferation and progression. Emerging evidences reveal mTOR activation is associated with tumorigenesis and drug-resistance in BTC. Rapalogs, such as sirolimus and everolimus, partially inhibit mTOR complex 1 (mTORC1) and exhibit anti-cancer activity in vitro and in vivo in BTC. Rapalogs in clinical trials demonstrate some activity in patients with advanced BTC. New-generation mTOR inhibitors against ATP-binding pocket inhibit both TORC1 and TORC2 and demonstrate more potent anti-tumor effects in vitro and in vivo, however, prospective clinical trials are warranted to prove its efficacy in patients with advanced BTC.

Role of the mTOR pathway in minor salivary gland changes in Sjogren\u2019s syndrome and systemic sclerosis

BackgroundTo examine the activity of the mammalian target of rapamycin (mTOR) pathway and its regulators, transforming growth factor (TGF)-β1 and phosphatase and tensin homolog (PTEN), in minor salivary gland biopsies of Sjogren’s syndrome (SS) and systemic sclerosis (SSc) patients.MethodsWe retrospectively evaluated SS, SSc, and SS-SSc overlap patients admitted to our outpatient rheumatology clinic between January 2007 and December 2015 who underwent a minor salivary gland biopsy. Patient demographics and some clinical features were obtained from hospital records. Immunohistochemistry was used to analyze total mTOR, total PTEN, and TGF-β1 expression in the biopsied tissues. The biopsy specimens were also examined for the presence and degree of fibrosis.ResultsMinor salivary gland biopsies of 58 SS, 14 SSc, and 23 SS-SSc overlap patients were included in the study. There was no significant difference in mTOR expression between these groups (P = 0.622). PTEN protein was expressed in 87.2% of patients with SS, 57.9% with overlap syndrome, and 100% of the SSC patients, and these differences were statistically different (P = 0.023). Although ductal epithelial TGF-β1 expression was similar between the groups (P = 0.345), acinar cell expression was found to be more frequent in the SSc (72.7%) and overlap patients (85.7%) in comparison with the SS cases (58.2%; P = 0.004).ConclusionmTOR may be one of the common pathways in the pathology of both SS and SSc. Hence, there may be a role for mTOR inhibitors in the treatment of both diseases. Additionally, PTEN and TGF-β1 expression may be a distinctive feature of SSc.

The Role of mTOR Inhibitors in the Management of Viral Infections: A Review of Current Literature.

Viruses are the leading cause of infections after solid organ transplant. The antiviral properties of mammalian target of rapamycin inhibitors (mTORis) have been ascribed to a variety of mechanisms and historical data have supported their use over other immunosuppressants for a myriad of viruses. Herein, we summarize the most current data to highlight the role of mTORis in the management of viral infections after solid organ transplant. The mTORis play a clear role in the management of cytomegalovirus, and have data supporting their potential use for BK virus and human herpesvirus 8-related Kaposi sarcoma. No data definitively supports mTORis for use in Epstein-Barr virus-mediated posttransplant lymphoproliferative disorder or hepatitis C virus viral replication. Although theoretically an advantageous therapy for hepatitis C virus-related liver allograft fibrosis and human immunodeficiency virus, mTORi use specifically for these indications is less attractive with modern treatments currently available. Data surrounding mTORi efficacy in preventing rejection, and their toxicity profile must be balanced with their potential antiviral effects in combination with patient-specific factors.

Perspectives in the development of novel treatment approaches.

Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been observed in many human tumors and has been found to be implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target of anticancer therapy. This paper focuses on the role of mTOR inhibition and on the recent developments of the mTOR inhibitor everolimus (RAD001) in this field.

Role of mTOR inhibitors in solid organ transplantation

Role of mTOR inhibitors in solid organ transplantation

Abstract B22: Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer

Abstract The anti-androgen bicalutamide is widely used in the treatment of advanced prostate cancer (CaP) in many countries, but its effect on castration resistant CaP (CRPC) is limited. We previously showed that resistance to bicalutamide results from increased activation of the mechanistic target of rapamycin (mTOR); indicating a role for mTOR inhibitors in CaP treatment. Interestingly, a clinical trial testing combinations of the mTOR inhibitor RAD001 with bicalutamide were initially effective (PSA decline>50%) in 62.5% CRPC patients, but many initial responders later developed resistance. Here we investigate causes for their difference in response. Evaluation of various CRPC cell lines identified resistant vs sensitive in vitro models, and revealed that increased eIF4E phosphorylation at S209 is associated with resistance to the combination. To recognize potential causes of resistance, we demonstrated using a human tumor xenograft mouse model, that bicalutamide use is associated with an increase in eIF4E(S209) phosphorylation. Investigations revealed that AR suppressed eIF4E phosphorylation, while the use of anti-androgens relieved this suppression, thereby triggering its increase. Additional investigation on the consequences of increased eIF4E phosphorylation in human prostatectomy samples revealed that increased eIF4E phosphorylation strongly correlated with the cell proliferation marker Ki67, indicating a role for eIF4E in tumor growth. Inhibition of eIF4E phosphorylation by siRNA suppression or treatment with CGP57380 (an inhibitor of MAPK interacting serine-threonine kinases Mnk1/2, the eIF4E upstream kinase,) sensitized CRPC cells to RAD001+bicalutamide, while eIF4E overexpression induced resistance. Our results demonstrate that bicalutamide treatment induced an increase in eIF4E phosphorylation by inhibition of AR which otherwise suppressed this phosphorylation. Increased eIF4E phosphorylation then induced resistance to the combination of anti-androgens with mTOR inhibitors by increasing proliferation. These results also indicate that resistance to RAD001+bicalutamide can be prevented by the concurrent use of a Mnk1/2 inhibitor. Citation Format: Leandro S. D'Abronzo, Michael Crapuchettes, Ryan Beggs, Ruth Vinall, Clifford Tepper, Salma Siddiqui, Maria Mudryj, Frank Melgoza, Blythe Durbin-Johnson, Ralph deVere White, Paramita Ghosh. Increased phosphorylation of eIF4E induces resistance to treatment with mTOR inhibitors together with AR antagonists in advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B22.

Is There a Role for mTOR Inhibitors in Renal Transplantation?

Is There a Role for mTOR Inhibitors in Renal Transplantation?

Abstract 1855: Role of mTOR inhibition in triple-negative breast cancer

Abstract BACKGROUND: Triple-negative breast cancers (TNBC) represent the 10-17% of all diagnosed breast cancers (BC) and are characterized by the absence of ER/PgR expression, HER2 amplification and often show a basal-like phenotype. TNBC are often diagnosed in patients with BRCA1 germline mutation and unfortunately treatment options are still limited. The mTOR (Mammalian Target Of Rapamycin) pathway seems to play an important role in BC pathogenesis and it is possible to target this pathway by inhibitors such as rapamycin. In human BC cross talk between ER/PgR receptors signaling and the mTOR pathway is believed to be responsible for resistance to hormone therapy probably due to a down regulation of hormone receptors. Based on these evidences we have hypothesized that the inhibitors of mTOR pathway may lead to the up-regulation of ER, PgR and HER2 in TNBC cell lines. METHODS: For this study we used TNBC cells (MDA-MB-231 and BT20) cultured in DMEM:F12 (Dulbecco's Modified Eagle's Medium) with 10% bovine serum (FBS), 100 U/mL penicillin (1%) and 50 mg/mL of streptomycin under standard conditions (37°C in an atmosphere composed of 16% O2, 79% N2 and 5% CO2). Cells were initially treated with Rapamycin (1, 5, 10, 15 microM) for 24, 48, and 72h in order to verify if the drug determines a blockade of cell proliferation. Before drug administration, the cells were subjected to serum starvation by eliminating serum from culture medium. The evaluation of cell viability following the administration of the drug was carried out using the MTT assay. Real time PCR analyses were carried out in order to evaluate gene expression modifications of ER, PgR and HER2 receptors, through Taqman probe chemistry. RESULTS: The preliminary cell viability experiments conducted on different TNBC cell lines (MDA-MB-231 and BT20), showed no significant cytotoxic effects by increasing Rapamycin concentrations (1, 5 and 10 microM) after 72h treatment, except for the higher concentration (15 microM) for which a cytotoxic effect was observed. The following qPCR approach highlighted significant variations in estrogen and progesterone receptor gene expression for the TNBC cell lines after 24, 48, 72h with 1, 5, 10 microM Rapamycin. In particular their expression level resulted up-regulated. Unlikely no association between mTOR inhibition and HER2 expression level were identified, suggesting no effects of mTOR inhibition on HER2 expression. CONCLUSION AND FUTURE PERSPECTIVES: To these preliminary results suggest that the mTOR inhibition leads to re-expression of hormone receptors. This finding supports a potential clinical application of mTOR inhibition in TNBC. The perspective of phenotype change upon rapamycin treatment prompts new therapeutic scenarios. However, further investigations are needed to explain the biological mechanisms driving these changes. Citation Format: Daniela Massihnia, Giuseppe Bronte, Marta Castiglia, Nadia Barraco, Antonina Cangemi, Alessandro Perez, Daniele Fanale, Gianni Pantuso, Salvatore Vieni, Valentina Calò, Christian D. Rolfo, Viviana Bazan, Antonio Russo. Role of mTOR inhibition in triple-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1855.

Role of mTOR Inhibitors in Growth Hormone-Producing Pituitary Adenomas Harboring Different FGFR4 Genotypes.

Pituitary adenomas (PAs) are common intracranial lesions. Available medical therapies are limited in PAs, and therefore, it is essential to identify treatments that control PA growth when surgery is not an option. Fibroblast growth factor 4 is implicated in PA pathogenesis; therefore, in this study, we used an isogenic mammosomatotroph cell line (GH4C1) harboring different fibroblast growth factor receptor (FGFR)-4 genotypes to establish and characterize intracranial xenograft mouse models that can be used for preclinical drug testing. We show that proliferating GH4C1 tumors have an average latency of 3 weeks to form. Histological analysis revealed that prototypic FGFR4 (G388) tumors express increased prolactin and less GH, whereas tumors possessing the polymorphic variant of FGFR4 (R388) express increased GH relative to prolactin. All tumors show abundant mammalian target of rapamycin (mTOR) signaling as confirmed using phosphorylated (p)-S6 and p-4E-binding protein 1 as downstream regulators of this pathway. We subsequently demonstrate that the mTOR inhibitor RAD001 decreases tumor growth rate and reduces p-S6 but not p-4E-binding protein 1 activation, regardless of FGFR4 status. More importantly, GH activity was significantly reduced after mTOR inhibition in the R388 polymorphic variant tumors. This reduction was also associated with a concomitant reduction in serum IGF-1 levels in the R388 group. In summary, we demonstrate that the GH4C1 FGFR polymorphic xenograft is a useful model for examining PAs. Furthermore, we show that RAD001 can efficiently reduce tumor growth rate by a reduction in mTOR signaling and more importantly results in control of GH expression and IGF-1 secretion, providing further support for using mTOR inhibitors in PA patients, in particular GH-producing adenomas.

The Role of mTOR Inhibitors in the Treatment of Patients with Tuberous Sclerosis Complex: Evidence-based and Expert Opinions.

Tuberous sclerosis complex (TSC) is a genetic disorder arising from mutations in the TSC1 or TSC2 genes. The resulting over-activation of the mammalian target of rapamycin (mTOR) signalling pathway leaves patients with TSC susceptible to the growth of non-malignant tumours in multiple organs. Previously, surgery was the main therapeutic option for TSC. However, pharmacological therapy with mTOR inhibitors such as everolimus and sirolimus is now emerging as an alternate approach. Everolimus and sirolimus have already been shown to be effective in treating subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML), and everolimus is currently being evaluated in treating TSC-related epilepsy. In November 2013 a group of European experts convened to discuss the current options and practical considerations for treating various manifestations of TSC. This article provides evidence-based recommendations for the treatment of SEGA, TSC-related epilepsy and renal AML, with a focus on where mTOR inhibitor therapy may be considered alongside other treatment options. Safety considerations regarding mTOR inhibitor therapy are also reviewed. With evidence of beneficial effects in neurological and non-neurological TSC manifestations, mTOR inhibitors may represent a systemic treatment for TSC.