- |||||||||| Journal: Urolithin A, a novel natural compound to target PI3K/AKT/mTOR pathway in pancreatic cancer. (Pubmed Central) - Nov 28, 2019
We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1a;LSL-Kras;Tgfbr2 (PKT) mice compared with vehicle or gemcitabine therapy alone...Additionally, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and regulatory T-cells (Tregs). Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.
- |||||||||| Biomarker, Journal: Cooperative effect of oncogenic MET and PIK3CA in an HGF-dominant environment in breast cancer. (Pubmed Central) - Nov 28, 2019
However, the levels of phosphorylated MET are not correlated with its expression, suggesting that MET expression level cannot be used as a sole criterion to recruit patients to clinical trials for MET-targeted therapy. All together, our data suggests that combined targeting of MET and PI3K could be a potential clinical strategy for breast cancer patients, where phosphorylated MET and PIK3CA mutation status would be biomarkers for selecting patients who are most likely to derive benefit from these co-targeted therapy.
- |||||||||| Journal: LncRNA DANCR upregulates PI3K/AKT signaling through activating serine phosphorylation of RXRA. (Pubmed Central) - Nov 28, 2019
Further study of underlying mechanisms demonstrated that DANCR bound with RXRA and increased its serine 49/78 phosphorylation via GSK3β, resulting in activating PIK3CA transcription, and subsequently enhanced PI3K/AKT signaling and TNBC tumorigenesis. Taken together, Our findings identified DANCR as an pro-oncogene and uncoverd a new working pattern of lncRNA to mediate TNBC tumorigenesis, which may be a potential therapeutic target for improving treatment of TNBC.
- |||||||||| Journal: A curated resource for phosphosite-specific signature analysis. (Pubmed Central) - Nov 27, 2019
We also applied our methods to analyze the phosphoproteomes of PI3K-inhibited human breast cancer cells and detected signatures of compounds inhibiting PI3K as well as targets downstream of PI3K (AKT, MAPK/ERK) covering a substantial fraction of the PI3K pathway. PTMsigDB and PTM-SEA can be freely accessed at https://github.com/broadinstitute/ssGSEA2.0.
- |||||||||| paclitaxel / Generic Mfg.
Preclinical, Journal, Heterogeneity: Cellular Metabolic Heterogeneity In Vivo Is Recapitulated in Tumor Organoids. (Pubmed Central) - Nov 27, 2019 Interestingly, these previously unappreciated heterogeneous metabolic responses in tumors and organoids could not be attributed to tumor cell fate or varying leukocyte content within the microenvironment, suggesting that heightened metabolic heterogeneity upon treatment is largely due to heterogeneous metabolic shifts within tumor cells. Together, these studies show that OMI revealed remarkable heterogeneity in response to treatment, which could provide a novel approach to predict the presence of potentially unresponsive tumor cell subpopulations lurking within a largely responsive bulk tumor population, which might otherwise be overlooked by traditional measurements.
- |||||||||| quercetin (LY294002) / Eli Lilly
Journal: Expression of Clusterin suppresses Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway. (Pubmed Central) - Nov 24, 2019 Blockage of the PI3K/AKT pathway with its inhibitor LY294002 eliminated the inhibitory effect of CLU on Cr(VI)-induced premature senescence. We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence.
- |||||||||| refametinib (BAY86-9766) / Bayer, apitolisib (GDC-0980) / Roche
Retrospective data, Journal: Co-targeting PI3K/Akt and MAPK/ERK pathways leads to an enhanced antitumor effect on human hypopharyngeal squamous cell carcinoma. (Pubmed Central) - Nov 24, 2019 We concluded that high expression of CLU suppressed Cr(VI)-induced premature senescence through activation of PI3K/AKT pathway, which will provide the experimental basis for the study of Cr(VI)-induced liver cancer, especially for the elucidation of the mechanism of liver cancer cells escaping from senescence. Dual inhibition of PI3K/Akt and MAPK/ERK pathway by GDC-0980 and Refametinib might be a promising treatment strategy for HSCC patients.
- |||||||||| Journal: Taxifolin inhibits the scar cell carcinoma growth by inducing apoptosis, cell cycle arrest and suppression of PI3K/AKT/mTOR pathway. (Pubmed Central) - Nov 23, 2019
Further investigation revealed that the anticancer effects of taxifolin on the SSCC cells is due to the induction of apoptosis and cell cycle arrest. Moreover, taxifolin could also inhibit the invasion of SSCC cells which was associated with downregulation of the MMP-2 and MMP-9 expression indicative of the potential of taxifolin in the treatment of scar cell carcinoma It is was found that taxifolin inhibited the growth of skin scar cell carcinoma growth by triggering apoptosis and cell cycle arrest and also inhibited cell invasion capacity and therefore this study warrants further investigation on the anticancerous potential of taxifolin.
- |||||||||| INCB040093 / Incyte, parsaclisib (INCB50465) / Incyte
Journal: INCB050465 (Parsaclisib), a Novel Next-Generation Inhibitor of Phosphoinositide 3-Kinase Delta (PI3Kδ). (Pubmed Central) - Nov 23, 2019 The unique structure of 20 contains a pyrazolopyrimidine hinge-binder in place of a purine motif that is present in other PI3Kδ inhibitors, such as idelalisib (1), duvelisib (2), and INCB040093 (3, dezapelisib). Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors. (Pubmed Central) - Nov 22, 2019 Parsaclisib (20) is a potent and highly selective inhibitor of PI3Kδ with drug-like ADME properties that exhibited an excellent in vivo profile as demonstrated through pharmacokinetic studies in rats, dogs, and monkeys and through pharmacodynamic and efficacy studies in a mouse Pfeiffer xenograft model. Novel MEK and PI3K bifunctional inhibitors ST-162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors.
- |||||||||| buparlisib (BKM120) / Novartis, Adlai Nortye
Journal: Buparlisib is a brain penetrable pan-PI3K inhibitor. (Pubmed Central) - Nov 22, 2019 We demonstrate that buparlisib has an excellent brain penetration that is unaffected by efflux transporters at the blood-brain barrier, complete oral bioavailability and efficient intracranial target inhibition at clinically achievable plasma concentrations. Together, these characteristics make buparlisib the ideal candidate for intracranially-targeted therapeutic strategies that involve PI3K inhibition.
- |||||||||| Journal: PVT1 protects diabetic peripheral neuropathy via PI3K/AKT pathway. (Pubmed Central) - Nov 22, 2019
PVT1 is lowly expressed in diabetic rats, leading to decreased mechanical withdrawal threshold, thermal withdrawal latency and sensory nerve conduction velocity. PVT1 protects diabetic peripheral neuropathy via PI3K/AKT pathway.
- |||||||||| dexamethasone / generics
Preclinical, Journal: IGF-1 reverses the osteogenic inhibitory effect of dexamethasone on BMP9-induced osteogenic differentiation in mouse embryonic fibroblasts via PI3K/AKT/COX-2 pathway. (Pubmed Central) - Nov 22, 2019 Glucocorticoid-Induced Osteoporosis (GIOP) is a prevalent clinical complication caused by large dose administration of glucocorticoids, such as Dexamethasone (Dex) and Prednisone...Regarding the inhibitory mechanism, we found that the level of AKT and p-AKT can be decreased by Dex and that Ly294002, the PI3K inhibitor, can block the reversal effect of IGF-1...Our findings indicated that IGF-1 may reverse the osteogenic inhibitory effect of Dex via PI3K/AKT pathway, which may be associated with the up-regulation of COX-2. This study may provide new clinical management strategy for GIOP cases.
- |||||||||| buparlisib (BKM120) / Novartis, Adlai Nortye
Clinical, P2 data, Journal, Tumor Mutational Burden: Efficacy and safety of buparlisib, a PI3K inhibitor, in patients with malignancies harboring a PI3K pathway activation: a phase 2, open-label, single-arm study. (Pubmed Central) - Nov 22, 2019 Buparlisib was well tolerated, however efficacy was limited despite selection of PI3K pathway aberrations. Future studies may provide insight into buparlisib efficacy by refining the molecular selection of different tumor types.
- |||||||||| The role of PI3K lipid effectors in melanoma () - Nov 21, 2019 - Abstract #SMR2019SMR_280;
However, it has not been shown if constitutively active AKT alone is able to substitute for this effect. Further research will elucidate the role of AKT in the initiating stages of melanoma and provide a more thorough understanding of the PI3K/AKT signaling pathway in promoting melanomagnesis.
- |||||||||| Co-inhibition of autophagy and oncogenic signaling in NRAS-driven melanoma () - Nov 21, 2019 - Abstract #SMR2019SMR_181;
Altogether, these data suggest that co-inhibition of autophagy and oncogenic signaling may represent potential new treatment strategies for NRAS-driven melanoma patients. Future experiments aim for a better mechanistic understanding of the combination treatment usingin vitro and in vivo tools, with the objective to propose novel therapeutic strategies for NRASdriven melanoma patientsin the clinical setting.
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