- |||||||||| hydroxychloroquine / Generic mfg., temozolomide / Generic mfg.
Journal: Antioxidant responses related to temozolomide resistance in glioblastoma. (Pubmed Central) - Feb 5, 2022
Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.
- |||||||||| telaglenastat (CB-839) / Calithera
Androgen Receptor (AR) Signaling Decreases Glutamine Metabolism in Th17 Cells to Decrease House Dust Mite-induced Airway Inflammation () - Feb 4, 2022 - Abstract #AAAAI2022AAAAI_2262;
In vitro, Th2 and Th17 cells were differentiated from wild-type male and ArTfm male mice, with a nonfunctional AR, in the presence of a glutaminase inhibitor, CB839 (0.5μM), and/or the androgen, 5a-DHT (0.1nM)...AR signaling decreased Th17 metabolism and glutaminolysis in Th17 cells but had no direct effect on Th2 metabolism. Understanding how androgens affect glutaminolysis in T cells provides new potential therapeutic targets in women with difficult-to-treat asthma.
- |||||||||| Piqray (alpelisib) / Novartis
Journal: Alpelisib combination treatment as novel targeted therapy against hepatocellular carcinoma. (Pubmed Central) - Feb 3, 2022
Our study demonstrates that alpelisib is effective for treating PIK3CA-mutated HCC by inhibiting MAPK and AKT cascades. Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC.
- |||||||||| telaglenastat (CB-839) / Calithera
Enrollment closed, Pan tumor: Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study (clinicaltrials.gov) - Feb 2, 2022
P2, N=108, Active, not recruiting,
Furthermore, combining alpelisib with mTOR or CDK4/6 inhibitors has a synergistic efficacy against PIK3CA-mutated HCC, providing novel opportunities for precision medicine against HCC. Recruiting --> Active, not recruiting
- |||||||||| telaglenastat (CB-839) / Calithera
Enrollment closed, Trial completion date, Trial primary completion date, Combination therapy: CB-839 HCl in Combination With Carfilzomib and Dexamethasone in Treating Patients With Recurrent or Refractory Multiple Myeloma (clinicaltrials.gov) - Feb 2, 2022
P1, N=36, Active, not recruiting,
Recruiting --> Active, not recruiting Recruiting --> Active, not recruiting | Trial completion date: Jan 2022 --> Jan 2023 | Trial primary completion date: Jan 2022 --> Jan 2023
- |||||||||| sapanisertib (CB-228) / Calithera, RapaLink-1 / University of California, Revolution Medicines
Clinical, Journal: CONSEQUENCES OF mTOR INHIBITION ON AAV HEPATIC TRANSDUCTION EFFICACY. (Pubmed Central) - Feb 1, 2022
Therefore, our results show a complex interaction between the mTOR pathway and AAV-mediated hepatic transduction and indicate that mTOR inhibition is not a straightforward strategy for improving AAV transduction. More studies are necessary to elucidate the molecular mechanisms involve in the positive and negative effects of mTOR inhibitors on AAV transduction efficiency.
- |||||||||| telaglenastat (CB-839) / Calithera, eprenetapopt (APR-246) / Aprea
M2 as a therapeutic target in HNSCC: differentiation from THP-1 to M1 and M2a macrophage phenotypes () - Feb 1, 2022 - Abstract #ECHNOICHNO2022ECHNO_ICHNO_176;
Conclusion With this study we highlight that appropriated polarization conditions are crucial to obtain some distinct immune cell lines for in vitro study. In the oncology field, targeting specifically these TAMs will be a promising therapeutic approach based on the continuum plasticity and flexibility between macrophages phenotypes.
- |||||||||| telaglenastat (CB-839) / Calithera
Enrollment closed, Trial completion date, Trial primary completion date, Metastases: CB-839 + Capecitabine in Solid Tumors and Fluoropyrimidine Resistant PIK3CA Mutant Colorectal Cancer (clinicaltrials.gov) - Jan 28, 2022
P1/2, N=53, Active, not recruiting,
Resensitizing iCCA cells to metabolic treatments could make them more susceptible to cytotoxic drugs, opening new possibility to improve the outcomes of the iCCA patients. Suspended --> Active, not recruiting | Trial completion date: Oct 2021 --> Dec 2022 | Trial primary completion date: Oct 2021 --> Apr 2022
- |||||||||| telaglenastat (CB-839) / Calithera
Development of a covalent inhibitor of GLS1 (In-Person Room (Virtual Room)) - Jan 28, 2022 - Abstract #ACSSp2022ACS_Sp_5398;
Here we describe the development of a BPTES derivative with an aldehyde functional group on its terminal benzene ring adjacent which contacts a lysine residue in the BPTES binding pocket. We will test if the compound forms an imine with the lysine residue and becomes a covalent inhibitor.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: Self-Assembled Micellar Glutaminase Allosteric Inhibitor for Effective Therapeutic Intervention. (Pubmed Central) - Jan 26, 2022
For glutaminase allosteric inhibitors such as BPTES, CB-839 and Selen derivatives, the low solubility remains as the main factor that limits in vivo efficacy...Interestingly, CPD 23@SOL micelles significantly improved the pharmacokinetic exposure, prolonged the in vivo circulation and dramatically changed tissue biodistributions of CPD 23. The current work provided an encouraging and practical delivery system for novel Selenadiazoles and glutaminase allosteric inhibitors whose poor water-soluble characteristic has been a bottleneck for the field.
- |||||||||| Zaltrap (ziv-aflibercept IV) / Sanofi, sapanisertib (CB-228) / Calithera
Enrollment closed, Trial completion date, Trial primary completion date, Combination therapy, Surgery, Metastases: Sapanisertib and Ziv-Aflibercept in Treating Patients With Recurrent Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (clinicaltrials.gov) - Jan 24, 2022
P1, N=83, Active, not recruiting,
The current work provided an encouraging and practical delivery system for novel Selenadiazoles and glutaminase allosteric inhibitors whose poor water-soluble characteristic has been a bottleneck for the field. Recruiting --> Active, not recruiting | Trial completion date: Dec 2021 --> Jan 2023 | Trial primary completion date: Dec 2021 --> Jun 2021
- |||||||||| Zolinza (vorinostat) / Merck (MSD), sapanisertib (CB-228) / Calithera
Journal: Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma. (Pubmed Central) - Jan 15, 2022
In the present study, two series of novel hybrid molecules targeting mTOR and HDACs were designed and synthesized based on parent inhibitors (MLN0128 and PP121 for mTOR, SAHA for HDACs) by using a fusion-type molecular hybridization strategy...DI06 displayed better stability in rat liver microsomes than DI07 and DI17. Collectively, DI06 as a novel mTOR and HDACs inhibitor presented here warrants further investigation as a potential treatment of HCC.
- |||||||||| Cabometyx (cabozantinib tablet) / Takeda, Exelixis, Ipsen
Journal, Combination therapy, PD(L)-1 Biomarker, IO biomarker: Cabozantinib-based combination therapy for the treatment of hepatocellular carcinoma. (Pubmed Central) - Jan 11, 2022
c-MET/ERK/p21/PKM2 cascade and VEGFR2-induced angiogenesis are the primary targets of cabozantinib in HCC treatment. Combination therapies with cabozantinib and mTOR inhibitors may be effective against human HCC.
- |||||||||| telaglenastat (CB-839) / Calithera
Clinical, Review, Journal: Enhancing the Efficacy of Glutamine Metabolism Inhibitors in Cancer Therapy. (Pubmed Central) - Jan 4, 2022
Recent research has yielded important insights into the mechanisms that determine the tumor and the host immune responses to pharmacological perturbation of glutamine metabolism. Here, we discuss these findings and suggest that, collectively, they point toward patient stratification and drug combination strategies to maximize the efficacy of glutamine metabolism inhibitors as cancer therapeutics.
- |||||||||| telaglenastat (CB-839) / Calithera
Preclinical, Journal: Biodegradable self-assembly micelles significantly enhanced the solubility, biological stability and in vivo antitumor efficacy of Hexylselen. (Pubmed Central) - Jan 4, 2022
However, the main issue with allosteric inhibitors-including BPTES, CB-839, and the recently developed KGA allosteric and glutamate dehydrogenase (GDH) dual inhibitor, Hexylselen (CPD-3B)-is their low solubility; it leads to limited in vivo efficacy...These advantages significantly enhanced the bioavailability and in vivo antitumor efficacy of CPD-3B@SOL micelles in the H22 hepatocarcinoma xenograft mouse model. Thus, the current study provided a practical delivery system for allosteric inhibitors of glutaminase, which is one of the bottlenecks of targeting tumor glutaminolysis.
- |||||||||| mivavotinib (CB-659) / Calithera
Enrollment closed, Metastases: TAK-659 and Paclitaxel in Treating Patients With Advanced Solid Tumors (clinicaltrials.gov) - Jan 3, 2022
P1, N=81, Active, not recruiting,
Thus, the current study provided a practical delivery system for allosteric inhibitors of glutaminase, which is one of the bottlenecks of targeting tumor glutaminolysis. Recruiting --> Active, not recruiting
- |||||||||| Zolinza (vorinostat) / Merck (MSD), sapanisertib (CB-228) / Calithera
Journal: Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy. (Pubmed Central) - Dec 29, 2021
In particular, compound 50 exhibited IC values of 0.49 and 0.91 nM against mTOR and HDAC1, respectively, along with remarkably enhanced anti-proliferative activity (IC = 1.74 μM) against MV4-11 cell line than mTOR inhibitor MLN-0128 (IC = 5.84 μM) and HDAC inhibitor SAHA (IC = 8.44 μM)...Moreover, as the first disclosed mTOR/HDAC dual inhibitor with selectivity for some specific HDAC subtypes, it has the potential to alleviate the adverse effects resulted from pan-HDAC inhibition. Attributed to its favorable in vitro performance, compound 50 is valuable for further functional investigation as a polypharmacological anti-cancer agent.
- |||||||||| telaglenastat (CB-839) / Calithera, sapanisertib (CB-228) / Calithera
Clinical, P1 data, Journal: Phase 1 Trial of MLN0128 (Sapanisertib) and CB-839 HCl (Telaglenastat) in Patients With Advanced NSCLC (NCI 10327): Rationale and Study Design. (Pubmed Central) - Dec 16, 2021
Collectively, our results demonstrate potent, synergistic, anti-tumor activity of telaglenastat plus signal transduction inhibitors cabozantinib or everolimus via a mechanism involving dual inhibition of glucose and glutamine consumption. This phase 1 study will determine the recommended expansion dose and preliminary efficacy of MLN0128 and CB-839 in advanced non-small-cell lung cancer with a focus on subsets of LSCC and KRAS-mutant LUAD harboring NFE2L2 or KEAP1 mutations.
- |||||||||| tamoxifen / Generic mfg.
Journal: Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells. (Pubmed Central) - Nov 24, 2021
In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.
- |||||||||| telaglenastat (CB-839) / Calithera
Journal: Simultaneous inhibition of PFKFB3 and GLS1 selectively kills KRAS-transformed pancreatic cells. (Pubmed Central) - Nov 21, 2021
We then demonstrate that GLS1 inhibition reduced fructose-2,6-bisphosphate levels, the product of PFKFB3, whereas PFKFB3 inhibition increased glutamine consumption, and these effects were augmented by the co-inhibition of GLS1 and PFKFB3, suggesting a reciprocal regulation between PFKFB3 and GLS1. In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth.
- |||||||||| numidargistat (INCB001158) / Calithera
Trial completion date, Trial primary completion date, Combination therapy, Metastases: A Phase 1/2 Study of INCB001158 in Combination With Chemotherapy in Subjects With Solid Tumors (clinicaltrials.gov) - Nov 12, 2021
P1/2, N=149, Active, not recruiting,
In conclusion, this study identifies a novel mutant KRAS-induced metabolic vulnerability that may be targeted via combinatorial inhibition of GLS1 and PFKFB3 to suppress PDAC cell growth. Trial completion date: Oct 2021 --> Mar 2022 | Trial primary completion date: Oct 2021 --> Mar 2022
- |||||||||| telaglenastat (CB-839) / Calithera
Inhibiting Glutamine Metabolism with CB-839 Reduces Erythrocytosis in MPN Mice (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_5274;
Our data show that inhibiting glutaminolysis ameliorated MPN phenotype and that the combination with the glycolytic inhibitor 3PO was able to induce complete hematological response. Since CB-839 is already in clinical trials for other cancers, our data suggest that it could also be tested for treatment of patients with polycythemia vera.
- |||||||||| numidargistat (INCB001158) / Incyte
Targeting M2-Tumor Associated Macrophages By Arginase-1 and PD-L1 in Regulating Juvenile Myelomonocytic Leukemia (JMML) Development and Relapse (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_3043;
After 8 weeks post transplantation, we investigated the role of Arg-1 and PD-L1 in Shp2* recipients using pharmacological inhibitors, CB-1158 (Arg-1 inhibitor; 100 mg/kg, orally) + anti-PD-L1 antibody (10 mg/kg, i.p) for 30 days...These data suggest that the suppression of arginase-1 allows for the arginine levels to increase, which promotes the proliferation of T-cells. Increasing arginine levels also promotes an anti-tumor immune response resulting in the emergence of CD45.1 WT HSCs as opposed to mutant CD45.2 HSCs, suggesting that Arg-1 + PD-L1 treatment is a novel therapeutic approach to treat patients with JMML and for preventing leukemia relapse after BM transplantation.
- |||||||||| telaglenastat (CB-839) / Calithera
Inhibiting Mitochondrial Complex II Exposes a Novel Metabolic Vulnerability in Acute Myeloid Leukemia (GWCC - Hall B5, Level 1) - Nov 5, 2021 - Abstract #ASH2021ASH_2864;
This is further evident through modulation of glutamine entry into the TCA cycle, where supplementation of cell-permeable α-ketoglutarate abrogated shikonin-mediated cell death while concomitant treatment with the glutaminase inhibitor CB-839, sensitized cells. Together, these results expose reductive carboxylation to support aspartate biosynthesis, as a novel metabolic vulnerability in AML that can be pharmacologically targeted through CII inhibition for clinical benefit.
- |||||||||| telaglenastat (CB-839) / Calithera
Trial completion, Trial completion date, Combination therapy, Metastases: A Study of Telaglenastat (CB-839) in Combination With Palbociclib in Patients With Solid Tumors (clinicaltrials.gov) - Oct 29, 2021
P1b/2, N=53, Completed,
Conclusions Simultaneous, lung-specific, and controlled release of drugs targeting YAP1 and GLS1 improved PH in rats, addressing unmet needs for the treatment of this deadly disease. Active, not recruiting --> Completed | Trial completion date: Nov 2022 --> Sep 2021
- |||||||||| numidargistat (INCB001158) / Incyte
Journal: Cytokine-Mediated Regulation of ARG1 in Macrophages and Its Impact on the Control of Salmonella enterica Serovar Typhimurium Infection. (Pubmed Central) - Oct 28, 2021
Furthermore, ARG1 was dispensable for pathogen control irrespective of the presence or absence of the phagolysosomal natural resistance-associated macrophage protein 1 (NRAMP1). Thus, unlike the detrimental function of ARG1 seen during infections with other intraphagosomal microorganisms, ARG1 did not support bacterial survival in systemic salmonellosis, indicating differential roles of arginine metabolism for host immune response and microbe persistence depending on the type of pathogen.
- |||||||||| paclitaxel / Generic mfg.
Metabolite profiling and RNA-seq identifies novel metabolomic-genomic biomarker and therapeutic options for rapidly proliferating breast cancers (Hall 1) - Oct 26, 2021 - Abstract #SABCS2021SABCS_1277;
Notably, when the DHODH inhibitor Brequinar was tested on four different immune-competent TNBC mouse models, it showed significant single agent activity, and in 3/4 cases had better activity than carboplatin/paclitaxel combination, and with less toxicity. Our study reveals a new molecularly targeted therapy for rapidly proliferating TNBCs, guided by a novel set of metabolic-genomic biomarkers, which might be translated quickly as DHODH inhibitors are already FDA approved for use in other diseases.
- |||||||||| telaglenastat (CB-839) / Calithera, Zejula (niraparib) / GSK, J&J
Enrollment open: CB-839 in Combination With Niraparib in Platinum Resistant BRCA -Wild-type Ovarian Cancer Patients (clinicaltrials.gov) - Oct 21, 2021
P1, N=33, Recruiting,
Our study reveals a new molecularly targeted therapy for rapidly proliferating TNBCs, guided by a novel set of metabolic-genomic biomarkers, which might be translated quickly as DHODH inhibitors are already FDA approved for use in other diseases. Not yet recruiting --> Recruiting
- |||||||||| CB-280 / Calithera
[VIRTUAL] A phase 1b, randomized, double-blind, placebo-controlled, dose escalation trial of CB-280, an arginase inhibitor, in patients with cystic fibrosis () - Oct 19, 2021 - Abstract #NACFCI2021NACFC_I_997;
P1b
In conclusion, CB-280 was well tolerated in the initial dose cohorts of this study, with no CB-280 patients experiencing dose-limiting toxicities. CB-280 exhibited linear pharmacokinetics, achieving continuous target coverage in plasma at the 100-mg dose, and trended favorably in FEV1 and FeNO parameters.
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