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  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  Glutaminase Inhibition on NSCLC Depends on Extracellular Alanine Exploitation. (Pubmed Central) -  Apr 1, 2021   
    Even though specific genetic lesions such as in KRAS and LKB1 have been associated with reliance on glutamine for their metabolic needs, we found no distinction between glutaminase inhibitor CB-839 sensitivity and resistant phenotypes in NSCLC cells with or without these genetic alterations...This response depended on the individual cell's ability to employ alanine aminotransferase (GPT2) to compensate the reduced glutamate availability. It may, therefore, be useful to determine GPT2 levels to predict which NSCLC patients would benefit most from glutaminase inhibitor treatment.
  • ||||||||||  telaglenastat (CB-839) / Calithera, Talzenna (talazoparib) / Pfizer
    New P2 trial, Combination therapy, Metastases:  Telaglenastat + Talazoparib In Prostate Cancer (clinicaltrials.gov) -  Apr 1, 2021   
    P2,  N=30, Not yet recruiting, 
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  A powerful drug combination strategy targeting glutamine addiction for the treatment of human liver cancer. (Pubmed Central) -  Mar 16, 2021   
    However, targeting glutamine addiction using the glutaminase inhibitor CB-839 as monotherapy had a very limited anticancer effect, even against the most glutamine addicted human liver cancer cells...Moreover, this combination also showed tumor inhibition in HCC xenograft mouse models in vivo. Our findings indicate that dual inhibition of glutamine metabolism by targeting both glutaminase and glutamine transporter ASCT2 represents a potential novel treatment strategy for glutamine addicted liver cancers.
  • ||||||||||  sirolimus / Generic mfg.
    [VIRTUAL] Bi-Steric mTORC1-Selective Inhibitors Demonstrate Improved Potency and Anti-Tumor Activity in Lung Diseases with mTORC1 Hyperactivation () -  Mar 14, 2021 - Abstract #ATS2021ATS_4102;    
    RMC-5552 is the first clinical candidate of this class and clinical testing is planned in 2021...Two months after treatment cessation, all mice treated with the bi-steric mTORC1 inhibitors were still alive, whereas survival was reduced in rapamycin and MLN0128 groups due to LAM burden...This is the first time that clear evidence for cell death after mTORC1 inhibition has been seen in TSC loss-of-function rodent models.In summary, RM-001 and RM-006 demonstrate improved inhibition of mTORC1 in comparison to rapamycin and induced more cell death in Tsc2-null tumors in vivo. These preclinical data suggest that bi-steric mTORC1-selective inhibitors may represent a novel therapeutic strategy to treat LAM and lung tumors with mTORC1 dysregulation.
  • ||||||||||  telaglenastat (CB-839) / Calithera, IACS-010759 / UT MD Anderson Cancer Center
    [VIRTUAL] Exploiting oncogene-conferred glutamine addiction as a therapeutic vulnerability in resistant mantle cell lymphoma () -  Mar 11, 2021 - Abstract #AACR2021AACR_3715;    
    In conclusion, we report that glutaminolysis and OXPHOS are upregulated in IBN-R MCL that could be partially due to high expression of GLS1. Our preliminary results revealed that the GLS inhibitor, CB-839, may present a clinical potential for a new indication and the combinatory treatment with our in-house inhibitor, IACS-010759, warrants more in-depth investigation as a novel therapeutic regimen.
  • ||||||||||  sirolimus / Generic mfg.
    [VIRTUAL] Bi-steric mTORC1-selective inhibitors demonstrate improved potency and efficacy in tumors with mTORC1 hyperactivation () -  Mar 11, 2021 - Abstract #AACR2021AACR_2889;    
    RMC-5552 is the first clinical candidate of this class and clinical testing is planned in 2021...Rapamycin, MLN0128 and both RM compounds markedly reduced kidney tumor burden in Tsc2+/- A/J mice after four weeks of treatment...This is the first time that clear evidence for cell death after mTORC1 inhibition has been seen in TSC rodent models. In summary, RM-001 and RM-006 demonstrate improved in vitro and in vivo inhibition of mTORC1 in comparison to rapamycin, and induced more cell death in TSC2 null tumors in vivo, indicating the potential of bi-steric mTORC1-selective inhibitors as a novel therapeutic strategy to treat tumors with mTORC1 dysregulation.
  • ||||||||||  Mekinist (trametinib) / Novartis, sapanisertib (TAK-228) / Takeda
    Journal:  Prognosis and regulation of an adenylyl cyclase network in acute myeloid leukemia. (Pubmed Central) -  Mar 9, 2021   
    Drug sensitivity tests showed that fasudil plus trametinib or sapanisertib had a synergistic effect suppressing AML cell viability and increasing apoptosis. These findings suggest that dysregulation of ADCY expression leads to altered signaling in the MAPK pathway in AML and that the ADCY expression profile may be predictive of prognosis in AML patients.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  SIRT7-mediated modulation of glutaminase 1 regulates TGF-β-induced pulmonary fibrosis. (Pubmed Central) -  Mar 2, 2021   
    Lastly, administration of the GLS1 inhibitor CB-839 attenuated bleomycin-induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF-β-dependent manner.
  • ||||||||||  sirolimus / Generic mfg.
    Journal:  Low-Level Ionizing Radiation Induces Selective Killing of HIV-1-Infected Cells with Reversal of Cytokine Induction Using mTOR Inhibitors. (Pubmed Central) -  Feb 25, 2021   
    Further, mTORi were found to enhance the selective killing of HIV-1-infected myeloid and T-cell reservoirs at the exclusion of uninfected cells, potentially via inhibition of viral transcription/translation and induction of autophagy. Collectively, the proposed regimen using cART, IR, and mTORi presents a novel approach allowing for the targeting of viral reservoirs, prevention of immune hyper-activation, and selectively killing latently infected HIV-1 cells.
  • ||||||||||  pidnarulex (CX-5461) / Cylene, Senhwa Biosci, sapanisertib (TAK-228) / Takeda
    Journal:  Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma. (Pubmed Central) -  Feb 25, 2021   
    Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.
  • ||||||||||  sapanisertib (CB-228) / Calithera
    Trial completion date:  Study of TAK-228 (MLN0128) in Soft Tissue Sarcomas (clinicaltrials.gov) -  Feb 24, 2021   
    P2,  N=6, Active, not recruiting, 
    Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment. Trial completion date: Sep 2020 --> Sep 2021
  • ||||||||||  sapanisertib (TAK-228) / Takeda
    Journal:  Regulating T Cell Population Alleviates SLE by Inhibiting mTORC1/C2 in MRL/lpr Mice. (Pubmed Central) -  Feb 20, 2021   
    INK128 effectively suppressed mTORC1 and mTORC2 activity in T cells, but rapamycin just suppressed mTORC1 activity. Thus, our results show that INK128 is can effectively alleviate SLE and be used as one of the potential clinical therapeutic candidates for SLE.
  • ||||||||||  sapanisertib (TAK-228) / Takeda, quisinostat (JNJ 26481585) / J&J, ChemRar
    Journal:  Modulation of mTOR and epigenetic pathways as therapeutics in gallbladder cancer. (Pubmed Central) -  Feb 13, 2021   
    We screened two focused small-molecule libraries that target these two pathways using GBC cell lines and identified the mTOR inhibitor INK-128 and the histone deacetylase (HDAC) inhibitor JNJ-26481585 as compounds that inhibited proliferation at low concentrations...Both synergized with the standard of care chemotherapeutic agent gemcitabine in cell lines and in mouse models...Phosphorylated mTOR or p-S6K1 in clinical samples is an independent indicator for overall survival in GBC patients. Taken together, our findings suggest that mTOR inhibitors and HDAC inhibitors can serve as potential therapeutics for GBC, and the phosphorylation of mTOR and S6K1 may serve as biomarkers for GBC.
  • ||||||||||  sapanisertib (CB-228) / Calithera, serabelisib (MLN1117) / Takeda, Eli Lilly
    Enrollment closed:  X31025: Evaluation of the Safety and Tolerability of TAK-228 With TAK-117 and Paclitaxel in Advanced Solid Tumors (clinicaltrials.gov) -  Feb 10, 2021   
    P1,  N=30, Active, not recruiting, 
    Moreover, our study demonstrates the usefulness of in vitro pharmaco-metabolomics to score target specificity of compounds thereby refining drug development and risk assessment. Recruiting --> Active, not recruiting
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  5-fluorouracil enhances the anti-tumor activity of the glutaminase inhibitor CB-839 against PIK3CA-mutant colorectal cancers. (Pubmed Central) -  Feb 3, 2021   
    Although not designed to test efficacy, an exploratory analysis of the phase I data showed a trend that PIK3CA-mutant CRC patients might derive greater benefit from this treatment strategy as compared to PIK3CA WT CRC patients. These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRCs and warrants further clinical evaluation.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Trial completion, Combination therapy, Metastases:  ENTRATA: CB-839 With Everolimus vs. Placebo With Everolimus in Participants With Renal Cell Carcinoma (RCC) (clinicaltrials.gov) -  Feb 2, 2021   
    P2,  N=63, Completed, 
    These results effectively demonstrate that targeting glutamine metabolism may be an effective approach for treating patients with PIK3CA-mutant CRCs and warrants further clinical evaluation. Active, not recruiting --> Completed
  • ||||||||||  CB-280 / Calithera
    Trial completion date, Trial primary completion date:  Study to Evaluate the Safety of CB-280 in Patients With Cystic Fibrosis (clinicaltrials.gov) -  Jan 28, 2021   
    P1b,  N=32, Recruiting, 
    Active, not recruiting --> Completed Trial completion date: Feb 2021 --> Dec 2021 | Trial primary completion date: Feb 2021 --> Dec 2021