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Journal: Blocking the TCA Cycle in Cancer Cells Potentiates CD36+ T-cell-Mediated Antitumor Immunity by Suppressing ER Stress-Associated THBS2 Signaling. (Pubmed Central) - Apr 28, 2025 In this study, using CPI-613 as a model drug for TCA cycle inhibition, we identified a molecular mechanism by which blocking the TCA cycle enhances T-cell-mediated antitumor immunity in the context of head and neck squamous cell carcinoma (HNSCC)...These findings uncover the immunomodulatory role of the TCA cycle in cancer cells and suggest that targeting it is a promising approach to harness tumor-reactive immune cells. Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism.
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Preclinical, Journal: Thiamine deficiency aggravates experimental colitis in mice by promoting glycolytic reprogramming in macrophages. (Pubmed Central) - Apr 3, 2025 Significance: The immunomodulatory role of the TCA cycle in cancer cells provides a therapeutic opportunity to enhance antitumor immunity by targeting tumor cell metabolism. Our study provides evidence linking thiamine deficiency with proinflammatory macrophage activation and colitis aggravation, suggesting that monitoring thiamine status and adjusting thiamine intake is necessary to protect against colitis.
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Preclinical evaluation of pharmacokinetic interactions among nebivolol, dasatinib and devimistat in mice (Section 20; Poster Board No: 12) - Mar 25, 2025 - Abstract #AACR2025AACR_6868; Co-administration with DAS slowed the NBV elimination, suggesting that NBV accumulation would be considered when used alongside DAS. Additionally, CPI exposure significantly increased in the presence of NBV, indicating that dose adjustments may be necessary in combination therapies.
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Journal: Lipoylation inhibition enhances radiation control of lung cancer by suppressing homologous recombination DNA damage repair. (Pubmed Central) - Mar 12, 2025 Mechanistically, lipoylation inhibition increased 2-hydroxyglutarate, leading to H3K9 trimethylation, disrupting TIP60 recruitment and ataxia telangiectasia mutated (ATM)-mediated DNA damage repair signaling, impairing homologous recombination repair. In summary, our findings reveal a critical role of LIPT1 in regulating DNA damage and chromosome stability and may suggest a means to enhance therapeutic outcomes with DNA-damaging agents.
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Preclinical, Journal: Protocol to evaluate fasting metabolism and its relationship to the core circadian clock in mice. (Pubmed Central) - Feb 25, 2025 We describe steps for time-course fasting/feeding experiment setup and performing staggered fasting and refeeding for 24 h. We then detail procedures for evaluating oxidative substrate selection and rescuing defective oxidative metabolism through FGF21 and CPI-613 injections. For complete details on the use and execution of this protocol, please refer to Sun et
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Journal: The function and mechanism of clinical trial agent CPI-613 in multiple myeloma. (Pubmed Central) - Feb 7, 2025 Furthermore, we found CPI-613 significantly inhibited tumor growth and induced intrinsic apoptosis in the MM mouse xenograft model. This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation.
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Trial completion: CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) - Nov 22, 2024 P1/2, N=49, Completed, This study reveals the mechanism and effect of CPI-613 in MM, which suggests that CPI-613 may be a new drug option for the clinical treatment of MM, but further clinical trials are needed for evaluation. Active, not recruiting --> Completed
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Devimistat Results in a Low Complete Remission Rate in Heavily Pre-Treated Burkitt Lymphoma (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_3128; P2 The first CR patient was 40 years old, HIV positive with a viral load of 23 copies/mL, and 4 previous lines of therapy (CODOX-M/R-IVAC, R-ICE, pembrolizumab+acalabrutinib, R-methotrexate cytarabine) before receiving 11 cycles of devimistat...The second CR patient was 21 years old, HIV negative, received 6 previous lines of therapy (R-CHOP, DA-R-EPOCH, R-HCVAD/R-MA and IT MTX, R-Hyper cyclophosphamide, axi-cel, allogeneic SCT)...(Manji, ASH,2021) Despite few treatment options, it was difficult to enroll pts who were often ineligible due to poor performance status, CNS disease or logistical constraints, leading to study closure. Considering the dismal prognosis with the current standard of care, efforts should be made to improve the outcome of those with high-risk BL with their first line of therapy.
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Trial primary completion date: CPI-613 Given With Metformin in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - May 3, 2024 P2, N=17, Not yet recruiting, These findings indicate that inhibiting PDH increases the rate of anaerobic glycolysis and pH decline, suggesting that mitochondria are potential regulators of postmortem metabolism. Trial primary completion date: Dec 2024 --> Apr 2025
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Journal, Synthetic lethality: OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma. (Pubmed Central) - Apr 23, 2024 In patient-derived xenograft models of GBM in mice, the combination treatment of ABT263 and CPI-613 suppressed tumor growth and extended animal survival more potently than each compound on its own. Therefore, combined inhibition of Bcl-xL along with interference of the TCA-cycle might be a treatment strategy for GBM.
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Deciphering the metabolic regulation of immunosuppressive CD11b+Gr1+ myeloid cells in epithelial ovarian cancer. (Exhibit Hall F1; Poster Board Number: B109) - Mar 29, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_994; In combination with CPI-613, ?KG was able to reverse the inhibitory effect of CPI-613 on immunosuppression, OXPHOS and decreased survival. Our study shows that ?KG generated by TCA- glutamine anaplerosis is crucial for supporting an immunosuppressive phenotype of CD11b+Gr1+ myeloid cells in EOC, and targeting ?KG may enhance anti-tumor immune responses.
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Deciphering the metabolic regulation of immunosuppressive CD11b+Gr1+ myeloid cells in epithelial ovarian cancer. (Room W181) - Mar 22, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_423; In combination with CPI-613, ?KG was able to reverse the inhibitory effect of CPI-613 on immunosuppression, OXPHOS and decreased survival. Our study shows that ?KG generated by TCA- glutamine anaplerosis is crucial for supporting an immunosuppressive phenotype of CD11b+Gr1+ myeloid cells in EOC, and targeting ?KG may enhance anti-tumor immune responses.
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Journal: Inducing Melanoma Cell Apoptosis by ERp57/PDIA3 Antibody in the Presence of CPI-613 and Hydroxychloroquine. (Pubmed Central) - Mar 4, 2024 siRNA-mediated downregulation of ERp57/PDIA3 did not significantly induce ICT-mediated apoptosis in melanoma cells in the presence of CPI-613 and hydroxychloroquine. Therefore, the ICT antibody acts as a tumor suppressor in melanoma cells by targeting the cell membrane ERp57/PDIA3, expression of which was enhanced by the combination of CPI-613 and hydroxychloroquine.
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Enrollment closed, Trial completion date, Trial primary completion date: Gemcitabine and Cisplatin With or Without CPI-613 as First Line Therapy for Patients With Advanced Unresectable Biliary Tract Cancer (BilT-04) (clinicaltrials.gov) - Feb 19, 2024 P1/2, N=75, Active, not recruiting, Therefore, the ICT antibody acts as a tumor suppressor in melanoma cells by targeting the cell membrane ERp57/PDIA3, expression of which was enhanced by the combination of CPI-613 and hydroxychloroquine. Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Nov 2025 | Trial primary completion date: Jun 2024 --> Nov 2024
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Trial primary completion date, Combination therapy, Metastases: CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) - Jan 28, 2024 P1/2, N=49, Active, not recruiting, Recruiting --> Active, not recruiting | Trial completion date: Jun 2025 --> Nov 2025 | Trial primary completion date: Jun 2024 --> Nov 2024 Trial primary completion date: Oct 2023 --> Sep 2024
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Associations between BMI, morphomics and survival in 528 patients with metastatic pancreatic cancer. (Poster Bd # K6) - Dec 6, 2023 - Abstract #ASCOGI2024ASCO_GI_553; BMI was not associated with PFS or OS in this large prospective study of patients with metastatic PDA receiving chemotherapy. However, morphomic variables including subcutaneous fat area, visceral fat density, and the muscle to fascia ratio were statistically significantly associated with metastatic PDA patient survival.
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Trial initiation date: CPI-613 Given With Metformin in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - Nov 29, 2023 P2, N=17, Not yet recruiting, However, morphomic variables including subcutaneous fat area, visceral fat density, and the muscle to fascia ratio were statistically significantly associated with metastatic PDA patient survival. Initiation date: Nov 2023 --> Feb 2024
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Trial completion date, Trial primary completion date, Combination therapy, Metastases: CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) - Jul 13, 2023 P1/2, N=49, Active, not recruiting, Active, not recruiting --> Completed | Trial completion date: Jun 2023 --> Jan 2023 Trial completion date: Apr 2024 --> Oct 2024 | Trial primary completion date: Apr 2023 --> Oct 2023
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