- |||||||||| Review, Journal: Are Wnt/β-catenin and PI3K/AKT/mTORC1 distinct pathways in colorectal cancer? (Pubmed Central) - Sep 9, 2021
The ability of the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways to reciprocally control themselves represents one of the main resistance mechanisms to selective inhibitors in CRC leading to the hypothesis that in specific settings, particularly in cancer driven by genetic alterations in Wnt/β-catenin signaling, the relationship between Wnt/β-catenin and PI3K/AKT/mTORC1 pathways could be so close that they should be considered as a unique therapeutic target. This review provides an update on the Wnt/β-catenin and PI3K/AKT/mTORC1 pathways interconnection in CRC, describing the main molecular players and the potential implications of combined inhibitors as an approach for CRC chemoprevention and treatment.
- |||||||||| Torisel (temsirolimus) / Pfizer
Clinical, Review, Journal: PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects. (Pubmed Central) - Sep 9, 2021 Currently, clinical studies evaluate inhibitors of the PI3K/AKT/mTOR axis. The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy.
- |||||||||| Zolinza (vorinostat) / Merck (MSD)
Journal: Berberine regulates the Notch1/PTEN/PI3K/AKT/mTOR pathway and acts synergistically with 17-AAG and SAHA in SW480 colon cancer cells. (Pubmed Central) - Sep 9, 2021 The main purpose of this review is to present general aspects of breast cancer, the components of the AKT signaling pathway, the factors that activate this protein kinase B, PI3K/AKT-breast cancer mutations, PI3K/AKT/mTOR-inhibitors, and the relationship between everolimus, temsirolimus and endocrine therapy. The integrative gene expression-based chemical genomic method using CMAP analysis may be applicable for mechanistic studies of other multi-targets drugs.
- |||||||||| Journal: Oral Hydrogen-Rich Water Alleviates Oxalate-Induced Kidney Injury by Suppressing Oxidative Stress, Inflammation, and Fibrosis. (Pubmed Central) - Sep 8, 2021
The expressions of molecules related to PI3K-AKT pathway (PI3K, AKT, and p-AKT), NF-κB pathway (NF-κB p65, p- NF-κB p65, NLRP3, and IL-1β) and TGF-β pathway (TGF-β, TGF-βRI, TGF-βRII, p-Smad2, and p-Smad3) in renal tissues were increased by oxalate diet, which were reduced by HRW administration. HRW may alleviate oxalate-induced kidney injury with its anti-oxidative, anti-inflammatory and anti-fibrotic effects via inhibiting PI3K/AKT, NF-κB, and TGF-β pathways.
- |||||||||| Journal: Non-Lyn Src Family Kinases Activate SIRPα-SHP-1 to Inhibit PI3K-Akt2 and Dampen Proinflammatory Macrophage Polarization. (Pubmed Central) - Sep 8, 2021
Pharmacological inhibition of SHP-1 or deficiency of SIRPα conversely attenuates SIRPα-mediated inhibition and, as such, augments macrophage proinflammatory polarization that in turn exacerbates proinflammation in mouse models of type I diabetes and peritonitis. Our results reveal an SFK-SIRPα-SHP-1 mechanism that fine-tunes macrophage proinflammatory phenotypic activation via inhibition of PI3K-Akt2, which controls the transcription and translation of proinflammatory cytokines, Ag presentation machinery, and other cellular programs.
- |||||||||| Zydelig (idelalisib) / Gilead
Journal: Critical Roles of Phosphoinositide 3-Kinase δ in the Humoral Immune Response to Trypanosoma congolense Infection. (Pubmed Central) - Sep 8, 2021 C57BL/6 wild-type (WT) mice treated with the PI3Kδ inhibitor (PI3Kδi) Idelalisib showed a similar transient decrease in parasitemia associated with reduced IL-10...Together our findings suggest that although PI3Kδ drives immune regulatory responses that antagonize early control of parasite growth in the peritoneum, it is also required for generation of Abs that are critical for protection from systemic trypanosome infection. The essential role of PI3Kδ for host survival of African trypanosome infection contrasts with findings for other pathogens such as Leishmania, underlining the critical importance of PI3Kδ-dependent humoral immunity in this disease.
- |||||||||| [VIRTUAL] Novel Treatment Approaches in Relapsed/ Refractory Mantle Cell Lymphoma () - Sep 6, 2021 - Abstract #SOHO2021SOHO_391;
P3 There are currently three FDA-approved irreversible BTKifor the treatment of R/R MCL, including ibrutinib, the first approved BTKi, and the more selective BTKi, acalabrutinib and zanubrutinib...A phase 3 trial in R/R MCL randomizing patients to the investigator’s choice of approved covalent BTKiversus pirtobrutinib is planned...A large phase 3 study (NCT03112174) comparing single-agent ibrutinib to the combination of ibrutinib and venetoclax has completed accrual but has yet to be reported...The selective PI3K inhibitor parsaclisib has activity in patients with BTKi-naïve and BTKipreviously treated MCL...VLS-101, an anti-ROR1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE), has shown early promising activity in R/R MCL...Chimeric Antigen Receptor T-Cells Brexucabtagene autoleucel was the first autologous CD19-directed cellular therapy approved by the FDA in R/R MCL, based on results of the pivotal phase 2 trial that reported on 60 patients evaluable for response, with an ORR of 93%, including 67% CR.11 With a median follow-up of 12 months, the 1-year PFS and OS were 61% and 83%, respectively...Lisocabtagene maraleucel is a second autologous CD19-directed cellular therapy being evaluated in R/R MCL with preliminary results of 32 patients treated in the phase 1 trial reporting an ORR of 84% and a CR rate of 66%; with a median follow-up of 6 months, the median PFS and OS were not reached.12 Any grade CRS was reported to be 59%, and any grade neurotoxicity 34%, suggesting an improved toxicity profile...However, almost all patients will progress on BTKitherapy, resulting in the need to both improve outcomes using BTKi-based combinations and the need for effective therapies at progression, which will become even more critical as BTKiare moved into upfront treatment approaches. The recent approval of a CAR-T cell product has provided an effective therapy option for such patients after progression on BTKitherapies, and the sequencing of this earlier in the treatment of patients with high-risk disease features is attractive.
- |||||||||| [VIRTUAL] BCMA-Directed CAR T-Cells: Early Results and Future Directions () - Sep 6, 2021 - Abstract #SOHO2021SOHO_389;
The initial results from the UNIVERSAL phase 1 study in RRMM are encouraging, with responses reported and more attenuated toxicity.26 Others, including CTX120, BCMAUCART, UCART CS1, and PBCAR269A, are in development and in early-phase studies...Despite these impressive results, however, patients with MM continue to relapse. Moving these therapies earlier in the course of the disease, continued refinement of next-generation products, and rational combination strategies that may defer or prevent relapse should continue to improve on these results with the goal of finally reaching that elusive cure.
- |||||||||| [VIRTUAL] Old Prognostic Markers Still Have a Role in CLL Management () - Sep 6, 2021 - Abstract #SOHO2021SOHO_384;
Randomized trials demonstrated superior efficacy and more favorable safety profiles of targeted agents compared to conventional agents, leading to regulatory approval of five targeted agents for the treatment of CLL: ibrutinib,6,7 acalabrutinib,8,9 idelalisib,10 duvelisib,11 and venetoclax12,13...PI3K inhibitors is less popular than other agents due to concerns of immune-related toxicity and CMV reactivation.28 This section will summarize prognostic markers in CLL with a focus on ibrutinib and venetoclax...In particular next-generation sequencing (NGS) holds promise as it enabled tremendous progress in characterization of the molecular underpinning of CLL. Further research is needed to render NGS more cost-efficient, accessible, and relevant to clinical practice.
- |||||||||| [VIRTUAL] New Agents in Marginal Zone Lymphomas () - Sep 6, 2021 - Abstract #SOHO2021SOHO_370;
Zanubrutinib, given orally at the dose of 160 mg twice daily, produced an ORR of 74%, with a CR rate of 24%...The time to response was 2.8 months, similar to that for ibrutinib...Idelalisib, duvelisib, copanlisib, parsaclisib, and umbralisib have all been tested in trials enrolling patients with pretreated indolent lymphomas, among which MZL patients represented a subset...The median PFS was 24 months, with 56% of patients remaining progression-free at two years.4 The subsequent CHRONOS-3 study randomly assigned patients to either copanlisib + rituximab or rituximab + placebo...At a median follow-up of 28 months, both the median DOR and the median PFS were not reached.6 Conclusions Sequential applications of various treatment strategies are the key to success in MZL. Innovative drugs and targeted agents offer new treatment opportunities in highly pretreated individuals and in particular categories of patients, limiting the reiterated application of cytotoxic drugs.
- |||||||||| sonolisib (PX 866) / Seagen
Journal: β-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling. (Pubmed Central) - Sep 5, 2021 Furthermore, the liver-protecting effect of ARRB2 was shown to depend on PI3K/Akt pathway activation. In summary, our results suggest that β-Arrestin-2 protects against hepatic IRI by activating PI3K/Akt signaling, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury.
- |||||||||| sirolimus / Generic mfg.
Journal: Rapamycin suppresses the PI3K/AKT/mTOR signaling pathway by targeting SIRT1 in esophageal cancer. (Pubmed Central) - Sep 4, 2021 In addition, SIRT1 transfection rescued the decreased level of phosphorylated (p)-PI3K, p-AKT and p-mTOR induced by rapamycin treatment. Taken together, the present results suggested that rapamycin suppressed the cell viability, migration, invasion and PI3K/AKT/mTOR signaling pathway in EC by negatively regulating SIRT1.
- |||||||||| Journal: Spinal Cord Injury Causes Insulin Resistance Associated with PI3K Signaling Pathway in Hypothalamus. (Pubmed Central) - Sep 4, 2021
Collectively, our results suggest abnormality in glucose metabolism after SCI, and demonstrate that SCI may impair activation of the PI3K signaling pathway in the hypothalamus. The reduced activity of the PI3K signaling pathway in the hypothalamus may lead to peripheral inflammation, which might be the mechanism underlying the development of insulin resistance and type 2 diabetes following SCI.
- |||||||||| Bay11-7082 / InvivoGen
Journal: Upregulation of polymeric immunoglobulin receptor expression in flounder (Paralichthys olivaceus) gill cells by cytokine tumor necrosis factor-α via activating PI3K and NF-κB signaling pathways. (Pubmed Central) - Sep 4, 2021 Furthermore, the gene expressions of PI3K and NF-κB were upregulated and present a tendency to increase first and then decrease after TNF-α treatment of FG cells; However, the expression of PI3K mRNA was inhibited significantly by wortmannin but not by Bay11-7082, and the expression of NF-κB mRNA was suppressed obviously by Bay11-7082 but not by wortmannin, suggesting that inhibition of PI3K or NF-κB had no influence on each other. All these results collectively revealed that TNF-α could transcriptionally upregulate fpIgR expression and SC production, and this TNF-α-induced pIgR expression was regulated by complex mechanisms that involved PI3K and NF-κB signaling pathways, which provided evidences for pro-inflammatory cytokine TNF-α acting as a regulator in pIgR expression and better understanding of regulation mechanism of pIgR expression in teleost fish.
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