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- Torisel (temsirolimus) / Pfizer
[VIRTUAL] mTOR inhibitor induces non-apoptotic, autophagy dependent cell death (ADCD) in TP53 mutant HNSCC () - Mar 11, 2021 - Abstract #AACR2021AACR_2878;
We investigated the mechanism by which the mTOR inhibitor CCI-779 inhibits cell growth of TP53 mutant HNSCC in vitro...This is a novel mechanism of how rapalogues induce ADCD through the stabilization/ activation of ULK1 in HPV-negative TP53 mutant HNSCC cells. Together these data highlight the importance of how mTORi can be used to accelerate tumor cell death in HPV-negative TP53 mutant HNSCC.
- [VIRTUAL] PTEN regulated PI3K-p110 and AKT isoform plasticity controls metastatic prostate cancer progression () - Mar 11, 2021 - Abstract #AACR2021AACR_2843;
Together these data highlight the importance of how mTORi can be used to accelerate tumor cell death in HPV-negative TP53 mutant HNSCC. Our data suggest that in the context of RB1 loss, PTEN controls a signaling plasticity and drug sensitivity through specific pairings of PI3K-p110 and AKT isoforms.
- [VIRTUAL] Structural and biochemical properties of DIRAS3 N-terminal extension that permit its function as a tumor suppressor of oncogenic K-RAS (Channel 06) - Mar 11, 2021 - Abstract #AACR2021AACR_2656;
The affinity of the NTE for PIP3 could contribute to the known regulation of PI3K by DIRAS3. Moreover, functional DIRAS3 may be tethered to the inner leaflet of the cell membrane at two points, by prenylation of the CAAX box at the C-terminal and by myristoylation of the NTE.
- quercetin (LY294002) / Eli Lilly, buparlisib (BKM120) / Novartis, Adlai Nortye
[VIRTUAL] Combined inhibition of EGFR and PI3Kinase signaling in EGFR amplified triple negative breast cancer cells induces apoptosis and reduces cancer stem cells () - Mar 11, 2021 - Abstract #AACR2021AACR_2239;
In summary, these data demonstrate that EGFR amplification in TNBC drives cell viability through EGFR and PI3K signaling, and EGFR/PI3K inhibitor combination causes apoptosis as well as reduction in the cancer stem cell population. We present evidence therefore that dual inhibition of EGFR/PI3K presents as a potential targetable pathway in TNBC with EGFR amplification and aberrant PI3K signaling.
- [VIRTUAL] Identifying clinically relevant molecular distinctions in gastric cancer development among US minorities to address cancer health disparities () - Mar 11, 2021 - Abstract #AACR2021AACR_2224;
Indeed, when treat our patient-derived models with these inhibitors, we observe significant responses both in vitro and in vivo. Our findings highlight an important molecular distinction of GC development in racial/ethnic U.S. minorities that provides a rationale for alternative treatments to address GC health disparities that plague these groups and help bring the field closer to precision cancer medicine.
- [VIRTUAL] A robust rapid mRNA based test to profile simultaneously ER, AR, PI3K and MAPK functional signaling pathway activity for precision oncology () - Mar 11, 2021 - Abstract #AACR2021AACR_2202;
The results of the signal pathway activity analysis correlate well with breast subtype classification, however, the assay has the potential to uncover specific pathway activation independent of subtype which may have significant value for precision oncology and targeted therapy selection. The test has potential for wide utilization as it can be performed on conventional FFPE prepared breast specimens, and may be complementary to conventional mutational and IHC analysis for classifying breast cancer and selecting appropriate therapy.
- Piqray (alpelisib) / Novartis
[VIRTUAL] RNF43 G659fs is an oncogenic mutation in colorectal cancer and sensitizes tumor cells to PI3K/mTOR inhibition () - Mar 11, 2021 - Abstract #AACR2021AACR_2055;
Furthermore, RNF43659mut and RNF43WT exhibited differential drug responses in the high-throughput drug repurposing screen which revealed that RNF43659mut cells were vulnerable to PI3K/AKT/mTOR inhibitors, including BYL-719 (Alpelisib)... This study confirms that RNF43659mut is an essential driver mutation in CRC and provides evidence that patients harboring RNF43_G659fs-mutant tumors may respond favorably to PI3K inhibition.
- Talzenna (talazoparib) / Pfizer
[VIRTUAL] Combination of ZEN-3694 with talazoparib is a novel therapeutic approach in ER positive breast cancer resistant to CDK4/6 inhibitors, independent of BRCA status () - Mar 11, 2021 - Abstract #AACR2021AACR_1952;
P2
Moreover, this combination led to the impairment of the homologous recombination pathway through downregulation of CtIP and WEE1 expression.Furthermore, our data demonstrate that ZEN-3694 targets several mechanisms of endocrine and CDK4/6i resistance including inhibition of estrogen receptor expression and ER signaling, a significant downregulation of several drivers of CDK4/6i resistance such as CDK6, CDK4 and CCND1, as well as inhibition of alternative pathways such as STAT3 and Erbb2. Our RNAseq analysis revealed that ZEN-3694 leads to a strong downregulation of key genes involved in the BRCA1-mediated DNA damage response pathway, as well as double-strand break repair by non-homologous end joining.We conclude that ZEN-3694 in combination with PARP inhibitors is a novel therapeutic strategy in ER+ breast cancer patients progressing on CDK4/6 inhibitors and a promising approach in HR proficient breast cancer.
- tamoxifen / Generic mfg.
[VIRTUAL] Boosting immune surveillance by low-dose PI3K inhibitor facilitates early intervention of breast cancer () - Mar 11, 2021 - Abstract #AACR2021AACR_1587;
Prevention of estrogen receptor–negative (ER-) breast cancer is an unmet challenge, although tamoxifen and aromatase inhibitors can successfully decrease the incidence of ER-positive (ER+) breast cancer...Both genetic knockdown of PIK3CA or intervention with low-doses of a PI3K inhibitor (GDC-0941) prevented the dysplasia phenotype of semi-transformed human ER- mammary epithelial cells in 3-dimensional culture in vitro...In human ER- breast cancer, PI3K activation is correlated with significantly reduced CCL5, CXCL10 and CD8A expression, suggesting that the decreased CD8+ T-cell recruitment and escape of immune surveillance may contribute to ER- breast cancer development. In summary, our study indicates that low-dose PI3K inhibitor treatment may intervene early stage ER- breast cancer development by enhancing immune surveillance via CCL5/CXCL10.
- [VIRTUAL] Dietary fat influences pancreatic cancer progression by altering cell membrane lipid content to impact the PI3K/AKT pathway () - Mar 11, 2021 - Abstract #AACR2021AACR_1576;
DHA treatment reduced PI3K interaction (not total PI3K) with PIP2 resulting in lower levels of PIP3 in the membrane and reduced pAKT activation. Our results are encouraging because these PUFAs impinge on AKT, a downstream target of Kras which serves as a logical alternative to the elusive therapies for Kras and often toxic effects of PI3K/AKT pathway inhibition.
- [VIRTUAL] Atomic-level insights into PI3K activation () - Mar 11, 2021 - Abstract #AACR2021AACR_1519;
The inhibitors that may modulate the iSH2 dynamics can allosterically prevent PI3K activation in the signaling pathways. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E.
- Aliqopa (copanlisib) / Bayer
[VIRTUAL] Evaluation of the pan-class I phosphoinositide 3-kinase (PI3K) inhibitor copanlisib in the Pediatric Preclinical Testing Consortium osteosarcoma in vivo models () - Mar 11, 2021 - Abstract #AACR2021AACR_1453;
While copanlisib induced prolonged EFS in 5/6 osteosarcoma models, no tumor regression was seen, with all models developing progressive disease suggesting minimal activity. While copanlisib did not result in tumor regression, further study is needed to fully explore the role of the PI3K pathway in the pathogenesis of osteosarcoma.
- voxtalisib (SAR245409) / Sanofi, Ibrance (palbociclib) / Pfizer, Verzenio (abemaciclib) / Eli Lilly
[VIRTUAL] Targeting CDK4/6 inhibitor resistance in relapsed osteosarcoma via PI3 Kinase inhibition () - Mar 11, 2021 - Abstract #AACR2021AACR_1441;
However, tumors progressed over time while still on treatment; evaluation of PI3K pathway activation is in progress. These data provide an opportunity to evaluate efficacy of targeting CDK4/6i-induced compensatory pathways in relapsed pediatric and AYA OS.
- Estybon (rigosertib) / Onconova, SymBio Pharma, Knight Therap
[VIRTUAL] Heating it up: Targeting RAS/RAF/PI3K pathway to make melanoma tumors ‘immunologically hot’ and suitable for checkpoint blockade immunotherapies () - Mar 11, 2021 - Abstract #AACR2021AACR_1403;
Notably, multiplex IHC analysis showed that BRAF inhibitor treatment significantly induces CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. Our preclinical data support the therapeutic use of RGS plus αPD1+αCTLA4 in RAS/RAF/MEK and/or PI3K pathway-activated melanoma tumors and point to the need for clinical trials to determine the clinical benefit of RGS plus ICB for metastatic melanoma patients who do not respond to ICB alone.The authors sincerely thank Onconova Therapeutics, Newtown, PA 18940 for kindly supplying Rigosertib for this work.
- 5-fluorouracil / Generic mfg.
[VIRTUAL] Mechanistic investigation of NAP1051, a lipoxin A4 biomimetic, in treating colorectal cancer () - Mar 11, 2021 - Abstract #AACR2021AACR_1034;
The molecular MoA of NAP1051 involves ERK1/2 and AKT signaling pathways which are interrelated closely. A PI3K-independent pathway may be activated and resulted in AKT activation.
- Piqray (alpelisib) / Novartis, NT-219 / Purple Biotech
[VIRTUAL] Adaptation of colorectal cancer cells to the brain microenvironment: the role of IRS2 () - Mar 11, 2021 - Abstract #AACR2021AACR_990;
These effects may be mediated, at least in part, by modulation of the AKT and β-catenin pathway. Given the molecular signature described, the approach to patients with BMs may be significantly impacted by agents such as NT219.
- temozolomide / Generic mfg.
[VIRTUAL] SY11.OD - Developing Rational Combinations of Targeted Drugs () - Mar 11, 2021 - Abstract #AACR2021AACR_955;
P. Workman will discuss the synergistic interaction between a Bcl2 inhibitor with Pi3K/Mek combinations, augmenting Chk1 inhibition by co-inhibition of B-family DNA polymerases, the kinase off-target kinase landscape of clinical Parp and Hsp90 inhibitors, the activity in aggressive NMYC-driven neuroblastoma of the dual Cdk9/2 inhibitor fadracliclib alone and in combination with temozolomide, and the discovery through phenotypic screening of a clinical candidate Hsf1 pathway inhibitor with therapeutic potential in clear cell ovarian cancer and multiple myeloma.
- [VIRTUAL] The transcriptomic landscape of oncogenic PI3K reveals key functions in splicing and gene expression regulation () - Mar 11, 2021 - Abstract #AACR2021AACR_757;
Analysis of paired tumor biopsies from PIK3CA-mutated breast cancer patients obtained prior and during treatment with PI3K inhibitors identified extensive splicing alterations, with specific isoforms in common with our cellular models. Our atlas of the transcriptional and splicing programs downstream of the PI3K pathway and across different preclinical and clinical models provides a valuable resource for future mechanistic and translational advancements.
- [VIRTUAL] AOS01.OD - Therapeutic Vulnerabilities and Resistance Mechanisms in Estrogen Receptor-Positive Breast Cancer () - Mar 11, 2021 - Abstract #AACR2021AACR_737;
Moreover, a 2020 NextGen Star recipient will present his new, exciting findings on dual PIK3CA mutations as a hallmark of oncogene addiction and determinant of sensitivity to PI3K inhibitors. Please Note: The presentation by Maurizio Scaltriti is not eligible for CME credit.
- [VIRTUAL] A characterization of cancer vasculogenic mimicry: Extracellular matrix induced cellular signaling to lumen formation. () - Mar 11, 2021 - Abstract #AACR2021AACR_679;
Furthermore, we identified Laminin as the essential matrix protein secreted and deposited by cancer cells to allow for VM assembly. Its interaction with integrin β1, and the consequent regulation of the activity of MMP leads to the remodeling of the ECM to favor the connection of the VM channels to the microcirculation system.
- temozolomide / Generic mfg.
[VIRTUAL] SY11.DISC - Panel-- Developing Rational Combinations of Targeted Drugs (Channel 02) - Mar 11, 2021 - Abstract #AACR2021AACR_579;
P. Workman will discuss the synergistic interaction between a Bcl2 inhibitor with Pi3K/Mek combinations, augmenting Chk1 inhibition by co-inhibition of B-family DNA polymerases, the kinase off-target kinase landscape of clinical Parp and Hsp90 inhibitors, the activity in aggressive NMYC-driven neuroblastoma of the dual Cdk9/2 inhibitor fadracliclib alone and in combination with temozolomide, and the discovery through phenotypic screening of a clinical candidate Hsf1 pathway inhibitor with therapeutic potential in clear cell ovarian cancer and multiple myeloma.
- fulvestrant / Generic mfg.
[VIRTUAL] Triple combination targeting ER, CDK4/6, and PI3K inhibits tumor growth in ER+ breast cancer resistant to combined fulvestrant and CDK4/6 or PI3K inhibitor () - Mar 11, 2021 - Abstract #AACR2021AACR_555;
Our data supports the use of combined therapy with either PI3Ki or CDK4/6i and fulvestrant following progression on or after an endocrine-based regime. However, following disease progression on combined therapy with fulvestrant and either CDK4/6i or PI3Ki, triple combination targeting ER, PI3K and either CDK4/6 or CDK2 is needed to inhibit tumor progression.
- [VIRTUAL] Identification of pathways that enhance cell death in NOTCH1-mutant HNSCC () - Mar 11, 2021 - Abstract #AACR2021AACR_316;
Trametinib (MEK inhibitor) and copanlisib were synergistic with the combination leading to 0.90 fraction of cells affected at concentrations of 30nM and 100nM respectively...Likewise, low concentrations of inhibitors of EGFR (10nM afatinib, 50nM AZ5104), HER2 (25nM sapitinib, 10nM poziotinib), and PLK1 (50nM BI2536, 50nM volasertib) were both effective and additive to synergistic with PI3K inhibitors...The identified pathways may give us insight into mechanisms of resistance. If validated, these combinations may lead to the first biomarker-specific, targeted therapy for HNSCC.
- [VIRTUAL] Sub-group of ovarian cancer patients with hyperactive RAS network signaling identified: Dynamic pathway activity test identifies patients that may benefit from PI3K/mTOR or PI3K/mTOR/BCL inhibitors () - Mar 11, 2021 - Abstract #AACR2021AACR_314;
These findings suggest that a significant sub-group of OC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted.
- [VIRTUAL] Sub-group of HER2-negative breast cancer patients with hyperactive RAS network signaling identified: Dynamic pathway activity test identifies patients that may benefit from PI3K/mTOR or PI3K/mTOR/BCL inhibitors () - Mar 11, 2021 - Abstract #AACR2021AACR_290;
These findings suggest that a significant sub-group of BC patients have a RAS-involved oncogenic driver that is responsive ex vivo to pan-PI3K/mTOR and pan-PI3K/mTOR/BCL inhibitors. A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted.
- | Preclinical, Journal: ETV6/RUNX1 Fusion Gene Abrogation Decreases the Oncogenicity of Tumour Cells in a Preclinical Model of Acute Lymphoblastic Leukaemia. (Pubmed Central) - Mar 11, 2021
A clinical trial to evaluate treatment response of this patient sub-group to combined PI3K/mTOR or PI3K/mTOR/BCL inhibitors is warranted. ETV6/RUNX1 fusion protein seems to play an important role in the maintenance of the leukemic phenotype and could thus become a potential therapeutic target.
- | Preclinical, Journal, IO biomarker: ERO1α promotes testosterone secretion in hCG-stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway. (Pubmed Central) - Mar 11, 2021
Furthermore, ERO1α could activate the PI3K/AKT/mTOR signaling pathway. In summary, these results suggest that ERO1α might play proliferation promotion and antiapoptotic roles and enhance testosterone secretion in PLC, at least partly, via activation of the PI3K/AKT/mTOR signaling pathway.
- | XAV-939 / Novartis
Journal: Wnt signaling associated small molecules improve the viability of pPSCs in a PI3K/Akt pathway dependent way. (Pubmed Central) - Mar 11, 2021
In a recent study, we got a new pPSCs using two Wnt signaling pathway regulators CHIR99021 and XAV939...Our study obtained new pPSCs, which were even closer to the naïve state with only two small molecule inhibitors, and the improved pluripotency of pPSCs could facilitate transgenic manipulation and regenerative medicine research. Besides, our study casted a light on the understanding of pPSCs and the derivation of authentic porcine embryonic stem cells.
- | Preclinical, Journal: PSMC6 promotes osteoblast apoptosis through inhibiting PI3K/AKT signaling pathway activation in ovariectomy-induced osteoporosis mouse model. (Pubmed Central) - Mar 11, 2021
Besides, we found that PI3K activation significantly decreased PSMC6-induced osteoblast apoptosis and promoted cell proliferation through regulating the protein levels of p53, cyclinD1, and cleaved caspase-3/9. In conclusion, PSMC6 aggravated the degree of OVX-induced osteoporosis by inhibiting the PI3K/AKT signal transduction pathway, thereby promoting the apoptosis of osteoblasts.
- | gefitinib / Generic mfg.
Journal, PD(L)-1 Biomarker, IO biomarker: NDAT Targets PI3K-Mediated PD-L1 Upregulation to Reduce Proliferation in Gefitinib-Resistant Colorectal Cancer. (Pubmed Central) - Mar 11, 2021
(4) Gefitinib might suppress PD-L1 expression but did not inhibit proliferation through PI3K in gefitinib-resistant primary CRC cells. However, NDAT not only down-regulated PD-L1 expression via blocking PI3K activation but also inhibited cell proliferation in gefitinib-resistant CRCs.
- || Review, Journal: Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies. (Pubmed Central) - Mar 11, 2021
Overcoming these responses with careful management of insulin levels is key to successful treatment. Further interest in specific TMEs via the insulin PI3K-pathway in obese women will provide insight into not only novel therapeutic strategies but also preventive strategies against EC.
- || Clinical, Journal: Alternative signaling pathways from IGF1 or Insulin to Akt activation and Foxo1 nuclear efflux in adult skeletal muscle fibers. (Pubmed Central) - Mar 11, 2021
We also found that inhibition of the protein kinases Ack1 or ATM, contributes to the suppression of Foxo1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1 or insulin induced regulation of Foxo1 and present information useful for both therapeutic interventions for muscle atrophy, as well as further investigative areas into insulin insensitivity and type 2 diabetes.
- | Journal: PIK3CA mutations matter for cancer in dogs. (Pubmed Central) - Mar 11, 2021
Therefore, PI3K inhibitors have potential in cancer therapy for dogs. This article concisely reviews the emerging evidence concerning the genetic and molecular properties of PIK3CA mutations to discuss future perspectives in veterinary and comparative oncology.
- | Journal, IO biomarker: Antiproliferative and Pro-Apoptotic Effect of Uvaol in Human Hepatocarcinoma HepG2 Cells by Affecting G0/G1 Cell Cycle Arrest, ROS Production and AKT/PI3K Signaling Pathway. (Pubmed Central) - Mar 11, 2021
A reduction in reactive oxygen species (ROS) levels in HepG2 cells was also observed. Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer.
- | quercetin (LY294002) / Eli Lilly
Journal, IO biomarker: Protection by rhynchophylline against MPTP/MPP-induced neurotoxicity via regulating PI3K/Akt pathway. (Pubmed Central) - Mar 11, 2021
Altogether, results showed anti-proliferative and pro-apoptotic effect of uvaol on hepatocellular carcinoma, constituting an interesting challenge in the development of new treatments against this type of cancer. Rhy exerts a neuroprotective effect is partly mediated by activating the PI3K/Akt signaling pathway.
- | Journal: Phosphoinositide 3-kinases in platelets, thrombosis and therapeutics. (Pubmed Central) - Mar 11, 2021
The implication of these kinases and their lipid products in fundamental platelet biological processes and thrombosis will be discussed. Finally, the relevance of developing potential antithrombotic strategies by targeting PI3Ks will be examined.
- | Review, Journal: circ-016910 sponges miR-574-5p to regulate cell physiology and milk synthesis via MAPK and PI3K/AKT-mTOR pathways in GMECs. (Pubmed Central) - Mar 10, 2021
Finally, according to the constructed circular RNA (circRNA) libraries and bioinformatics prediction approach, we selected circ-016910 and found it acted as a sponge for miR-574-5p and blocked its relevant behaviors to undertake biological effects in GMECs. The circRNA-miRNA-mRNA network facilitates further probes on the function of miR-574-5p in mammary development and milk synthesis.
- | Review, Journal: Role of regulatory miRNAs of the PI3K/AKT/mTOR signaling in the pathogenesis of hepatocellular carcinoma. (Pubmed Central) - Mar 10, 2021
The recognition of the crucial role of miRNAs in hepatocarcinogenesis represents a promising area to identify novel anticancer therapeutics for HCC. The present study summarizes the major findings about the regulatory role of miRNAs in the PI3K/AKT/mTOR pathway in the pathogenesis of HCC.
- | sirolimus / Generic mfg.
Journal: Targeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-cell acute lymphoblastic leukemia. (Pubmed Central) - Mar 10, 2021
Phosphatidylinositol 3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β-catenin signaling pathways play a crucial role in T-cell development and in self-renewal of healthy and leukemic stem cells...ICG-001 and ZSTK-474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells...All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β-catenin and PI3K/Akt/mTOR pathways in T-ALL settings.
- | Journal: miR-210-5p promotes epithelial-mesenchymal transition by inhibiting PIK3R5 thereby activating oncogenic autophagy in osteosarcoma cells. (Pubmed Central) - Mar 10, 2021
Taken together, our results demonstrated that miR-210-5p promoted EMT and oncogenic autophagy by suppressing the expression of PIK3R5 and regulating the AKT/mTOR signaling pathway. Therefore, inhibition of miR-210-5p may represent a promising treatment for OS.
- | Journal: A cathelicidin-related antimicrobial peptide suppresses cardiac hypertrophy induced by pressure overload by regulating IGFR1/PI3K/AKT and TLR9/AMPKα. (Pubmed Central) - Mar 10, 2021
This was confirmed by a TLR9 knockout mouse experiment, in which a TLR9 knockout partly reversed the anti-hypertrophic effect of mCRAMP and completely counteracted the anti-oxidative effect of mCRAMP. In summary, mCRAMP protected against pressure overload-induced cardiac hypertrophy by activating both the IGFR1/PI3K/AKT and TLR9/AMPKa pathways in cardiomyocytes.
- || Review, Journal: The PI3K-AKT-mTOR Pathway and Prostate Cancer: At the Crossroads of AR, MAPK, and WNT Signaling. (Pubmed Central) - Mar 10, 2021
In this review, we outline the emerging diversity of the genetic alterations that lead to activated PI3K-AKT-mTOR signaling in prostate cancer, and discuss new mechanistic insights into the interplay between the PI3K-AKT-mTOR pathway and several key interacting oncogenic signaling cascades that can cooperate to facilitate prostate cancer growth and drug-resistance, specifically the androgen receptor (AR), mitogen-activated protein kinase (MAPK), and WNT signaling cascades. Ultimately, deepening our understanding of the broader PI3K-AKT-mTOR signaling network is crucial to aid patient stratification for PI3K-AKT-mTOR pathway-directed therapies, and to discover new therapeutic approaches for prostate cancer that improve patient outcome.
- | quercetin (LY294002) / Eli Lilly
Journal, IO biomarker: Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3β signaling pathway. (Pubmed Central) - Mar 10, 2021
Interestingly, co-treatment with PI3K inhibitor of LY294002 counteracted those effects induced by syringic acid. In conclusion, pretreatment with syringic acid can mitigate myocardial ischemia reperfusion injury by inhibiting mitochondria-induced apoptosis which is regulated by the PI3K/Akt/GSK-3β signaling pathway.
- Piqray (alpelisib) / Novartis
[VIRTUAL] Metformin (MF) in the prevention of hyperglycemia (HG) in patients (pts) with PIK3CA-mutated, hormone receptor (HR)[+]/HER2[–] advanced breast cancer (ABC) treated with alpelisib (ALP) plus fulvestrant (F): METALLICA () - Mar 9, 2021 - Abstract #ESMOBC2021ESMO_BC_284;
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The stage II will be conducted if G3/4 HG after the first 2 cycles are observed in ≤3 pts of 23 in cohort A and ≤2 pts of 7 in cohort B. The final analysis will be defined as positive if ≤6 pts of 48 in cohort A and ≤4 pts of 20 in cohort B have G3/4 HG. The Simon two-stage design was planned to attain an 80% power at 5% nominal alpha level.
- [VIRTUAL] Is evaluation of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutational status on circulating tumor DNA (ctDNA) by liquid biopsy ready for prime-time? A systematic review and an individual patient meta-analysis () - Mar 9, 2021 - Abstract #ESMOBC2021ESMO_BC_182;
We would suggest the use of NGS rather than conventional RT-PCR to screen for the presence of a PIK3CA mutation in BC patients. Finally, given the not well-established applications of ctDNA analysis in the clinical management of BC, this meta-analysis could add intriguing insights supporting the introduction of liquid biopsy in clinical practice as a routine procedure.
- ||| Clinical: I’m struggling to get patients through single-agent PI3K inhibitor to be honest. (Twitter) - Mar 9, 2021
- |||| Clinical: We propose the combination of PI3K-alpha and mTOR inhibitors (using low doses of mTOR inhibitor) in patients bearing these genomic alterations in breast cancer. Also thanks to @FlaviaMichelini @castel_pau @FAndreMD @EnedaToska and many others. (Twitter) - Mar 9, 2021
- | pictilisib (GDC-0941) / Roche
Journal: Design, synthesis and biological evaluation of substituted 2-(thiophen-2-yl)-1,3,5-triazine derivatives as potential dual PI3Kα/mTOR inhibitors. (Pubmed Central) - Mar 9, 2021
And western blot analysis indicated compound 13g could efficiently suppress the phosphorylation of AKT at the dose of 0.1 µM, which further demonstrated compound 13g had significant inhibitory effect on the PI3K/Akt/mTOR pathway. Furthermore, compound 13g could stimulate A549 cells arrest at G0/G1 phase in a dose-dependent manner, and induced apoptosis at a low concentration.
- | Journal: α5-nAChR modulates melanoma growth through the Notch1 signaling pathway. (Pubmed Central) - Mar 9, 2021
Moreover, we confirmed that the Notch1 signaling pathway is the downstream target of α5-nAChR in melanoma. Our findings suggest that α5-nAChR plays a critical role in melanoma development and progression, and that targeting α5-nAChR may be a strategy for melanoma treatment.
- | Nerlynx (neratinib) / Puma, Knight Therap, Pierre Fabre
Journal: Neratinib degrades MST4 via autophagy that reduces membrane stiffness and is essential for the inactivation of PI3K, ERK1/2, and YAP/TAZ signaling. (Pubmed Central) - Mar 9, 2021
P1/2
Beclin1 knockdown prevented MST4 degradation, Ezrin dephosphorylation and neratinib-induced alterations in tumor cell morphology. Our findings demonstrate that neratinib enhances LATS1/2 phosphorylation independently of RAP2A/MAP4K4 and that MST4 degradation and Ezrin dephosphorylation may represent a universal trigger for the biological actions of neratinib.