Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention

The EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway plays prominent roles in malignant transformation, prevention of apoptosis, drug resistance and metastasis. The expression of this pathway is frequently altered in breast cancer due to mutations at or aberrant expression of: HER2, ERalpha, BRCA1, BRCA2, EGFR1, PIK3CA, PTEN, TP53, RB as well as other oncogenes and tumor suppressor genes. In some breast cancer cases, mutations at certain components of this pathway (e.g., PIK3CA) are associated with a better prognosis than breast cancers lacking these mutations. The expression of this pathway and upstream HER2 has been associated with breast cancer initiating cells (CICs) and in some cases resistance to treatment. The anti-diabetes drug metformin can suppress the growth of breast CICs and herceptin-resistant HER2+ cells. This review will discuss the importance of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway primarily in breast cancer but will also include relevant examples from other cancer types. The targeting of this pathway will be discussed as well as clinical trials with novel small molecule inhibitors. The targeting of the hormone receptor, HER2 and EGFR1 in breast cancer will be reviewed in association with suppression of the EGFR/PI3K/PTEN/Akt/mTORC1/GSK-3 pathway.USAMRMC {[}BC022276]; Intramural RECDA Award; Italian Association for Cancer Research (AIRC); MIUR-PRIN; Italian MIUR-FIRB Accordi di Programma; Italian ``Ministero dell'Istruzione, dell'Universita e della Ricerca (Ministry for Education, Universities and Research) - FIRB-MERIT {[}RBNE08YYBM]; Italian Ministry of Economy and Finance; Italian Ministry of Health, Ricerca Finalizzata Stemness; MIUR FIRB {[}RBAP11ZJFA\_001]; CRO; Italian Association for Cancer Research, (AIRC) (RM PI); Italian Association for Cancer Research, (AIRC) {[}MCO10016]; Italian Ministry of Health; Regione Friuli Venezia-Giuli

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Inhibition of the peptidyl-prolyl-isomerase Pin1 enhances the responses of acute myeloid leukemia cells to retinoic acid via stabilization of RARand PML-RAR

The peptidyl-prolyl-isomerase Pin1 interacts with phosphorylated proteins, altering their conformation. The retinoic acid receptor RARalpha and the acute-promyelocytic-leukemia-specific counterpart PML-RARalpha directly interact with Pin1. Overexpression of Pin1 inhibits ligand-dependent activation of RARalpha and PML-RARalpha. Inhibition is relieved by Pin1-targeted short interfering RNAs and by pharmacologic inhibition of the catalytic activity of the protein. Mutants of Pin1 catalytically inactive or defective for client-protein-binding activity are incapable of inhibiting ligand-dependent RARalpha transcriptional activity. Functional inhibition of RARalpha and PML-RARalpha by Pin1 correlates with degradation of the nuclear receptors via the proteasome-dependent pathway. In the acute myelogenous leukemia cell lines HL-60 and NB4, Pin1 interacts with RARalpha in a constitutive fashion. Suppression of Pin1 by a specific short hairpin RNA in HL-60 or NB4 cells stabilizes RARalpha and PML-RARalpha, resulting in increased sensitivity to the cytodifferentiating and antiproliferative activities of all-trans retinoic acid. Treatment of the two cell lines and freshly isolated acute myelogenous leukemia blasts (M1 to M4) with ATRA and a pharmacologic inhibitor of Pin1 causes similar effects. Our results add a further layer of complexity to the regulation of nuclear retinoic acid receptors and suggest that Pin1 represents an important target for strategies aimed at increasing the therapeutic index of retinoids

Carotenoids in Age-related Maculopathy Italian Study (CARMIS): two-year results of a randomized study

PURPOSE. The high concentration of carotenoids in the macula, plus evidence linking oxidative stress to age-related macular degeneration (AMD) and carotenoids to antioxidation, generated the hypothesis that higher antioxidant intakes can prevent AMD. The aim of this study was to determine whether nutritional supplementation with a targeted nutritional supplement improves visual acuity and visual function in AMD.METHODS. In this multicenter, prospective open-label randomized study, 145 patients were randomly assigned to 2 different treatment groups. Interventions were lutein (10 mg), zeaxanthin (1 mg), astaxanthin (4 mg; AZYR SIFI, Catania, Italy), and antioxidants/vitamins supplementation formula or no dietary supplementation for 2 years. Primary outcome was mean changes in visual acuity (VA) at 12 and 24 months. Other measures included contrast sensitivity (CS) and National Eye Institute visual function questionnaire (NEI VFQ-25) scores at 12 and 24 months.RESULTS. Patients in the treated group showed stabilization of VA with significantly (p=0.003) better VA scores (81.4 +/- 7.2) compared to the nontreated group (76.8 +/- 8.9) at 24-month follow-up. An improvement in CS (p=0.001) and final mean NEI VFQ-25 composite scores at 12 and 24 months higher in treated group compared to nontreated group were also shown (p<0.001).CONCLUSIONS. Patients treated with lutein/zeaxanthin and astaxanthin together with other nutrients were more likely to report clinically meaningful stabilization/improvements in VA, CS, and visual function through 24 months compared with nontreated subjects. Further studies are needed with more patients and for longer periods of time