PI3K inhib 
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  • ||||||||||  fimepinostat (CUDC-907) / Curis, Farydak (panobinostat) / Novartis, buparlisib (BKM120) / Novartis, Adlai Nortye
    [VIRTUAL] Novel dual inhibitors of HDAC and PI3Kinase signaling pathways in treatment of p53 driven medulloblastoma () -  Mar 13, 2021 - Abstract #AACR2021AACR_4889;    
    Results demonstrated that: 1) GAB-1 was highly expressed in the SHH group (82%) and KV1 expression was evenly distributed in all subtypes; 2) loss of p53 and overexpression of MYC varied in each subtype, but did not correlate with metastasis; 3) Patients displaying iso17q, exhibited metastatic disease; 4) Combined treatment with LBH-589 and BKM-120 or single treatment with CUDC-907 inhibited cell proliferation, migration and S-phase entry; 5) MB cells displayed strong resistance to BKM-120, whereas LBH-589 or CUDC-907 caused apoptosis; 6) BKM-120 in combination with mTOR inhibitors suppressed tumor formation; 7) AKT and 4E-BP1 were dephosphorylated following treatments with BKM-120 or CUDC-907. In conclusion, these findings underscore use of HDAC and PI3K inhibitors in the treatment of genetically driven MB.
  • ||||||||||  Piqray (alpelisib) / Novartis, CNX-1351 / BMS, taselisib (GDC-0032) / Roche
    [VIRTUAL] Development of optimized chemical probes targeting PI3Ka to deconvolute the role of class I PI3Ks isoforms in insulin signaling () -  Mar 13, 2021 - Abstract #AACR2021AACR_4707;    
    However, the availability of claimed isoform-selective PI3Kα inhibitors is limited to BYL719 (Alpelisib)[6] and GDC0032 (Taselisib)[7], which do not maintain PI3Kα selectivity at a concentration required in cellular experimental settings and clinical applications...An extensive Structure Activity Relationship (SAR) study was performed using CNX-1351[8] reacting group and introducing different heteroaliphatic rings in the linker...The generation of a novel class of covalent PI3Kα-specific inhibitors with improved selectivity and persistency of PI3Kα-inhibition will shed light on the role of PI3Kα in cancer and metabolism. Our results will pave the way for the dissociation of PI3Ki antitumor activity from adverse effects on insulin action.
  • ||||||||||  Mekinist (trametinib) / Novartis
    [VIRTUAL] MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer () -  Mar 13, 2021 - Abstract #AACR2021AACR_4438;    
    Taken together, MEK inhibition is a promising therapeutic strategy in the basal subtype of bladder cancer, particularly in combination with parallel pathway inhibition. Moving forward, we plan to test PI3K/AKT/MTOR combinations with trametinib in trametinib-resistant basal bladder cancer cell lines to investigate how this affects signaling and re-sensitization to trametinib.
  • ||||||||||  gemcitabine / Generic mfg.
    [VIRTUAL] Optimizing gemcitabine in metastatic TNBC by rational PI3K/AKT combination () -  Mar 13, 2021 - Abstract #AACR2021AACR_4432;    
    Moreover, further supporting our hypothesis, preliminary results indicate Chou-Talalay synergy at therapeutically relevant doses when gemcitabine is combined with PI3K/AKT inhibition. In future studies, we will evaluate the ability of the gemcitabine biomarker to predict response, and the efficacy of the prioritized combinations using ex vivo patient models of metastatic breast cancer established in our laboratory.
  • ||||||||||  paclitaxel / Generic mfg.
    [VIRTUAL] Impact of PI3K/mTOR inhibitors on the development of taxane resistance () -  Mar 13, 2021 - Abstract #AACR2021AACR_4417;    
    Several different regimens were used and in various orders; however, earlier use of PI3K or mTOR inhibitors with paclitaxel trended toward better patient outcomes with fewer lines of treatment. Adequately controlled and powered prospective studies are needed to determine a true relationship between PI3K and/or mTOR inhibitor therapy and re-initiation of taxane sensitivity.
  • ||||||||||  fulvestrant / Generic mfg.
    [VIRTUAL] Combination PI3K and NOS targeted therapy for metaplastic breast cancer () -  Mar 13, 2021 - Abstract #AACR2021AACR_4415;    
    Further studies are currently ongoing to elucidate the molecular mechanisms involved in enhanced cell death and decreased tumorigenesis with L-NMMA and alpelisib dual therapy. Our results support the concept that LNMMA and alpelisib combination therapy has therapeutic potential in the treatment of MpBC.
  • ||||||||||  Piqray (alpelisib) / Novartis, CNX-1351 / BMS
    [VIRTUAL] A novel, highly potent PI3Kα covalent inhibitor deconvolutes class I PI3K isoforms in cancer cells () -  Mar 13, 2021 - Abstract #AACR2021AACR_4414;    
    Overall, 19 exhibited excellent cellular activity with a superior profile compared to CNX-1351[3], a previously reported covalent PI3Kα inhibitor...Importantly, 19 provided a considerable gain in potency over BYL719, a clinically approved non-covalent PI3Kα-selective inhibitor...This strategy is a step towards the development of drug-like, isoform-selective, covalent PI3K inhibitor scaffolds, and 19 provides a template for the development of PI3Kα inhibitors with overall reduced adverse side effects in cancer therapy. Moreover, our covalent inhibition strategy will pave the way for a better molecular understanding of PI3K isoform signaling in general.
  • ||||||||||  sirolimus / Generic mfg.
    [VIRTUAL] Volume scanning, a rational approach to covalent PI3Kα inhibitors () -  Mar 13, 2021 - Abstract #AACR2021AACR_4413;    
    A considerable effort has been dedicated to the development of drugs targeting class I PI3Ks, which are evaluated in preclinical and clinical studies.[1-5] Here we present a strategy to convert a phase II clinical candidate, a pan-PI3K inhibitor (PQR309, bimiralisib)[5,6], into a highly selective, covalent PI3Kα inhibitor with the aim to minimize off-target and on-target metabolic side effects of PI3K inhibitor cancer therapy...Our pilot compounds exceed specificity and potency over an experimental dimethyl-substituted enone, CNX-1351.[7] Moreover, our compounds display increased stability in rat liver microsomal assays and outperform the rapidly metabolized CNX-1351...Moreover, we provide highly selective chemical tools to dissect PI3K isoform signaling in physiology and disease. A clarification of the role of the different PI3K isoforms in insulin signaling allows to address the challenges in isoform selectivity and to develop PI3K inhibitors showing ideal isoform specificity.
  • ||||||||||  [VIRTUAL] PO.ET06.05 - PI3K/AKT Inhibitors () -  Mar 13, 2021 - Abstract #AACR2021AACR_4411;    
    Although further studies are needed to evaluate time-dependent drug exposure in tumor and plasma samples, these preliminary findings support the BID clinical schedule of MEN1611 in the B-PRECISE-01 clinical trial (NCT03767335). Posters will be available for viewing to meeting registrants until Monday, June 21.
  • ||||||||||  ipatasertib (GDC-0068) / Roche
    [VIRTUAL] Identification and characterization of the PIK3R1-mutant subtype in PI3K-addicted prostate cancer () -  Mar 13, 2021 - Abstract #AACR2021AACR_4326;    
    Most importantly we showed that Akt-inhibitors ipatasertib and MS2206 strongly reduced the viability of prostate cancer cells (LAPC4 and 22RV1) with PIK3R1 knockdown or PIK3R1 mutated mCRPC derived organoid (MSKPCa3) compared to PIK3R1 wild type cells irrespective of their PTEN status.In summary, our study identified an association between PIK3R1 alterations and lethal prostate cancer and demonstrated that men with mCRPC who harbor defective PIK3R1 may benefit from Akt inhibitors. Further in-depth studies are warranted to uncover the biological and phenotypic characterization of PIK3R1-altered prostate cancer.
  • ||||||||||  Piqray (alpelisib) / Novartis
    Clinical, Review, Journal:  Role of Alpelisib in the Treatment of PIK3CA-Mutated Breast Cancer: Patient Selection and Clinical Perspectives. (Pubmed Central) -  Mar 13, 2021   
    With appropriate toxicity management and patient selection using validated testing methods, all eligible patients can potentially benefit from this new treatment. Further clinical trials to assess combinations of hormone therapy with PI3K, AKT, mTOR, or CDK 4/6 inhibitors, or studies in men and women with other breast subtypes are ongoing.
  • ||||||||||  Journal:  Dysregulation of FOXO transcription factors in Epstein-Barr virus-associated gastric carcinoma. (Pubmed Central) -  Mar 12, 2021   
    FOXO1, FOXO3 and FOXO4 proteins are upregulated following PI3K inhibition in GT39 cells, confirming that they are partially suppressed by the PI3K/AKT pathway. However, the upregulation of FOXO1 and FOXO3 by single transfection with LMP1 or LMP2A implies that the dysregulation of FOXOs in EBVaGC is affected by various EBV latent genes and that PI3K/AKT signaling is not the only mechanism of FOXO regulation.
  • ||||||||||  Journal:  Eupafolin inhibits breast cancer cell proliferation and induces apoptosis by inhibiting the PI3K/Akt/mTOR pathway. (Pubmed Central) -  Mar 12, 2021   
    Taken together, the present findings demonstrate that Eupafolin has a significant inhibitory effect on the proliferation of EO771 cells, inhibits cell migration and invasion, and promotes cell apoptosis, thereby causing G/G phase arrest, at least partially through the PI3K/Akt/mTOR signaling pathway. Therefore, the findings provide novel insights regarding the use of Eupafolin for the treatment of breast cancer.
  • ||||||||||  Journal:  Effects of PI3K/AKT/mTOR Pathway Regulation of HIF-1α on Lanthanum-Induced Neurotoxicity in Rats. (Pubmed Central) -  Mar 12, 2021   
    LaCl poisoning can induce developmental injuries in hippocampal neurons and can increase cell apoptosis. As a result, learning and memory abilities of offspring rats, as well as the expressions of PI3K/AKT/mTOR, are decreased, thus inhibiting activation of HIF-1α and influencing the expression of the downstream VEGF gene.
  • ||||||||||  Erbitux (cetuximab) / Eli Lilly, EMD Serono
    [VIRTUAL] Overcoming acquired cetuximab resistance in head and neck squamous cell carcinoma: An in vitro study on the potential of PI3K inhibition () -  Mar 11, 2021 - Abstract #AACR2021AACR_3698;    
    Preliminary results also show an additive to synergistic interaction between both drugs in the SCC22b-PBS and SCC22b-R cell lines.In conclusion, these results can serve as a preclinical rationale for a novel therapeutic strategy combining buparlisib with cetuximab in HNSCC patients who experience acquired cetuximab resistance. Further research is necessary to obtain a more profound understanding of the molecular mechanisms underlying this targeted combination therapy.
  • ||||||||||  Keytruda (pembrolizumab) / Merck (MSD)
    [VIRTUAL] Evolution of OncoKB, a precision oncology knowledgebase (Channel 04) -  Mar 11, 2021 - Abstract #AACR2021AACR_3096;    
    The tumor agnostic approval of the checkpoint blockade inhibitor, pembrolizumab, in TMB-H solid tumors additionally gave rise to a ~4% increase in Level 1 samples.Analysis of the AACR Project GENIE cohort also revealed significant changes to the OncoKB process, including those reflected in the updated OncoKB Levels of Evidence v2.0...This change was based on clinical data demonstrating that patients with investigational predictive biomarkers for a specific tumor type based on compelling clinical evidence from phase 3 trials (currently Level 3A) are more likely to experience clinical benefit compared to patients with predictive biomarkers that are considered standard care in a different tumor type (previously Level 2B, currently Level 3B), and is consistent with guidelines published by ASCO/AMP/CAP and ESMO.Knowledgebases such as OncoKB have emerged as key informational resources that the clinical oncology and scientific communities have used to rapidly connect sequencing results to clinical actionability. Their utility depends on their ability to stay abreast of clinical data and seamlessly adapt their rules and processes to the evolving field of precision medicine.