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

Role of mTOR signaling in tumor microenvironment. An overview

The mammalian target of rapamycin (mTOR) pathway regulates major processes by integrating a variety of exogenous cues, including diverse environmental inputs in the tumor microenvironment (TME). In recent years, it has been well recognized that cancer cells co-exist and co-evolve with their TME, which is often involved in drug resistance. The mTOR pathway modulates the interactions between the stroma and the tumor, thereby affecting both the tumor immunity and angiogenesis. The activation of mTOR signaling is associated with these pro-oncogenic cellular processes, making mTOR a promising target for new combination therapies. This review highlights the role of mTOR signaling in the characterization and the activity of the TME’s elements and their implications in cancer immunotherapy

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

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

Severe rhabdomyolysis associated with pemetrexed-based chemotherapy

Pemetrexed is an antifolate metabolite that inhibits several enzymes involved in the folate pathway. It has activity against various solid tumours, and has been approved for treatment of malignant pleural mesothelioma on the basis of findings from a randomised phase III trial.1 The main toxic effects noted for pemetrexed have been rash, myelosuppression, diarrhoea, mucositis, and reversible elevation of liver enzymes—effects that are preventable partly by vitamin supplementation.

Dry bone and virtual modality interchangeability for the estimation of sex on the human pelvis and skull

Background: Traditional osteological methods are typically based on visual and tactile observational approaches. However, the tactile sensation is excluded when investigating skeletal remains in virtual reality. This raises the question of the actual comparability of data obtained from osteological analysis on analogous versus virtual modality. The aim of this work is to address this topic and quantify the deviation between the scoring on dry bone and virtual models of sexually dimorphic features on the human pelvis and skull. Materials and methods: We applied seven widely used sex estimation methods to 200 archaeological pelves and 223 skulls. We scored and measured each method-specific trait on dry bone and computed tomographic (CT) models of the same individual. We added observations on 3D surface scans from sample subsets of pelves (N=39) and skulls (=50) for comparability. We compared the scores and measurements obtained from the application of each method to the three sets of observations using Cohen's κ tests and relative technical error of measurement (rTEM). Results: 1) metric traits are more repeatable and consistent than nonmetric traits; b) virtual modalities compared better to each other than visual-tactile modalities and c) precise trait descriptions are more important than the modality. Discussion: Our data suggest that traditional sex estimation methods developed on dry bone (visual-tactile sensations) can be applied interchangeably to virtual specimens (visual-only sensation) without obtaining substantially different information. More than other factors, however, precise trait definition is pivotal for the interchangeability of analogous and virtual modalities

Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review

The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity

COX-2 targeting in cancer: a new beginning?

Cyclo-oxygenase-2 (COX-2), the inducible enzyme catalyzing the rate-limiting step in the conversion of arachidonic acid into eicosanoids, is overexpressed in a wide variety of malignancies and associates with poor prognostic features [1]. Consequently, selective COX-2 inhibitors have been explored as therapeutic or chemopreventive agents in different settings; however, initial enthusiasm was tempered by reports of substantial gastrointestinal toxicity as well as of increased cardiovascular risk, mostly coming from postmarketing use as anti-inflammatory drugs and Cancer Research Campaign (UK) chemoprevention trials and eventually resulting in the withdrawal of rofecoxib from the market [2]

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

Abstract Identifying putative biomarkers of clinical outcomes in cancer is crucial for successful enrichment, and for the selection of patients who are the most likely to benefit from a specific therapeutic approach. Indeed, current research in personalized cancer therapy focuses on the possibility of identifying biomarkers that predict prognosis, sensitivity or resistance to therapies. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene that regulates several crucial cell functions such as proliferation, survival, genomic stability and cell motility through both enzymatic and non-enzymatic activities and phosphatidylinositol 3-kinase (PI3K)-dependent and -independent mechanisms. Despite its undisputed role as a tumor suppressor, assessment of PTEN status in sporadic human tumors has yet to provide clinically robust prognostic, predictive or therapeutic information. This is possibly due to the exceptionally complex regulation of PTEN function, which involves genetic, transcriptional, post-transcriptional and post-translational events. This review shows a brief summary of the regulation and function of PTEN and discusses its controversial aspects as a prognostic/predictive biomarker