- |||||||||| telaglenastat (CB-839) / Calithera, Farydak (panobinostat) / Secura Bio
Journal, Combination therapy: Inhibition of glutaminolysis alone and in combination with HDAC inhibitor has anti-myeloma therapeutic effects. (Pubmed Central) - Jul 26, 2024
Glutaminolysis contributes to the viability of MM cells, and the GLS inhibitor CB-839 has been proven to be an effective treatment for enhancing the cytotoxic effect of HDAC inhibition. These results are clinically relevant and suggest that CB-839 is a potential therapeutic candidate for patients with MM.
- |||||||||| telaglenastat (CB-839) / Calithera, MYCi975 / Northwestern University Feinberg School of Medicine
Journal: Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer. (Pubmed Central) - Jul 18, 2024
Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.
- |||||||||| 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.
- |||||||||| Tagrisso (osimertinib) / AstraZeneca, sapanisertib (CB-228) / Calithera
Trial completion date, Trial primary completion date, Combination therapy, Metastases: Testing the Combination of MLN0128 (TAK-228) and AZD9291 in Advanced EGFR (Epidermal Growth Factor Receptor) Mutation Positive Non-small Cell Lung Cancer (clinicaltrials.gov) - Jun 26, 2024
P1, N=36, Active, not recruiting,
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. Trial completion date: Jun 2024 --> May 2025 | Trial primary completion date: Jun 2024 --> May 2025
- |||||||||| Review, Monotherapy: Efficacy and safety of FLT3 inhibitors in monotherapy of hematological and solid malignancies: a systemic analysis of clinical trials. (Pubmed Central) - Jun 3, 2024
We searched and reviewed clinical trial reports on the monotherapy of 13 FLT3 inhibitors, including sorafenib, lestaurtinib, midostaurin, gilteritinib, quizartinib, sunitinib, crenolanib, tandutinib, cabozantinib, pexidartinib, pacritinib, famitinib, and TAK-659 in patients with hematological and solid malignancies before May 31, 2023...The ORRs of FLT3 inhibitors in hematologic malignancies and solid tumors were 40.8% and 18.8%, respectively, indicating FLT3 inhibitors were more effective for hematologic malignancies than for solid tumors. In addition, time to maximum plasma concentration (Tmax) in these FLT3 inhibitors ranged from 0.7-12.0 hours, but the elimination half-life (T1/2) range was highly variable, from 6.8 to 151.8 h. FLT3 inhibitors monotherapy has shown significant anti-tumor effect in clinic, and the effectiveness may be further improved through combination medication.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer growth. (Pubmed Central) - May 15, 2024
Glutaminase-1 inhibitor CB-839 reversed the effects of SLC38A1 overexpression...In conclusion, METTL3-mediated m6A methylation of SLC38A1 stimulates cervical cancer progression. SLC38A1 inhibition is a potential therapeutic strategy for cervical cancer.
- |||||||||| CORE TARGETS INTERACTOMICS UNVEILED THE MECHANISM OF ACTION IN NOVEL DRUG COMBINATORIAL THERAPY OF AML () - May 15, 2024 - Abstract #EHA2024EHA_1094;
This exploration brings to light the significant potentialof the ruxolitinib-ulixertinib and LY3009120-sapanisertib combinations to transcend traditional treatmentbarriers and engage essential metabolic pathways, including the central carbon metabolism. These findingsadvocate for a new direction in AML treatment strategy development, promising more effective and preciselytargeted therapies that could lead to better patient outcomes.
- |||||||||| telaglenastat (CB-839) / Calithera
Trial completion date, Trial primary completion date, Metastases: Glutaminase Inhibition and Chemoradiation in Advanced Cervical Cancer (clinicaltrials.gov) - May 14, 2024
P2, N=42, Not yet recruiting,
In vivo assays using xenografted zebrafish further supported the efficiency ofthese combinations compared to single agents and controls. Trial completion date: Jul 2030 --> Oct 2030 | Trial primary completion date: Jul 2030 --> Oct 2030
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy. (Pubmed Central) - May 2, 2024
Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839)...The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.
- |||||||||| mivavotinib (CB-659) / Calithera
A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors. (Hall A; Poster Bd #: 297) - Apr 24, 2024 - Abstract #ASCO2024ASCO_2123;
P1
Future studies will focus on tumors known to have high rates of PI3K mutations including gynecologic tumors where there is a high unmet need. The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1. (Pubmed Central) - Apr 15, 2024
CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: SLC38A2 promotes cell proliferation and invasion by promoting glutamine metabolism in adenomyosis. (Pubmed Central) - Apr 9, 2024
SLC38A2 overexpression promoted Gln metabolism and oxygen consumption rate, resulting in an increase in cell proliferation and invasion in the adenomyosis context. The present study indicated that reduction of SLC38A2 expression could be a novel target for adenomyosis therapy, and SLC38A2 may be a valuable clinical diagnostic molecule for adenomyosis.
- |||||||||| sapanisertib (CB-228) / Calithera
Trial completion date, Trial termination, Surgery: Sapanisertib Before and After Surgery in Treating Patients With Recurrent Glioblastoma (clinicaltrials.gov) - Apr 4, 2024
P1, N=40, Terminated,
The present study indicated that reduction of SLC38A2 expression could be a novel target for adenomyosis therapy, and SLC38A2 may be a valuable clinical diagnostic molecule for adenomyosis. Trial completion date: Mar 2025 --> Oct 2023 | Active, not recruiting --> Terminated; Other - Lapse in funding
- |||||||||| telaglenastat (CB-839) / Calithera, Evrenzo (roxadustat) / FibroGen
HIF1? regulates Tfr induction that restrains Tfh13 polarization in a murine model of allergy (Exhibit Hall F1; Poster Board Number: B863) - Mar 29, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_948;
Finally, in a murine model of allergic asthma, treatment with Roxadustat reduced airway hyperresponsiveness compared to vehicle control. Our results support a model where downstream gene expression induced by HIF1a may be necessary for the induction of Tfh13-restraining Tfr cells.
- |||||||||| mivavotinib (CB-659) / Calithera, Opdivo (nivolumab) / Ono Pharma, BMS
P1 data, P2 data, Clinical Trial,Phase I, Clinical Trial,Phase II, Journal, Combination therapy, Metastases: A phase Ib study evaluating the recommended phase II dose, safety, tolerability, and efficacy of mivavotinib in combination with nivolumab in advanced solid tumors. (Pubmed Central) - Mar 23, 2024
P1b
Low response rates highlight the challenges of treating unresponsive tumor types, such as TNBC, with this combination and immunotherapies in general. TRIAL REGISTRATION ID: NCT02834247.
- |||||||||| telaglenastat (CB-839) / Calithera
Covalent inhibitors of glutaminase enzymes | Poster Board #1424 (In-person; Poster Board #1424; Hall C (Ernest N. Morial Convention Center)) - Mar 12, 2024 - Abstract #ACSSp2024ACS_Sp_4634;
One such compound named CB-839 is in clinical trials for several cancers...The inhibition of glutaminase is time-dependent, and the k inact /K I values show moderate potency. Conversion of the compound into an alkyne click chemistry probe will allow measurement of its protein selectivity in cells.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: Improved Photodynamic Therapy Based on Glutaminase Blockage via Tumor Membrane Coated CB-839/IR-780 Nanoparticles. (Pubmed Central) - Mar 11, 2024
The Gln metabolism intervention relieves hypoxia and decreases the levels of nicotinamide adenine dinucleotide phosphate (NADPH) as well as reduced glutathione (GSH) in vitro and in vivo, which are the dual amplification effects on the IR-780-mediated lethal PDT. The antitumor effects against gastric cancer are ultimately evoked in vivo, thus offering a novel concept for enhancing PDT and other ROS-dependent therapeutic approaches.
- |||||||||| 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.
- |||||||||| telaglenastat (CB-839) / Calithera
A positive feedback loop between GLS1 and c-Myc drives tumor aggressiveness (Section 19) - Mar 5, 2024 - Abstract #AACR2024AACR_5699;
The GLS1-c-Myc axis thus represents a novel positive feedback loop that is critical for driving the aggressiveness of HNSCC. As the treatment of HNSCC remains a major challenge, these novel findings provide the molecular basis for combining GLS1-specific inhibitors with c-Myc-targeted therapy for the treatment of HNSCC patients.
- |||||||||| sapanisertib (CB-228) / Calithera
Improving targeted therapy in female patients with lung squamous cell carcinoma (Section 26) - Mar 5, 2024 - Abstract #AACR2024AACR_5349;
P1, P2
These results suggest that the estrogen may play a key role in the observed pattern of female resistance to mTOR inhibition. As such, the goal of the current proposal is to evaluate the catalytic mTOR kinase inhibitor TAK228, in combination with anti-estrogen therapy as a therapeutic strategy to treat LUSC in females.
- |||||||||| KEAP1-NRF2 mediated resistance against KRASG12D inhibitor in pancreatic ductal adenocarcinoma (Section 24) - Mar 5, 2024 - Abstract #AACR2024AACR_4022;
Recently, the clinical candidate KRASG12D-selective inhibitor MRTX1133 (G12Di) has been shown to potently suppress both activation of the RAF-MEK-ERK signaling pathway downstream of KRAS and tumorigenic growth of KRASG12D-mutant PDAC in vitro and in vivo...We further discovered that combination treatment with a glutaminase inhibitor (CB-839) synergistically enhanced G12Di growth suppression not only of KEAP1-knockout but also of parental PDAC cells. In summary, our study establishes a role for KEAP1 loss as a mechanism that drives PDAC resistance to KRAS inhibitors and identifies GLS inhibition as a possible approach to overcome NRF2-driven resistance.
- |||||||||| telaglenastat (CB-839) / Calithera, Tibsovo (ivosidenib) / Servier
Exploring targetable pathways: Unveiling changes in tumor physiology through dietary modification by a ketogenic diet (Section 18) - Mar 5, 2024 - Abstract #AACR2024AACR_2979;
A ketogenic diet demonstrates a robust anti-tumor effect in various pancreatic cancer mouse models, likely arising from the diminished glucose and increased fatty acid load inherent in the diet. Metabolic adaptation towards an oxidative phosphorylation (OXPHOS) phenotype makes pancreatic cancer especially susceptible to antioxidant and mitochondrial inhibitors, as well as inhibitors of glutamine-metabolizing enzymes.
- |||||||||| 5-fluorouracil / Generic mfg.
Journal: NETs unleashed: neutrophil extracellular traps boost chemotherapy against colorectal cancer. (Pubmed Central) - Mar 5, 2024
This chemotherapy treatment strongly induced the recruitment of neutrophils that formed neutrophil extracellular traps in cancer, which actively killed cancer cells by inducing apoptosis. This study substantially advances our understanding of the multifaceted role of neutrophils and NETs in the outcome of anticancer treatment.
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