Publications by authors named "Elena Lopez-Guadamillas"
Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3Kα isoform, a crucial effector of growth factor signalling.
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- The study evaluates the effects of PI3Kδ inhibitor AMG319 in patients with head and neck cancer, showing that it reduces regulatory T cells while boosting the activity of tumor-fighting T cells.
- However, the treatment resulted in significant immune-related adverse events (irAEs) in nearly half of the patients, raising concerns about systemic effects on T cells.
- Mouse models suggest that altering dosing regimens could reduce these toxic effects while still effectively shrinking tumors, prompting further exploration of treatment strategies.
Article Synopsis
- Immunotherapies often fail to effectively enhance cancer-specific T cell responses in patients, but blocking the PI3Kδ enzyme shows promise in improving tumor immunity in early trials.
- In a study using mice with mammary tumors, treatment with a PI3Kδ inhibitor, either alone or in combination with anti-LAG3 antibodies, resulted in significant variations in tumor response, characterized by different levels of T cell activity.
- The combination therapy was successful in treating all mice, highlighting the role of LAG3 in tumor non-regression and suggesting that an initial response to PI3Kδ inhibition is crucial for maximizing the effects of anti-LAG3 treatment.
Liver injury results in rapid regeneration through hepatocyte proliferation and hypertrophy. However, after acute severe injury, such as acetaminophen poisoning, effective regeneration may fail. We investigated how senescence may underlie this regenerative failure.
View Article and Find Full Text PDFPartial inhibition of PI3K is one of the best-validated and evolutionary conserved manipulations to extend longevity. The best known health beneficial effects of reduced PI3K are related to metabolism and include increased energy expenditure, reduced nutrient storage, and protection from obesity. We have previously shown that a dual chemical inhibitor of the alpha and delta PI3K isoforms (CNIO-PI3Ki) reduces obesity in mice and monkeys, without evident toxic effects after long-term treatment.
View Article and Find Full Text PDFFasting is a physiological stress that elicits well-known metabolic adaptations, however, little is known about the role of stress-responsive tumor suppressors in fasting. Here, we have examined the expression of several tumor suppressors upon fasting in mice. Interestingly, p21 mRNA is uniquely induced in all the tissues tested, particularly in liver and muscle (>10 fold), and this upregulation is independent of p53.
View Article and Find Full Text PDFGenetic inhibition of PI3K signaling increases energy expenditure, protects from obesity and metabolic syndrome, and extends longevity. Here, we show that two pharmacological inhibitors of PI3K, CNIO-PI3Ki and GDC-0941, decrease the adiposity of obese mice without affecting their lean mass. Long-term treatment of obese mice with low doses of CNIO-PI3Ki reduces body weight until reaching a balance that is stable for months as long as the treatment continues.
View Article and Find Full Text PDFAging in worms and flies is regulated by the PI3K/Akt/Foxo pathway. Here we extend this paradigm to mammals. Pten(tg) mice carrying additional genomic copies of Pten are protected from cancer and present a significant extension of life span that is independent of their lower cancer incidence.
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