MTOR cross-talk in cancer and potential for combination therapy

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). CONCLUSION: Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation

Preparation and characterisation of titania/hydroxyapatite composite coatings obtained by sol-gel process

In the present work a titania network encapsulating a hydroxyapatite particulate phase is proposed as a bioceramic composite coating. The coating on a titanium substrate was produced starting from a sol containing a mixture of titania colloidal particles and hydroxyapatite submicron particles using the dip-coating technique. The microstructure, the morphology and the surface chemical composition of the coating were characterised using X-ray diffraction (XRD), scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS), respectively. Adhesion tests were also performed. These analyses showed that the obtained coating was chemically clean, homogeneous, rough, porous, with a low thickness and well-defined phase composition as well as a good adhesion to the substrate. Copyright © 2001 Elsevier Science Ltd

Weekly epirubicin plus lonidamine in advanced breast carcinoma

: Lonidamine has been demonstrated to potentiate the cytotoxic activity of several antineoplastic drugs, for example anthracyclines. Moreover, epirubicin is considered one of the most active drugs in advanced breast cancer, although optimal dose and schedule remains to be defined. In the present study we have treated 51 patients with advanced breast cancer with a combination of lonidamine (450 mg/day orally from day 1 throughout treatment) and epirubicin (25 mg/m2 i.v.) administered according to a weekly schedule for 24 weeks. Objective responses were observed in 29 out of 51 patients (57%; CR 16%, PR 41%). Liver metastases responded in eight out of 12 evaluable patients (67%). Average response duration was 12.4 months and median overall survival was 23 months (range 1-90+). Toxicity was negligible. The combination of weekly epirubicin and lonidamine is feasible and active in advanced breast cancer patients

mTOR Cross-Talk in Cancer and Potential for Combination Therapy.

The mammalian Target of Rapamycin (mTOR) pathway plays an essential role in sensing and integrating a variety of exogenous cues to regulate cellular growth and metabolism, in both physiological and pathological conditions. mTOR functions through two functionally and structurally distinct multi-component complexes, mTORC1 and mTORC2, which interact with each other and with several elements of other signaling pathways. In the past few years, many new insights into mTOR function and regulation have been gained and extensive genetic and pharmacological studies in mice have enhanced our understanding of how mTOR dysfunction contributes to several diseases, including cancer. Single-agent mTOR targeting, mostly using rapalogs, has so far met limited clinical success; however, due to the extensive cross-talk between mTOR and other pathways, combined approaches are the most promising avenues to improve clinical efficacy of available therapeutics and overcome drug resistance. This review provides a brief and up-to-date narrative on the regulation of mTOR function, the relative contributions of mTORC1 and mTORC2 complexes to cancer development and progression, and prospects for mTOR inhibition as a therapeutic strategy

Quantitative single cell determination of ERK phosphorylation and regulation in relapsed and refractory primary acute myeloid leukemia

: We investigated the constitutive activation of the MEK/ERK pathway in acute myelogenous leukemia (AML) via a flow cytometric technique to quantitate expression of phosphorylated ERK (p-ERK). A total of 42 AML samples (16 newly diagnosed, 26 relapsed/refractory) were analyzed. Normal bone marrow CD34+ cells (n = 10) had little or no expression of p-ERK, while G-CSF-mobilized CD34+ cells exhibited enhanced p-ERK levels. Markedly elevated p-ERK levels were found in 83.3% of the AML samples, with no differences observed between the newly diagnosed and relapsed/refractory samples. Treatment with a MEK inhibitor resulted in significantly decreased p-ERK levels in both the newly diagnosed and relapsed/refractory samples, which was associated with growth arrest, but not apoptosis induction. In summary, we defined conditions for the analysis of MAPK signaling in primary AML samples. Normal CD34+ cells expressed very low levels of p-ERK, and increased p-ERK levels were found in normal G-CSF-stimulated circulating CD34+ cells. Constitutively high p-ERK levels observed in the majority of AML samples suggest deregulation of this pathway that appears to be independent of disease status. The ability of ERK inhibition to promote growth arrest rather than apoptosis suggests that clinical trials of MEK/ERK inhibitors may be more effective when combined with chemotherapy

Phytochemicals of minthostachys diffusa epling and their health-promoting bioactivities

The genus Minthostachys belonging to the Lamiaceae family, and is an important South American mint genus used commonly in folk medicine as an aroma in cooking. The phytochemical-rich samples of the aerial parts of Minthostachys diffusa Epling. were tested for pharmacological and health-promoting bioactivities using in vitro chemical and enzymatic assays. A range of radical scavenging activities of the samples against biological radicals such as nitric oxide and superoxide anion and against synthetic 2,2-diphenyl-1-picrylhydrazyl and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) radicals, the ferric reducing antioxidant power and the lipid peroxidation inhibition were determined and ranked using the 'relative antioxidant capacity index' (RACI). The ethyl acetate fraction showed the highest RACI of +1.12. Analysis of the various fractions' inhibitory ability against enzymes involved in diabetes (α-amylase and α-glucosidase), and against enzymes associated with Parkinson's or Alzheimer's diseases (acetylcholinesterase and butyrylcholinesterase) also suggested that the ethyl acetate fraction was the most active. Liquid chromatography-tandem mass spectrometry analysis of the ethyl acetate fraction showed more than 30 polyphenolic compounds, including triterpenes. The inhibitory cholinesterase effects of the triterpenes identified from M. diffusa were further analysed by in silico docking of these compounds into 3D-structures of acetylcholinesterase and butyrylcholinesterase. This is the first study on pharmacological activities and phytochemical profiling of the aerial parts of M. diffusa, showing that this plant, normally used as food in South America, is also rich in health-promoting phytochemicals

Is cerebrospinal fluid amyloid-β42 a promising biomarker of response to nusinersen in adult spinal muscular atrophy patients?

Introduction: Nusinersen was approved as the first treatment for all types of spinal muscular atrophy (SMA), including adults with SMA types 2 and 3. Robust biomarkers of treatment response in SMA adults are lacking. Our aim was to examine cerebrospinal fluid (CSF) amyloid-β40 (Aβ40) and amyloid-β42 (Aβ42) peptides as biomarkers of treatment response. Methods: Eight patients with SMA types 2 and 3 were recruited consecutively in a single-center study. CSF was sampled at baseline, after a loading dose, and after three maintenance doses. Levels of Aβ42 and Aβ40 were evaluated for each CSF sampling. Wilcoxon matched-pairs signed-rank test was used to detect longitudinal changes. Results: CSF levels of Aβ42 increased from baseline to day 420 (95% confidence interval, P =.018), with a significant increase at days 180 and 420 compared with days 0 and 300, respectively (95% confidence interval, P =.012 and P =.018). Discussion: The maintenance and promotion of wellness of residual motor neurons mediated by the restored level of SMN protein due to nusinersen could result in an increased level of amyloid peptides

Alopecia in a premenopausal breast cancer woman treated with letrozole and triptorelin

Alopecia in a premenopausal breast cancer woman treated with letrozole and triptoreli

HCV and diabetes: Towards a 'sustained' glycaemic improvement after treatment with DAAs?

We read with interest the paper by Pavone and colleagues [1] describing the rapid reduction of fasting glucose (FG) levels in diabetic hepatitis C virus (HCV)-positive patients receiving directacting antiviral agents (DAAs). We aimed to assess if a similar decreasing trend of FG levels occurred in our study population and if it was maintained after the end of treatment (EOT). Therefore, we retrospectively evaluated 449 patients treated with DAAs at our centre (64 HIV/HCV coinfected)