- |||||||||| indisulam (E7070) / Eisai, RVT-2001 / Roivant, dactolisib (RTB101) / Adicet Bio
m6A-modified circTET2 interacting with HNRNPC regulates fatty acid oxidation to promote the proliferation of chronic lymphocytic leukemia (Hynes Convention Center Meeting Room 302/304. Level 3 900 Boylston St., Boston, MA) - Aug 14, 2023 - Abstract #IWCLL2023IWCLL_135;
CircTET2 that was upregulated in CLL was modulated by the splicing factors RBMX and YTHDC1, and that circTET2 interacted with HNRNPC, occupying a vital role in the modulation of lipid metabolism and cell proliferation of CLL. The data generated by this study collectively provide new evidence for a role and underlying mechanism for circRNAs in CLL lipid metabolism, and this may engender novel potential targets in clinical treatment.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal, Metastases: UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease. (Pubmed Central) - May 22, 2023
Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.
- |||||||||| Votrient (pazopanib) / Novartis, motesanib (AMG 706) / Takeda, dactolisib (RTB101) / Adicet Bio
Biomarker, Journal: The Expression of ARMCX1 in Gastric Cancer Contributes to Prognosis and Influences Chemotherapy. (Pubmed Central) - Feb 3, 2023
Among which, ARMCX1 exhibited great potential to serve as a prognostic biomarker for gastric patients; furthermore, patients with low expression of ARMCX1 could be more sensitive to these 9 chemotherapeutic agents: A-770041, AMG-706, ATRA, BEZ235, bortezomib, CGP60474, dasatinib, HG-64-1, and pazopanib, rather than the other chemotherapeutic agents. This study helps the improvement of evaluating the prognosis of gastric cancer patients, and would help optimize chemotherapeutic strategies in consideration of the expression of ARMCX1.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal: NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2). (Pubmed Central) - Dec 12, 2022
In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, dactolisib (RTB101) / Adicet Bio
Journal: Microfluidic-based dynamic BH3 profiling predicts anticancer treatment efficacy. (Pubmed Central) - Dec 2, 2022
We then validated µDBP on a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic priming. In summary, this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform DBP in situ as a routine assay to identify the best treatment for cancer patients.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Preclinical, Journal: BEZ235 Prolongs Murine Cardiac Allograft Survival Through the Autophagy Pathway. (Pubmed Central) - Nov 9, 2022
It seems BEZ235 could induce autophagy and prolonged murine cardiac allograft survival in a mechanism that involved the autophagy pathway and changed multiple inflammatory factors. This study has proposed a theoretical foundation for the strong connection between mTOR-induced autophagy and heart transplant.
- |||||||||| Pharmacological Modulation of CD21 Antigen Density Enhances Chimeric Antigen Receptor (CAR-T) Cell Function (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2845;
We therefore incubated six T-ALL cell lines with four inhibitors of the PI3K/mTOR/AKT pathway (AZD5363, GDC0941, BEZ235 and rapamycin) for 48 and 72hrs and showed surface CD21 up-regulation by flow cytometry of > two-fold at both time points for all inhibitors, with BEZ235 showing the greatest fold increases across all cell lines...When clinically approved PI3K inhibitors (Idelalisib, Duvelisib, Copanlisib, Everolimus) were used, an increase in CD21 expression was again seen across 5 T-ALL cell lines tested...In vivo models analyzing the impact of copanlisib tumor priming on CAR-T efficacy and persistence are ongoing. Target antigen modulation is a promising strategy for enhancing CAR efficacy and reducing risk of antigen negative relapse in low antigen density targets.
- |||||||||| voxtalisib (SAR245409) / Sanofi, apitolisib (GDC-0980) / Roche, dactolisib (RTB101) / Adicet Bio
Journal, IO biomarker: Integrative genomic analysis facilitates precision strategies for glioblastoma treatment. (Pubmed Central) - Oct 28, 2022
Furthermore, the GBM classification and GPS score model could be considered as potential biomarkers for immunotherapy response. In summary, an integrative genomic analysis was conducted to advance individual-based therapies in GBM.
- |||||||||| PI-103 / Roche, Zydelig (idelalisib) / Gilead, dactolisib (RTB101) / Adicet Bio
Journal: mTORC2 Is the Major Second Layer Kinase Negatively Regulating FOXO3 Activity. (Pubmed Central) - Sep 18, 2022
Furthermore, specific inhibition of mTOR kinase activity affecting both mTORC1 and mTORC2 potently induced nuclear translocation of FOXO3, while rapamycin, which specifically inhibits the mTORC1, failed to affect FOXO3...We also measured the effect of the test compounds on the phosphorylation status of AKT, FOXO3 and ERK, on FOXO-dependent transcriptional activity and on the subcellular localization of other FOXO isoforms. We conclude that mTORC2 is the most important second layer kinase negatively regulating FOXO activity.
- |||||||||| Odomzo (sonidegib) / Sun Pharma, TriptoSar (triptolide) / Pierre Fabre, dactolisib (RTB101) / Adicet Bio
Review, Journal, Cancer stem cells: Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective. (Pubmed Central) - Sep 10, 2022
Thus, combining inhibition of critical genes and proteins can be a potential therapy strategy. Therefore, functioning of γ-secretase inhibitors (GSI-IX, Presenilin1/2, Pen-2, Nicastrin, APH-1), BEZ235, GANT61 inhibitor, NVP-LDE225, GSK3β inhibitor, AMPK activator (Aza- podophyllotoxin, demethoxycurcumin, N, N-diarylurea FND-4b) and MYC inhibitors (Triptolide, Quinoxalines) in TNBC are reviewed extensively.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal: Jagged-1 is induced by mTOR inhibitors in renal cancer cells through an Akt/ALK5/Smad4-dependent mechanism. (Pubmed Central) - Aug 24, 2022
Here we provide the first report that expression of the Notch ligand Jagged-1 (JAG1), which is associated with aggressiveness of RCCs, is induced by several inhibitors of mTOR (rapamycin (Rap), BEZ235, KU-0063794) in human clear cell RCC (ccRCC) cells...Moreover, inhibition of Notch signaling with γ-secretase inhibitors enhanced or permitted mTOR inhibitors to suppress the motility of ccRCC cells. We suggest targeting JAG1 may enhance therapeutic responses to mTOR inhibitors in ccRCCs.
- |||||||||| Preclinical, Journal: Novel patient-derived xenograft and cell line models for therapeutic screening in NF2-associated schwannoma. (Pubmed Central) - Aug 3, 2022
Furthermore, we demonstrated two orally bioavailable inhibitors AZD8055 and PQR309 suppressed NF2-associated schwannoma growth both in vitro and in vivo. In conclusion, our novel patient-derived models of NF2-associated schwannoma closely mimic the phenotypes and genotypes of patient tumors, making them reliable preclinical tools for testing novel personalized therapies.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Investigating NVP-BEZ235 on aggressive subtypes of Lung Cancer (Poster Area) - Jun 28, 2022 - Abstract #EACR2022EACR_944;
Conclusion Protein analysis is currently being implemented on the treated cells to investigate the effect of the drug on proteins related to the drug mechanism. Additionally, the drug’s potential in reducing metastatic ability in such aggressive subtypes is also being studied using cell invasion assays.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie
Journal: Targeting PI3K/AKT/mTOR pathway to enhance the anti-leukemia efficacy of venetoclax. (Pubmed Central) - Jun 22, 2022
Additionally, the drug’s potential in reducing metastatic ability in such aggressive subtypes is also being studied using cell invasion assays. The combination of BEZ235 and ABT199 exhibits a synergistic anti-tumor effect in AML by down-regulating MCL-1 protein.
- |||||||||| LY294002 / Eli Lilly, dactolisib (RTB101) / Adicet Bio
Journal: Dual inhibition of autophagy and PI3K/mTOR pathway as a potential therapeutic strategy against laryngeal squamous cell carcinoma. (Pubmed Central) - Jun 22, 2022
When combined with various autophagy inhibitors, along with siRNA against ATG7, NVP-BEZ235 showed a synergic antitumor effect in LSCC through increasing cell apoptosis and death both in vitro and vivo. NVP-BEZ235 exerted potent antitumor effects on LSCC, especially when combined with the autophagy inhibitor both in vitro and vivo, providing convincing experimental data for new molecular targeted therapy for LSCC.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Preclinical, Journal: Maturation of induced pluripotent stem cell-derived cardiomyocytes and its therapeutic effect on myocardial infarction in mouse. (Pubmed Central) - Jun 18, 2022
Subsequently, we combined the PI3K/AKT/mTOR pathway inhibitor BEZ-235 with Gel and found that the two combined increased the sarcomere length and action potential amplitude (APA) of iPSC-CMs, and improved the Ca processing ability, the maturation of mitochondrial morphological structure and metabolic function. Not only that, Gel can also prolong the retention rate of iPSC-CMs in the myocardium and increase the expression of Cx43 and angiogenesis in the transplanted area of mature iPSC-CMs, which also provides a reliable basis for the subsequent treatment of mature iPSC-CMs.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal: Development and validation of an RNA-seq-based transcriptomic risk score for asthma. (Pubmed Central) - May 25, 2022
Further in-silico analyses of the 73 genes using Connectivity map shows that drugs (mepacrine, dactolisib) and genetic perturbagens (PAK1, GSR, RBM15 and TNFRSF12A) were identified and could potentially be repurposed for treating asthma. These findings show the promise for RNA-seq risk scores to stratify and predict disease risk.
- |||||||||| ibrutinib / Generic mfg.
Review, Journal: Ibrutinib in the Treatment of Solid Tumors: Current State of Knowledge and Future Directions. (Pubmed Central) - Apr 30, 2022
Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better.
- |||||||||| AZD8055 / AstraZeneca, buparlisib (BKM120) / Novartis, Adlai Nortye, dactolisib (RTB101) / Adicet Bio
Preclinical, Journal: In vitro effect of PIK3CA/mTOR inhibition in triple-negative breast cancer subtype cell lines. (Pubmed Central) - Apr 19, 2022
Additionally, sCLU-overexpressing HCC might be susceptible to mTOR inhibition. This study identified that the Luminal androgen receptor subtype of triple-negative breast cancer with PIK3CA mutation may be targeted with PIK3CA inhibitors with a favorable outcome.
- |||||||||| SPR965 / Sphaera Pharma
SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma (Section 16) - Mar 9, 2022 - Abstract #AACR2022AACR_2472;
In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity.
- |||||||||| Yondelis (trabectedin) / Otsuka, PharmaMar, Valeo Pharma, dactolisib (RTB101) / Adicet Bio
Clinical, Journal: Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma. (Pubmed Central) - Mar 8, 2022
Proof-of principal efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal: BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells. (Pubmed Central) - Mar 4, 2022
The data indicated that the abnormal activation of ATM/ATR/DNA-PKcs kinases and AKT/mTOR pathway might induce wtEGFR NSCLC cell resistance to cisplatin. The effects of the combination of BEZ235 and cisplatin suggested that BEZ235 should be considered as a combination therapy for patients with cisplatin-resistant wtEGFR NSCLC.
- |||||||||| AG1478 / IDT Australia, navitoclax (ABT 263) / AbbVie, dactolisib (RTB101) / Adicet Bio
Journal: Selective therapeutic benefit of X-rays and inhibitors of EGFR, PI3K/mTOR, and Bcl-2 in breast, lung, and cervical cancer cells. (Pubmed Central) - Mar 3, 2022
It was found that breast cancer cell lines were more sensitive to X-ray irradiation, whilst cervical and lung cancer cell lines were more sensitive to EGFR and PI3K/mTOR inhibitor therapy. These data suggest that patients with breast cancer possessing similar characteristics to MDA-MB-231 and MCF-7 cells may derive therapeutic benefit from X-ray irradiation, whilst EGFR and PI3K/mTOR inhibitor therapy may potentially benefit cancer patients possessing cancers similar to HeLa and A549 cells.
- |||||||||| Venclexta (venetoclax) / Roche, AbbVie, AZD5991 / AstraZeneca, dactolisib (RTB101) / Adicet Bio
Journal, IO biomarker: Inhibition of MCL1 induces apoptosis in anaplastic large cell lymphoma and in primary effusion lymphoma. (Pubmed Central) - Mar 3, 2022
The combination of specific BH3 mimetics yielded synergistic effects, pointing to a novel strategy for the treatment of ALCL. The PI3K/mTOR inhibitor BEZ-235 could also efficiently be applied in combination with AZD-5991, offering an alternative to avoid thrombocytopenia which is associated with the use of BCLXL inhibitors.
- |||||||||| JQ-1 / Roche, dactolisib (RTB101) / Adicet Bio
Journal: BET protein inhibition evidently enhances sensitivity to PI3K/mTOR dual inhibition in intrahepatic cholangiocarcinoma. (Pubmed Central) - Feb 22, 2022
As a novel phosphoinositide 3-kinase (PI3K)/mTOR dual inhibitor, BEZ235, exerts antitumour activity by effectively and specifically blocking the dysfunctional activation of the PI3K/serine/threonine kinase (AKT)/mTOR pathway...However, Bromo- and extraterminal domain (BET) inhibition by JQ1 downregulates c-Myc and YAP transcription, which could enhance the efficacy of PI3K/mTOR inhibitors...Our data further confirmed that the combination of PI3K/mTOR dual inhibitor and BET inhibition induces M1 polarization and suppresses M2 polarization in macrophages by regulating the expression of HIF-1α. Our study provides a novel and efficient therapeutic strategy in treating primary ICC.
- |||||||||| pictilisib (GDC-0941) / Roche, dactolisib (RTB101) / Adicet Bio
Clinical, Journal: Level of Decoy Receptor 3 for Monitoring Clinical Progression of Severe Burn Patients. (Pubmed Central) - Feb 11, 2022
To explore the mechanisms, the HaCaT or THP-1 cells were stimulated by the plasma of burn patients, 45°C, LPS or stimulators of TLRs or NOD2 (PGN, CL264, MDP, iE-DAP, Gardiquimod), and their DcR3 was increased, which could be reduced by GDC-0941 or BEZ235 (inhibitors of PI3K and mTOR). The levels of DcR3 appeared to be a useful biomarker for monitoring the clinical severity and a predictor of mortality of severe burns.
- |||||||||| Nexavar (sorafenib) / Bayer, Amgen
Biomarker, Review, Journal: New frontiers against sorafenib resistance in renal cell carcinoma: From molecular mechanisms to predictive biomarkers. (Pubmed Central) - Feb 10, 2022
Herein, we comprehensively summarize the underlying mechanisms of sorafenib resistance and molecular biomarkers for predicting sorafenib responsiveness. Moreover, we outline strategies suitable for overcoming sorafenib resistance and prospect potential approaches for identifying biomarkers associated with sorafenib resistance in RCC, which contributes to guide individualized and precision drug therapy.
- |||||||||| imatinib / Generic mfg.
Journal: Oncogene-independent resistance in Philadelphia chromosome - positive (Ph) acute lymphoblastic leukemia (ALL) is mediated by activation of AKT/mTOR pathway. (Pubmed Central) - Feb 4, 2022
Tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, dasatinib, and ponatinib have significantly improved the life expectancy of Philadelphia chromosome-positive (Ph) acute lymphocytic leukemia (ALL) patients; however, resistance to TKIs remains a major clinical challenge...Here we report the development of a nonmutational resistance cell line SupB15-RT; conferring resistance to approved ABL kinase inhibitors (AKIs) and allosteric inhibitors GNF-2, ABL001, and crizotinib, except for dasatinib (IC90 50nM), a multitarget kinase inhibitor...Furthermore, Torin-1 and NVP-BEZ235 induced apoptosis in PH and BV cells but not in HP cells. Our experiments provide evidence of the involvement of AKT/mTOR pathway in the evolution of nonmutational resistance in Ph ALL which will assist in developing novel targeted therapy for Ph ALL patients with BCR-ABL1 independent nonmutational resistance.
- |||||||||| dactolisib (RTB101) / Adicet Bio
Journal: NVP-BEZ235 Inhibits Renal Cell Carcinoma by Targeting TAK1 and PI3K/Akt/mTOR Pathways. (Pubmed Central) - Jan 28, 2022
We conclude that besides PI3K/Akt/mTOR signaling, NVP-BEZ235, and PP242 simultaneously target TAK1-dependent pathways in RCC cells. Notably, these effects were more marked in the presence of NVP-BEZ235 than PP242, indicating the potential application of NVP-BEZ235 in combination therapy for RCC.
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