- |||||||||| gefitinib / Generic mfg.
Journal, PD(L)-1 Biomarker, IO biomarker: Gefitinib Reverses PD-L1-Mediated Immunosuppression Induced by long-term Glutamine blockade in Bladder Cancer. (Pubmed Central) - Oct 29, 2024
Combination treatment of JHU083 and gefitinib reversed the up-regulation of PD-L1 in bladder cancer cells induced by prolonged glutamine blockade, resulting in the alleviation of T-cell immunosuppression and a significant improvement in therapeutic outcome. These preclinical findings show promise for glutamine metabolism targeting as a viable therapeutic strategy for bladder cancer, with the potential for further enhancement through combined treatment with gefitinib.
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
Journal: Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer. (Pubmed Central) - Jul 23, 2024
Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.
- |||||||||| telaglenastat (CB-839) / Calithera, JHU083 / Johns Hopkins University, AstraZeneca
Review, Journal: Glutaminase - A potential target for cancer treatment. (Pubmed Central) - Jun 28, 2024
Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.
- |||||||||| telaglenastat (CB-839) / Calithera, JHU083 / Johns Hopkins University, AstraZeneca
Alpha-Ketoglutarate is a master regulator of epigenetic reprogramming in pancreatic ductal adenocarcinoma progression (Section 17) - Mar 5, 2024 - Abstract #AACR2024AACR_7092;
Together, these data suggest that decreasing AKG in PDAC distant metastasis cells, through glutamine deprivation or JHU083, leads to chromatin changes that specify less malignant phenotypes, providing a rationale for targeting glutamine metabolism as a therapy for late-stage PDAC. *APF and MM are co-corresponding authors.
- |||||||||| telaglenastat (CB-839) / Calithera, JHU083 / Johns Hopkins University, AstraZeneca, IPN60090 / UT MD Anderson Cancer Center, Ipsen
Co-targeting asparagine and glutamine metabolism is a viable treatment strategy for PI3K/PTEN mutated cervical cancer (Section 12) - Mar 5, 2024 - Abstract #AACR2024AACR_5940;
This study suggests a potential strategy for improving the treatment of PI3K-AKT-altered cervical tumors by targeting glutamine and asparagine metabolism in combination with standard therapies. These treatment strategies are currently being evaluated in vivo using a patient derived xenograft model with PIK3CA E545K mutation as well as an immunocompetent cervical tumor model in mice with PTEN deletion.
- |||||||||| TT-301 / OPKO Health
Biomarker, Phase classification, Trial completion date: Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) (clinicaltrials.gov) - Dec 12, 2023
P2, N=120, Recruiting,
These treatment strategies are currently being evaluated in vivo using a patient derived xenograft model with PIK3CA E545K mutation as well as an immunocompetent cervical tumor model in mice with PTEN deletion. Phase classification: P2a --> P2 | Trial completion date: Jun 2026 --> Oct 2026
- |||||||||| RG2833 / BioMarin, Johns Hopkins University
Schlafen11 is a powerful biomarker of chemosensitivity in medulloblastomas (Room 121-122) - Nov 11, 2023 - Abstract #SNO2023SNO_1515;
Importantly, markedly increased sensitivity to cisplatin and SN-38 was seen in initially SLFN11-negative medulloblastoma cells also treated with RG2833, suggesting an approach by which more aggressive medulloblastoma subtypes might be targeted. Our findings suggest a novel mechanism for the increased chemosensitivity of some medulloblastoma subtypes linked to a specific biomarker, as well as a novel combinatorial chemotherapeutic strategy for the treatment of more aggressive medulloblastoma subtypes (Groups 3 and 4) lacking SLFN11.
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
Leveraging metabolic vulnerabilities induced by TERT expression for glioblastoma therapy in vivo. (Exhibit Hall A/B) - Nov 11, 2023 - Abstract #SNO2023SNO_1181;
This effect is specific to TERT-expressing GBM cells because the combination of DON and BSO does not affect viability of normal astrocytes or astrocytomas that use the ALT pathway for telomere maintenance. Importantly, in vivo stable isotope tracing confirmed that combined treatment with JHU-083 (a brain-penetrant prodrug of DON) and BSO abrogates synthesis of GSH, aspartate, and pyrimidine nucleotides from [U-13C]-glutamine and induces apoptotic death in mice bearing intracranial GBM6 tumors.Collectively, our studies highlight the therapeutic potential of targeting metabolic vulnerabilities induced by TERT expression in GBMs in vivo.
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
Glutamine blockade and anti-PD1 treatment reprograms the tumor infiltrating myeloid cells in mouse model of soft tissue sarcomas (Exhibit Hall B) - Sep 27, 2023 - Abstract #SITC2023SITC_1181;
3 We used JHU083, a novel prodrug of a glutamine antagonist (6-Diazo-5-oxo-L-norleucine) to rid the TME of glutamine and interrogate its downstream effects on the TIME...Transcriptional changes upon glutamine blockade, especially upregulation of Apoe, a key apolipoprotein implicated in cholesterol transport points towards rewiring of metabolism of the myeloid cells. This hints that the heterogenous metabolome/lipidome might hold clues to the differential responses to glutamine blockade in the myeloid subsets.
- |||||||||| acriflavine / Johns Hopkins University
Preclinical, Journal: Targeting hypoxia-inducible factors with 32-134D safely and effectively treats diabetic eye disease in mice. (Pubmed Central) - Jul 4, 2023
However, while the HIF inhibitor acriflavine prevented retinal vascular hyperpermeability in diabetic mice for several months following a single intraocular injection, accumulation of acriflavine in the retina resulted in retinal toxicity over time, raising concerns for its use in patients...Intraocular administration of 32-134D prevented retinal neovascularization and vascular hyperpermeability in mice. These results provide the foundation for clinical studies assessing 32-134D for the treatment of patients with diabetic eye disease.
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
Journal: T cell metabolic reprogramming in acute kidney injury and protection by glutamine blockade. (Pubmed Central) - May 11, 2023
Given a convergent role for glutamine in T cell metabolic pathways and the availability of a relatively safe glutamine antagonist JHU083, effects on AKI were evaluated...In vitro hypoxia demonstrated upregulation of glycolysis-related enzymes. T cells undergo metabolic reprogramming during AKI, and reconstitution of metabolism by targeting T cell glutamine pathway could be a promising novel therapeutic approach.
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
ZFTA-RELA fusion aberrantly drives glutamine metabolism in lethal pediatric ependymomas (Section 11; Poster Board #20) - Mar 14, 2023 - Abstract #AACR2023AACR_8689;
Moreover, JHU-083, a specific pharmacologic inhibitor of glutaminase, killed ZFTA-RELAFUS tumor cells in vitro and in vivo. To summarize, our results suggest that the ZFTA-RELA fusion expressing tumor cells exhibit strong glutamine dependence, and targeting it has significant therapeutic relevance.
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Trial completion, Trial completion date: CSSC-004: Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (clinicaltrials.gov) - Jan 31, 2023
P2, N=1225, Completed,
These data identify altered glutamine metabolism as a target in FLC, and may provide an explanation for immune suppression seen in the FLC tumor microenvironment. Active, not recruiting --> Completed | Trial completion date: Sep 2022 --> Dec 2022
- |||||||||| JHU083 / Johns Hopkins University, AstraZeneca
Preclinical, Journal: In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. (Pubmed Central) - Dec 17, 2022
Infusions with [amide-N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.
- |||||||||| HDAC Inhibition Involves CD26 Induction on Multiple Myeloma Cells Via the c-Myc/Sp1-Mediated Prompter Activation and Overcomes Therapeutic Resistance By Humanized Antibody (ENMCC - Hall D) - Nov 4, 2022 - Abstract #ASH2022ASH_2199;
Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), cultured alone, the increased expression in CD26 levels of MM cells was detectable within 24 hr of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA by flow cytometry... HDACi not only shows anti-MM activity itself but sensitizes MM cells with CD26 antigen loss to CD26mAb via c-Myc/Sp1-mediated CD26 induction and augments its cytotoxicity.
- |||||||||| TT-301 / OPKO Health
Biomarker, Trial completion date: Biomarker and Edema Attenuation in IntraCerebral Hemorrhage (BEACH) (clinicaltrials.gov) - Oct 13, 2022
P2a, N=120, Recruiting,
High SLFN11 expression is one factor which renders favorable outcomes in WNT-activated and a subset of SHH-activated medulloblastoma possibly through enhancing response to cisplatin. Trial completion date: Oct 2026 --> Jun 2026
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Trial completion date, Trial primary completion date: CSSC-004: Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (clinicaltrials.gov) - Jun 7, 2022
P2, N=1225, Active, not recruiting,
No abstract available Trial completion date: Jan 2023 --> Sep 2022 | Trial primary completion date: Dec 2022 --> Jan 2022
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Trial completion, Enrollment change, Trial completion date, Trial primary completion date: Convalescent Plasma to Stem Coronavirus (CSSC-001) (clinicaltrials.gov) - Mar 10, 2022
P2, N=180, Completed,
Trial completion date: Jan 2023 --> Sep 2022 | Trial primary completion date: Dec 2022 --> Jan 2022 Active, not recruiting --> Completed | N=500 --> 180 | Trial completion date: Jan 2023 --> Jun 2021 | Trial primary completion date: Dec 2022 --> Apr 2021
- |||||||||| Isoform-selective HDAC inhibition up-regulates CD26 expression on multiple myeloma cells and augments cytotoxic efficacy by humanized monoclonal antibody (E-Poster Website) - Mar 9, 2022 - Abstract #AACR2022AACR_6933;
Although the cell surface expression of CD26 was relatively low or not detected on 5 MM cell lines (KMS26, KMS27, KMS28, KMS11, RPMI8226), the increased expression in CD26 levels was detectable within 24 h of the treatment with HDAC1i; FK228, HDAC3i; BG45, MS-275, RG2833 or HDAC6i; nexturastat A, tubastatin A, ACY-1215 as well as broad HDACi; LBH-589, SAHA... Combination with isoform-selective HDACi not only shows anti-MM activity but supports as immunopotentiators by sensitizing CD26neg MM cells to CD26mAb and augment its cytotoxicity against MM cells.
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Trial completion, Enrollment change, Trial completion date, Trial primary completion date: Human Convalescent Plasma for High Risk Children Exposed or Infected With SARS-CoV-2 (COVID-19) (clinicaltrials.gov) - Dec 15, 2021
P1, N=14, Completed,
In summary, these data show the neuroprotective potential of the class IIa HDI, LMK235, in cell models of relevance to PD. Active, not recruiting --> Completed | N=30 --> 14 | Trial completion date: Jul 2023 --> Dec 2021 | Trial primary completion date: Jul 2022 --> Sep 2021
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Enrollment change, Trial termination: Convalescent Plasma in ICU Patients With COVID-19-induced Respiratory Failure (clinicaltrials.gov) - Nov 8, 2021
P1, N=6, Terminated,
Active, not recruiting --> Completed | N=30 --> 14 | Trial completion date: Jul 2023 --> Dec 2021 | Trial primary completion date: Jul 2022 --> Sep 2021 N=60 --> 6 | Recruiting --> Terminated; The initiation of the expanded access program for convalescent plasma.
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Enrollment closed: CSSC-004: Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (clinicaltrials.gov) - Oct 7, 2021
P2, N=1344, Active, not recruiting,
N=60 --> 6 | Recruiting --> Terminated; The initiation of the expanded access program for convalescent plasma. Recruiting --> Active, not recruiting
- |||||||||| COVID-19 convalescent sera / Johns Hopkins University
Trial completion date, Trial primary completion date: Human Convalescent Plasma for High Risk Children Exposed or Infected With SARS-CoV-2 (COVID-19) (clinicaltrials.gov) - Jul 21, 2021
P1, N=30, Active, not recruiting,
Trial completion date: May 2022 --> Aug 2021 | Active, not recruiting --> Terminated; Sponsor shift in focus Trial completion date: Jun 2022 --> Jul 2023 | Trial primary completion date: Jun 2021 --> Jul 2022
- |||||||||| Zolinza (vorinostat) / Merck (MSD), RG2833 / BioMarin
Journal, Epigenetic controller: Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models. (Pubmed Central) - Jun 16, 2021
Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUSmutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.
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