Search

Acute myeloid leukemia (AML) is an aggressive disease associated with very poor prognosis. Most patients are older than 60 years, and in this group only 5–15% of cases survive over 5 years. Therefore, it is urgent to develop more effective targeted therapies. Inactivation of protein phosphatase 2 A (PP2A) is a recurrent event in AML, and overexpression of its endogenous inhibitor SET is detected in ~30% of patients. The PP2A activating drug FTY720 has potent anti-leukemic effects; nevertheless, FTY720 induces cardiotoxicity at the anti-neoplastic dose. Here, we have developed a series of non-phosphorylable FTY720 analogues as a new therapeutic strategy for AML. Our results show that the lead compound CM-1231 re-activates PP2A by targeting SET-PP2A interaction, inhibiting cell proliferation and promoting apoptosis in AML cell lines and primary patient samples. Notably, CM-1231 did not induce cardiac toxicity, unlike FTY720, in zebrafish models, and reduced the invasion and aggressiveness of AML cells more than FTY720 in zebrafish xenograft models. In conclusion, CM-1231 is safer and more effective than FTY720; therefore, this compound could represent a novel and promising approach for treating AML patients with SET overexpression.

Ochratoxin A (OTA) is a potent rodent nephrocarcinogen; being males more sensitive than females. The objective was to study the response between sexes at gene expression level (whole genome transcriptomics) in kidneys of F344 rats treated with 0.21 or 0.50 mg/kg bw OTA for 21 days. DNA methylation analysis of selected genes was also studied (MALDI-TOF mass spectrometry). OTA-induced response was dose-dependent in males and females, although clearer in males. Females showed a higher number of altered genes than males but functional analysis revealed a higher number of significantly enriched toxicity lists in 0.21 mg/kg treated males. OTA modulated damage, signaling and metabolism related lists, as well as inflammation, proliferation and oxidative stress in both sexes. Eleven toxicity lists (damage, fibrosis, cell signaling and metabolism) were exclusively altered in males while renal safety biomarker and biogenesis of mitochondria lists were exclusively enriched in females. A high number of lists (39) were significantly enriched in both sexes. However, they contained many sex-biased OTA-modulated genes, mainly phase I and II, transporters and nuclear receptors, but also others related to cell proliferation/apoptosis. No biologically relevant changes were observed in the methylation of selected genes.

The prediction of microRNA targets is a challenging task that has given rise to several prediction algorithms. Databases of predicted targets can be used in a microRNA target enrichment analysis, enhancing our capacity to extract functional information from gene lists. However, the available tools in this field analyze gene sets one by one limiting their use in a meta-analysis. Here, we present an R system for miRNA enrichment analysis that is suitable for systems biology. These collection of R scripts and embedded data allow using predicted targets of public databases or a custom integration of them. As a proof-of-principle, we have successfully performed the challenging analysis of 2158 tumoral samples at a time. The obtained results have been summarized in a network where each cancer disease is linked to enriched miRNAs and overrepresented functions. These network connections have proven to be an invaluable resource for the study of biological and pathological causes and effects of the expression of miRNAs.

The Ontario Clinical Oncology Group (OCOG) – ALMERA trial (NCT02186847) is a Canadian multicenter randomized phase II trial funded by the Canadian Institute for Health Research, which is designed to examine whether metformin has chemo-radio-sensitization activity as well as activity as a single agent in advanced localized NSCLC. A total of 94 patients will be randomized in this screening trial to standard CRT with or without treatment with 2000mg of metformin, which is delivered during CRT (2 cycles of cisplatin based chemotherapy, concurrent with chest RT of 63 Gy in 30 fractions) but continues also as a single agent for a total of 12 months. ALMERA is designed to detect a 20% improvement in lung cancer progression free survival at 12 months. This trial is now open in several centers across Canada. The primary outcome is 12 month Progression Free Survival (PFS) and secondary outcomes include 1 and 2 y overall survival (OAS), time to loco-regional progression, distant progression free survival, adverse events and collection of biospecimens for biomarker studies. These will involve investigation of circulating serum and blood cell biomarkers of metformin activity and tumor biomarkers such as tumor histology, TP53, LKB1 and K-Rasmutation status. When completed ALMERAwill provide some of the first prospective evidence on the potential of metformin to improve the outcomes of standard cytotoxic therapy in locally advanced NSCLC. Biospecimen collect will allow us to investigate serum and tumors biomarkers ofmetformin response. Comparison of the results of ALMERA with other studies, like NRG-LU001, may be able to provide evidence on the value of metformin as maintenance therapy and assist in the design of future phase III trials with metformin in the setting of locally advanced NSCLC.

The interpretation of the complex molecular descriptions generated by high-throughput gene expression technologies is still challenging. The development of new tools to identify common regulatory mechanisms involved in the control of the expression of a set of co-expressed genes, might enhance our capacity to extract functional information from genomic data sets. Here we present FactorY, a website that allows identification of enriched transcription factor binding sites (TFBSs) in the proximal promoter of a cluster of genes, as well as functional interpretation, and intuitive visualization of the results.