Role Of mTOR Inhibitors Research Articles

The role of mTOR inhibitors in targeting a putative cancer stem cell-like population in esophageal cancer.

43 Background: Despite modern advances in the treatment of esophageal cancer (EC), using neoadjuvant chemoradiotherapy (CRT) and esophagectomy, most patients face poor outcome. Growing evidence indicates that cancer stem cells (CSCs) might contribute to the poor prospects. CSCs are usually resistant to CRT and ultimately can generate a new tumor. The mammalian target of rapamycin (mTOR) pathway is associated with cancer stemness. However, its role in EC CSC-like populations needs to be elucidated. Here, we investigate the role of mTOR pathway on the stemness of a putative CSC-like population. Methods: Previously, we identified a putative CSC-like population (CD44+/CD24-) in EC cell lines and in tumor biopsy from EC patients. qPCR was used to measure the expression of mTOR in CD44+/CD24- CSC-like population of OE21 squamous cell carcinoma and OE33 adenocarcinoma cell lines compared to controls, that consisted of solid tumors generated from the same cell lines obtained from xenografts. mTOR inhibitors rapamycin and torin-1 were used to see their effect on CD44+/CD24- expression and sphere formation. Results: mTOR expression was 2-fold up-regulated in the OE33 CD44+/CD24- CSC-like population compared to control. Furthermore, in OE21 this up-regulation was 1.9-fold. Surprisingly, inhibiting the mTOR pathway with rapamycin enhanced OE33 CD44+/CD24- expression compared to its control (p = 0.01). In pilot experiments this effect was dose dependent and cells treated with rapamycin formed more spheres than control. Rapamycin did not alter the expression of CD44+/CD24- in OE21. Inhibiting the mTOR pathway with Torin-1 enhanced OE21 CD44+/CD24- expression by 1.2-fold compared to control (N = 2). In another pilot experiment Torin-1 treated cells were able to form more spheres compared to control. Torin-1 did not have an effect on the expression of CD44+/CD24- in OE33. Conclusions: These findings indicate that inhibiting the mTOR pathway may enhance CSC-like properties in EC. Additional research needs to be done to further support this hypothesis and elucidate the mechanism in this process. Furthermore, the effect of mTOR pathway inducers in EC needs to be explored.

Blockade of the acute activation of mTOR complex 1 decreases hypertrophy development in rats with severe aortic valve regurgitation.

BackgroundHypertrophy (H) is an adaptive response of the heart to a hemodynamic overload. Severe left ventricular (LV) volume overload (VO) from valve regurgitations (aortic (AR) or mitral regurgitation) leads to eccentric LVH. Increased protein turnover is a major event during development of LVH and the mechanistic target of rapamycin (mTOR) is a key molecule for its control. The role of mTOR inhibition in the development of LVH using rapamycin for relatively short periods of time (days to a few weeks) has been studied in the past in pressure overload models but not in VO models. We investigated if mTOR pathway was activated during LVH development in a model of severe VO (AR) in rats and if a rapamycin treatment can slow heart remodeling in this situation.Methods and ResultsMale rats with severe AR were studied acutely at 2 days, at 8 weeks (compensated phase) and 6 months (late phase) after VO induction. mTOR complex (mTORC) 1 (ribosomal S6 protein phosphorylation) was activated early after AR induction but not later in the disease whereas mTORC2 activity levels (Akt phosphorylation at Ser473) remained stable. We observed that a moderate dose of rapamycin (2 mg/kg/day; orally) for 8 weeks prevented severe LVH caused by AR (−46 %: p < 0.001). Rapamycin treatment specifically inhibited LV mTORC1 without altering mTORC2 activity at 8 weeks. Rapamycin also prevented cardiac myocyte hypertrophy caused by AR.ConclusionRapamycin slows hypertrophy in LV VO by inhibiting early activation of mTORC1 without modulating mTORC2.

OP53 – 2462: The role of mTOR inhibitors in TSC associated epilepsy

We evaluated prospectively the effect of Everolimus on epilepsy in children and adolescents with TSC treated with Everolimus for SEGA at our center. Methods This is a retrospective analysis of prospectively collected data: included were patients ≤19 years with epilepsy, treated with Votubia, who had regular prospective follow-up every 3 months at the study center (clinical inspection and EEG, seizure diaries, blood sampling). Everolimus is orally administered once per day, starting with 4.5 mg/m 2 and titration to achieve blood trough concentrations of 5–15 ng/ml. Response was defined as ≥50% reduction in seizure count. Results We present pilot data of 12 patients (4 female, 8 male), with genetically confirmed diagnosis of TSC (3 TSC1, 9 TSC2 mutations). The median age at initiation of Votubia was 10 years (y) (range: 2–19 y). The median duration of epilepsy prior to treatment was 9.5 y (range: 1.75–16.75 y). The median number of AEDs prior to treatment was 1 (range: 1–3). The median seizure frequency prior to treatment was 30 seizures/month (range: 2–1470 seizures/month). 8/12 (66%) patients were responders. The median follow up after initiation of Everolimus was 13.5 months (range: 2–31 months). The median reduction in seizure frequency was 93% (range: 0–100%). Four patients became seizure free. The median number of AED after treatment was 1 (range: 1–2). The effect on seizure frequency was accompanied by significant developmental progress in all seizure free children. 4 patients were non-responders, one of them was incompliant. Side effects were observed in 7 patients (58%). The most common side effects were aphtae (7/7); 1 patient was hospitalized because of angina herpetica and pneumonia. In no case the Everolimus treatment had to be interrupted or withdrawn. Conclusions Everolimus seems to be effective and safe in treating TSC associated epilepsy in pediatric patients (even in cases prior refractory to AEDs).

The role of mTOR inhibitors in the prevention of organ rejection in adult liver transplant patients: a focus on everolimus

Liver transplantation remains the therapy of choice for patients with end-stage liver disease and in selected cases of hepatocellular carcinoma. While short-term allograft survival has improved significantly in recent years, there has been little improvement in long-term survival after liver transplantation. A growing body of evidence on factors influencing the long-term outcomes and the safety profiles of existing immunosuppressive agents after liver transplant points to a need to continue searching for alternative strategies. The calcineurin inhibitors (CNIs) (cyclosporine and tacrolimus) currently represent the backbone of most immunosuppressor regimens. They have had a revolutionary effect on the overall success of transplantation, as is reflected in greatly reduced rates of acute rejection. However, the CNIs have significant toxici - ties that produce renal dysfunction, cardiovascular disease, and other unwanted effects, such as malignancies. The recognition of these risk factors has sparked interest in regimens that limit exposure to CNIs. Nowadays, the use of immunosuppressive drugs with different mechanisms of action, which allow for a reduction or avoidance of CNIs, is common. Everolimus, which belongs to the mammalian target-of-rapamycin inhibitor family and is best known for its use in kidney and heart transplantation, has recently been approved for liver transplantation. This overview discusses the emerging evidence on the role of everolimus in the prevention of rejection after liver transplantation, in de novo transplants, conversion regimens, or as a rescue therapy. In addition, some of the most relevant and current clinical problems related to everolimus in this field are discussed.

Role of mTOR inhibitor in cholangiocarcinoma cell progression

Cholangiocarcinoma (CCA) is a lethal malignancy of the biliary epithelium. CCA is resistant to currently available chemotherapy; therefore, new drugs as well as new molecular targets must be identified for the development of an effective treatment for CCA. The present study showed that RAD001 (everolimus), a derivative of rapamycin and an orally bioavailable mammalian target of rapamycin (mTOR) inhibitor, exhibits cytotoxic and antimetastatic effects in a CCA cell line, RMCCA-1. Treatment with low concentrations of RAD001 resulted in a significant reduction of in vitro invasion and migration of RMCCA-1, concomitant with a reduction of filopodia and alteration of the actin cytoskeleton. Although, matrix metalloproteinase-9 and -14 activities were unaltered. However, at high concentrations, RAD001 exhibited cytotoxic effects, reducing cell proliferation and inducing apoptotic cell death. Overall, RAD001 exhibits multiple effects mediated by the inhibition of the mTOR, which may serve as a promising agent for the treatment of CCA.

The Role of mTOR Inhibitors in Liver Transplantation: Reviewing the Evidence.

Despite the success of liver transplantation, long-term complications remain, including de novo malignancies, metabolic syndrome, and the recurrence of hepatitis C virus (HCV) and hepatocellular carcinoma (HCC). The current mainstay of treatment, calcineurin inhibitors (CNIs), can also worsen posttransplant renal dysfunction, neurotoxicity, and diabetes. Clearly there is a need for better immunosuppressive agents that maintain similar rates of efficacy and renal function whilst minimizing adverse effects. The mammalian target of rapamycin (mTOR) inhibitors with a mechanism of action that is different from other immunosuppressive agents has the potential to address some of these issues. In this review we surveyed the literature for reports of the use of mTOR inhibitors in adult liver transplantation with respect to renal function, efficacy, safety, neurological symptoms, de novo tumors, and the recurrence of HCC and HCV. The results of our review indicate that mTOR inhibitors are associated with efficacy comparable to CNIs while having benefits on renal function in liver transplantation. We also consider newer dosing schedules that may limit side effects. Finally, we discuss evidence that mTOR inhibitors may have benefits in the oncology setting and in relation to HCV-related allograft fibrosis, metabolic syndrome, and neurotoxicity.

Role of mTOR Inhibitors in Heart Transplant Immunosuppressive Regimens

Role of mTOR Inhibitors in Heart Transplant Immunosuppressive Regimens

Role of mTOR inhibition in the treatment of patients with renal angiomyolipomas

To describe the role of mammalian target of rapamycin (mTOR) inhibition in the treatment of tuberous sclerosis complex (TSC) patients with renal angiomyolipoma in relation to available clinical data and clinical practice guidance for the nurse practitioner (NP). A review of the scientific literature, key clinical congresses, and key clinical trials. TSC-associated renal angiomyolipomas have a propensity to grow over time and predispose patients to serious and life-threatening consequences. Surgery or invasive interventional therapies may not be the most optimal treatments because of the multiple, bilateral growth pattern of TSC-associated renal angiomyolipomas. Targeted therapies, such as mTOR inhibitors, which have demonstrated efficacy in maintaining and reducing renal angiomyolipoma size, are of great benefit to patients. Treatment with everolimus, an oral mTOR inhibitor, offers patients a noninvasive pharmacotherapeutic treatment option. The NP, as a key member of the healthcare team overseeing TSC patients, must be knowledgeable about the safety and efficacy of mTOR inhibitors as their use in the patient population increases.

Birt–Hogg–Dubé syndrome

Birt–Hogg–Dubé syndrome

Clinical evidence of the efficacy of everolimus and its potential in the treatment of breast cancer.

The PI3K/Akt/mTOR (phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin) pathway regulates several key cellular functions and its dysregulation creates an environment that promotes tumorigenesis as well as resistance to therapy. The mTOR inhibitor everolimus has emerged as a promising agent in the treatment of breast cancer and was recently approved in combination with exemestane for advanced hormone receptor-positive disease after progression on a nonsteroidal aromatase inhibitor. Everolimus may also be effective in combination with cytotoxic and human epidermal growth factor receptor-2-directed therapies for the treatment of other subtypes of breast cancer. This paper highlights preclinical and clinical data that have emerged on the role of mTOR inhibition in breast cancer. Although generally well tolerated, everolimus carries a unique side effect profile of which both patients and providers should be made aware. Recommendations related to the administration of everolimus in the clinical setting are also discussed.

Abstract 3515: Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers.

Abstract Despite the established role of MTOR inhibitors (rapalogs) in treating advanced kidney cancer, therapeutic benefit varies and predictive biomarkers are lacking. Intratumor branching heterogeneity, a recently discovered hallmark of this disease, has raised concerns about the feasibility of developing genomic biomarkers for targeted agents in kidney cancer. We undertook an outlier approach to interrogate the genetic determinants underlying long-term therapeutic response (&amp;gt;20 months) to rapalogs in 6 patients. An integrated ultra-deep targeted-exome (∼500x) and standard whole-exome (∼100x) sequencing was performed. Additionally, to address intratumor and intertumor heterogeneity, spatially separated tumor specimens from the same individuals were analyzed whenever possible. Multiregional sequencing unveiled surprising MTOR pathway convergent evolution, manifested by MTOR pathway activation by means of distinct genomic events in spatially separate sites of disease within the same individual. Amongst the core components of the MTORC1 pathway, complete functional loss of TSC1 and TSC2, and a hyperactive MTOR mutant were discovered in 4 of 6 long-term responders. Mutations in MTOR Clustered at FAT and kinase domains confer hyperactivity and yet remain sensitive to rapamycin. Here, we affirm intratumor heterogeneity, identify genomic determinants of drug response, and discover pathway convergent evolution in the majority of long-term responders. We propose a “river” model in which intratumor and intertumor clonal heterogeneity in cancer patients evolves like a branching river that converges at critical nodes. These convergent points provide unique opportunities for the treatment of genetically diverged yet functionally converged cancers in any given patient. Citation Format: Martin H. Voss, A Ari Hakimi, Can G. Pham, A Rose Brannon, Ying-Bei Chen, Luis F. Cunha, Oguz Akin, Han Liu, Shugaku Takeda, Sasinya N. Scott, Nicholas D. Socci, Agnes Viale, Nikolaus Schultz, Chris Sander, Victor E. Reuter, Paul Russo, Emily H. Cheng, Robert J. Motzer, Michael F. Berger, James J. Hsieh. Pathway convergent evolution underscores treatment response to MTOR inhibitors in kidney cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3515. doi:10.1158/1538-7445.AM2013-3515

MTOR as a Potential Target for the Prevention and Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is a global health problem and responsible for up to 500.000 deaths annually. It usually occurs secondary to infections with hepatitis B or C viruses, alcohol consumption, non-alcoholic steatohepatitis or hereditary liver diseases. The prognosis for patients with advanced disease is dismal; therefore, new strategies to prevent or treat this malignancy are urgently needed. Over recent years, several molecular pathways have been identified contributing to the molecular pathogenesis of this devastating disease, among them the PI3K/AKT/mTOR pathway. mTOR is effectively inhibited by rapamycin and its derivatives such as temsirolimus and everolimus. The anti-tumor activity of rapamycin was identified more than 30 years ago in a screen performed at the National Cancer Institute, but was subsequently not developed for cancer treatment. In the 1990s, activation of the mTOR pathway was recognized in various malignancies spurring again the interest in mTOR inhibitors for anti-cancer treatment. In 2007, the US Food and Drug Administration approved the first mTOR inhibitor, temsirolimus, for the treatment of renal cell carcinoma. Currently, several clinical studies are underway to define the role of mTOR inhibitors for the treatment of hepatocellular carcinoma. The aim of this review is to outline the role of mTOR for hepatocarcinogenesis. We will also discuss the latest preclinical and clinical data of mTOR inhibitors for the prevention and treatment of HCC.

Targeting mTOR Pathways in Human Malignancies

The mammalian target of rapamycin (mTOR) is a protein kinase involved in the phosphatidylinositol 3-Kinase (PI3K)/AKT signalling pathway with a central role in the control of cell growth, survival and angiogenesis. Multiple and frequent dysregulations of this pathway in human tumors make it a central target in the development of new anticancer treatments. To review the most significant data on mTOR pathway, role of mTOR inhibitors in cancer treatment, preclinical and clinical data of the three first generation mTOR inhibitors (temsirolimus, everolimus and deferolimus), rationales, preclinical and clinical data of second generation mTOR inhibitors. Review of published literature on mTOR and related pathways, rapalogs and novel mTOR inhibitors. Temsirolimus and everolimus have been approved for the treatment of metastatic Renal Cell Carcinoma (RCC), temsirolimus also for Mantle Cell Lymphoma (MCL) and everolimus will be approved for pancreatic neuroendocrine tumors; all three rapalogs are currently evaluated in phase III studies in several tumors. Only limited published data are available on new mTOR inhibitors; however, in vitro and in vivo in preclinical studies they have shown a significant antiproliferative activity against a broad panel of tumors and a favourable safety profile, with disease stabilization or even tumor regression, either as single agent or in combination.

Atteintes rénales de la sclérose tubéreuse de Bourneville : recommandations de prise en charge

To review existing literature and deduce guidelines for the management of renal disease in patients with tuberous sclerosis complex (TSC). After review of literature, a core panel of five physicians wrote a draft that was evaluated by 14reviewers who used a 9-level scale (1: total disagreement; 9: total agreement). The guidelines were then reformulated until each item received a median score superior or equal to 8. Forty-eight to 80% of TSC patients have significant renal involvement including angiomyolipomas (AMLs), cysts, malignant tumors and renal insufficiency. It is recommended to perform an abdominal ultrasound (and serum creatinine if abnormal ultrasound) when TSC is diagnosed. This work-up will be repeated every 3-5years if normal. Associated autosomal dominant polycystic kidney disease must be suspected in case of numerous and large cysts. After the age of 20, follow-up should use computed tomography (CT) or MRI that are more precise than ultrasound for the measurement of AMLs. Biopsy of a renal mass should be discussed in case of calcifications, necrosis or rapid growth. Females with TSC should undergo screening for pulmonary lymphangioleiomyomatosis by CT at the age of 18, and, if negative at the age of 30-40. Acute bleeding should be treated with percutaneous embolization. Asymptomatic angiomyolipomas with several risk factors (size>80mm, predominant vascular component, micro-aneurysms) should undergo prophylactic treatment, if possible using embolization. The role of mTOR inhibitors in the management of angiomyolipomas needs to be defined. Standardization of follow-up and treatment is necessary to improve the management of TSC renal involvement.

The role of mTOR inhibitors in the inhibition of growth and cortisol secretion in human adrenocortical carcinoma cells

Patients with adrenocortical carcinoma (ACC) need new treatment options. The aim of this study was to evaluate the effects of the mTOR inhibitors sirolimus and temsirolimus on human ACC cell growth and cortisol production. In H295, HAC15, and SW13 cells, we have evaluated mTOR, IGF2, and IGF1 receptor expressions; the effects of sirolimus and temsirolimus on cell growth; and the effects of sirolimus on apoptosis, cell cycle, and cortisol production. Moreover, the effects of sirolimus on basal and IGF2-stimulated H295 cell colony growth and on basal and IGF1-stimulated phospho-AKT, phospho-S6K1, and phospho-ERK in H295 and SW13 were studied. Finally, we have evaluated the effects of combination treatment of sirolimus with an IGF2-neutralizing antibody. We have found that H295 and HAC15 expressed IGF2 at a >1800-fold higher level than SW13. mTOR inhibitors suppressed cell growth in a dose-/time-dependent manner in all cell lines. SW13 were the most sensitive to these effects. Sirolimus inhibited H295 colony surviving fraction and size. These effects were not antagonized by IGF2, suggesting the involvement of other autocrine regulators of mTOR pathways. In H295, sirolimus activated escape pathways. The blocking of endogenously produced IGF2 increased the antiproliferative effects of sirolimus on H295. Cortisol production by H295 and HAC15 was inhibited by sirolimus. The current study demonstrates that mTOR inhibitors inhibit the proliferation and cortisol production in ACC cells. Different ACC cells have different sensitivity to the mTOR inhibitors. mTOR could be a target for the treatment of human ACCs, but variable responses might be expected. In selected cases of ACC, the combined targeting of mTOR and IGF2 could have greater effects than mTOR inhibitors alone.

Absence of mTOR Inhibitor Effect on Hepatic Cyst Growth: A Case Report of a Kidney Transplant Recipient with Autosomal Dominant Polycystic Kidney Disease

Some experimental studies have suggested a beneficial effect of the mammalian target of rapamycin (mTOR) inhibitor use on hepatic and renal cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). However, the results of clinical studies are conflicting and the role of mTOR inhibitors is still uncertain. We report the case of a patient with ADPKD who underwent deceased kidney transplantation because of an end-stage renal disease. The evolution was uneventful with an excellent graft function under cyclosporine (CsA) monotherapy. Some years later, the patient developed a symptomatic hepatomegaly due to growth of cysts. CsA was replaced by sirolimus, an mTOR inhibitor, in order to reduce or control the increase in the cyst and liver volume. Despite the switch, the hepatic volume increased by 25% in two years. Finally sirolimus was stopped because of the lack of effect on hepatic cyst growth and the presence of sirolimus side effects. The interest of our case resides in the followup by MRI imaging during the mTOR inhibitor treatment and 15 months after the restart of the initial immunosuppressive therapy. This observation indicates that mTOR inhibitors did not have significant effect on cyst-associated hepatic growth in our patient, which is consistent with some results of recent large clinical studies.

Molecular-Targeted Therapies for Hematologic Malignancies

Major advances in the disciplines of hematology, genetics, biochemistry, and chemistry over the past decades have empowered investigators with the background and methods required for development of customized molecular-targeted therapies. The ability to identify signaling pathways that are dysregulated, to determine the associated mutations, and to develop chemical drugs toward a desired correction is now a realistic work flow. The landmark demonstration that BCR-ABL could be molecularly targeted and could have a major impact upon disease progression really ignited the field of targeted therapies for hematologic malignancies. Through much hard work, we now know the key drivers of some hematologic malignancies, and depending on the particular disease, we have an arsenal of agents available to act at multiple nodal points. Some enabling technologies that have been a key for these advances include small molecule screening, high throughput whole genome sequencing, mouse models for cancer, and gene and microRNA expression array analyses. In this special issue, we present a collection of seven articles that contribute to our understanding of molecular targets and the development of approaches for their inhibition or rationale use of existing agents or their derivatives. These targets range from very early initiators of malignancy to molecules that are already advanced into clinical studies. The first paper in this issue by A. Fathi and T. Abdel-Wahab “Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy” addresses the series of mutations identified that alter DNA and/or histone lysine methylation. These early epigenetic changes predispose to leukemogenesis and are relevant in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients. The second paper by J. Okabe-Kado et al. “Extracellular NM23 protein as a therapeutic target for hematologic malignancies” describes extracellular NM23-H1 protein and its relationship with altered signaling pathways and growth/survival in AML. The third paper by S. Verma et al. “Gab adapter proteins as therapeutic targets for hematologic disease” describes the Grb2-associated adapter proteins (Gabs) as potential therapeutic targets playing major roles in regulation of multiple signaling pathways. These first three papers describe potential new targets that require further validation and greater specificity, but could have significant impact on the initiation and progression of hematologic malignancy. The fourth paper by X. Liu et al. “Molecular targets for the treatment of juvenile myelomonocytic leukemia” describes the outstanding progress made in identifying the mutations associated with activation of the Ras pathway in juvenile myelomonocytic leukemia (JMML), several of which are already targets of drugs that are being tested such as Ras and SHP-2. This paper additionally points toward protein:protein interactions as potential therapeutic targets such as SHP-2/Gab2 in hematopoiesis. The fifth paper by P. Argyriou et al. “The role of mTOR inhibitors for the treatment of B-cell lymphomas” focuses on the downstream activation of the mTOR pathway and the development and testing of new rapalogues and ATP-competitive inhibitors for clinical use. The mTOR pathway is central to cell survival and metabolism and represents a common target for many types of cancers. The sixth paper by F. Tzifi et al. “The role of Bcl2 family of apoptosis regulator proteins in acute and chronic leukemias” describes the exciting new advances in understanding and targeting the Bcl-2 family of proteins and gives a comprehensive update on new agents that are in clinical studies targeting survival in acute and chronic leukemias. All of these three papers describe bona fide targets that are already subject to significant validation and commercial drug development. The seventh paper by P. Koehler et al. “Engineered T cells for the adoptive therapy of B cell-chronic lymphocytic leukemia (B-CLL)” in the issue addresses immunotherapy using T-cell therapies against CD19, which has recently been very successful and received widespread attention for treatment of chronic lymphocytic leukemia. This approach promises to provide sustained targeted therapy based on cell surface phenotype and although it has to deal with issues such as B-cell deficiency and intravenous immunoglobuin infusions, such approaches when combined with chemotherapy are very promising as a form of targeted gene-based therapy. In summary, the articles in this special issue address the spectrum of new targeted therapy development, from basic understandings of structure-function to mature rationale drugs already being tested in patients. We sought to cover the full spectrum of therapeutic development and are pleased to present a series of papers that do just that. As editors of this issue, we appreciate the important contributions of the authors of these review articles and hope that this issue will encourage expanded translational research toward developing novel therapies for hematologic malignancies. Kevin D. Bunting Cheng-Kui Qu Michael H. Tomasson

Résultats de la transplantation rénale pédiatrique en France

Significant progress has been observed in pediatric renal transplantation over the last 20 years, leading to an increase in graft and patient survival. Mortality is low and is mainly due to infections, neoplasias and complications related to the initial disease. Graft survival is 67% at 10 years. Factors which influence graft survival are: donor type (results are better with a live donor), donor age, recipient age (with 2 periods at risk: < 2 years old and teenagers), HLA incompatibilities, and recurrence of the initial disease. Chronic allograft nephropathy (CAN) is the major cause of late graft loss. Poor compliance, especially in teenagers, may lead to late rejections and graft loss. Calcineurin inhibitors nephrotoxicity is in part responsible for the development of CAN, thus treatments and the role of mTOR inhibitors will probably evolve. These different factors are discussed in this article.

MTOR inhibition in kidney transplant recipients

The ASCERTAIN study has confirmed previous findings that conversion from calcineurin inhibitors to mammalian target of rapamycin (mTOR) inhibitors does not seem to improve glomerular filtration rate in renal transplant recipients, although it does seem beneficial in patients with better renal function at baseline. Questions remain regarding the role of mTOR inhibitors in kidney transplantation.

Inhibitors of mTOR overcome drug resistance from topoisomerase II inhibitors in solid tumors

The present study was performed to investigate the possible role of mTOR inhibitors in restoring chemosensitivity to adriamycin/cisplatin and elucidate the underlying mechanism. Combining adriamycin/cisplatin with torisel synergistically inhibited the cell proliferation in human oropharyngeal carcinoma cell line KB and its multidrug-resistant subclone KB/7D. Combining adriamycin and torisel inhibited the phosphorylation of 4EBP-1 and p70S6 K, the proteins involved in mTOR pathway, increased expression of γH2AX indicative of DNA damage, triggered cell cycle arrest at G2/M and apoptosis. We conclude that chromatin decondensation by DNA damage provided an easy access for torisel to block the translation of proteins essential for DNA repair thereby restoring the chemosensitivity.