scholarly journals Rescue of TCA Cycle Dysfunction for Cancer Therapy

2019 ◽  
Vol 8 (12) ◽  
pp. 2161 ◽  
Author(s):  
Jubert Marquez ◽  
Jessa Flores ◽  
Amy Hyein Kim ◽  
Bayalagmaa Nyamaa ◽  
Anh Thi Tuyet Nguyen ◽  
...  
Keyword(s):  
Tca Cycle ◽  
Mitochondrial Enzymes ◽  
Mitochondrial Enzyme ◽  
Therapeutic Approaches ◽  
Atp Production ◽  
Tca Cycle Enzymes ◽  
Subcellular Organelle ◽  
The Tca Cycle ◽  
Transport Chain ◽  
Cancer Types

Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction.

Abstract P443: Loss Of Pkm2 Alters Myocardial Metabolism And Increases Oxidative Stress After Infarction

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Katie C Lee ◽  
Allison L Williams ◽  
Ralph V Shohet
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Tca Cycle ◽  
Pentose Phosphate ◽  
Mitochondrial Enzymes ◽  
Rna Seq ◽  
Atp Production ◽  
The Tca Cycle ◽  
Alternatively Spliced ◽  
Altered Gene

Introduction: Pyruvate kinase (Pkm1) directs pyruvate to the TCA cycle for oxidative metabolism in the healthy heart. Our lab described a hypoxia-mediated switch to the alternatively spliced isoform Pkm2, enhancing pyruvate to lactate conversion. Recently, we have also found that Pkm2 knockout (KO) mice had profound depletion of basal glucose in the heart compared to control mice. Pkm2 has also been shown to reduce oxidative damage and promote cardiomyocyte cell proliferation after myocardial infarction (MI). We hypothesize that the upregulation of Pkm2 alters metabolic pathways after injury to promote glycolysis and preserve ATP production in hypoxia, which protects the heart from the stresses of hypoxia and injury. Methods: Global Pkm2 KO mice were subjected to permanent ligation of the left anterior descending coronary artery to mimic an MI. RNA-seq analysis of left ventricles from control (n=8) and Pkm2 KO mice (n=8) before and 3 days after sham or MI surgery was performed. Semiquantitative real-time PCR (qPCR) was used to confirm changes in selected genes of interest. Results: Loss of Pkm2 did not alter gene expression substantially at baseline. 68 genes were differentially expressed in Pkm2 KO hearts after MI (q<0.05, FDR<0.05) not observed in control MI hearts. MI in Pkm2 KO hearts resulted in considerable reduction of transcripts of enzymes in the insulin signaling pathway, mitochondrial oxidative phosphorylation, fatty acid metabolism, and increase in transcripts encoding enzymes in the pentose phosphate pathway, response to oxidative stress, and apoptotic signaling. qPCR of selected genes involved in glucose metabolism confirmed RNA-seq results. Conclusions: RNA-seq analysis of Pkm2 KO hearts demonstrated that loss of Pkm2 altered gene expression of metabolic and mitochondrial enzymes. Conversely, Pkm2 KO hearts showed increased abundance of pro-apoptotic markers which may be a result of increased oxidative stress.

Metabolism of glycolic acid by Azotobacter chroococcum PRL H62

1973 ◽  
Vol 19 (3) ◽  
pp. 321-324 ◽  
Author(s):  
W. G. W. Kurz ◽  
T. A. G. LaRue
Keyword(s):  
Nitrogen Fixation ◽  
Dicarboxylic Acid ◽  
Glycolic Acid ◽  
Tca Cycle ◽  
Azotobacter Chroococcum ◽  
Acid Cycle ◽  
Isocitric Dehydrogenase ◽  
Tca Cycle Enzymes ◽  
The Tca Cycle ◽  
Reduced Nitrogen

When Azotobacter chroococcum grows on glycolic acid as sole C source, it cannot utilize N2 and must be provided with reduced nitrogen. Glycolic acid is metabolized via Kornberg's dicarboxylic acid cycle. The TCA cycle enzymes are low in activity, and isocitric dehydrogenase is absent. It is likely that isocitric dehydrogenase is the source of reductant for nitrogen fixation by Azotobacter nitrogenase.

Effect of thermal injury on the TCA cycle enzymes of Staphylococcus aureus MF 31 and Salmonella typhimurium 7136

1971 ◽  
Vol 17 (6) ◽  
pp. 759-765 ◽  
Author(s):  
Richard I. Tomlins ◽  
Merle D. Pierson ◽  
Z. John Ordal
Keyword(s):  
Lactate Dehydrogenase ◽  
Malate Dehydrogenase ◽  
Thermal Injury ◽  
Specific Activity ◽  
Fumarate Hydratase ◽  
Tca Cycle ◽  
Tca Cycle Enzymes ◽  
The Tca Cycle ◽  
Oxoglutarate Dehydrogenase ◽  
Metabolic Activities

The heating of S. aureus MF-31 and S. typhimurium 7136 at 52C and 48C respectively, produced a sublethal heat injury. When injured cells were placed in fresh growth medium they recovered. The recovery of S. aureus was not inhibited by chloramphenicol. The metabolic activities of tricarboxylic acid (TCA) cycle enzymes, as well as other selected enzymes in crude extracts of normal and heat-injured cells of both microorganisms were assayed. In extracts from S. typhimurium there was some loss of specific activity with fumarate hydratase, glutamate dehydrogenase, fructose diphosphate aldolase, lactate dehydrogenase, and the NAD(P) oxidases as a result of heating. In extracts from S. aureus oxoglutarate dehydrogenase, malate dehydrogenase and lactate dehydrogenase were severely inactivated after heating. Other enzymes in comparison were only moderately sensitive to heat. No significant increase in enzyme activity was observed in extracts from injured cells of either microorganism. Re-naturation of lactate dehydrogenase and malate dehydrogenase occurred during the recovery of S. aureus both in the presence and absence of chloramphenicol. No renaturation of oxoglutarate dehydrogenase was found under the same conditions.

Low glucose and high pyruvate reduce the production of 2-oxoaldehydes, improving mitochondrial efficiency, redox regulation and stallion sperm function

2021 ◽  
Author(s):  
J M Ortiz-Rodríguez ◽  
F E Martín-Cano ◽  
G Gaitskell-Phillips ◽  
A Silva ◽  
C Ortega-Ferrusola ◽  
...  
Keyword(s):  
Redox Regulation ◽  
Krebs Cycle ◽  
Tca Cycle ◽  
Mitochondrial Activity ◽  
Atp Production ◽  
Transport Chain ◽  
Low Glucose ◽  
Mitochondrial Efficiency ◽  
Metabolic Strategies ◽  
Go Terms

Abstract Energy metabolism in spermatozoa is complex and involves the metabolism of carbohydrate fatty acids and amino acids. The ATP produced in the electron transport chain (ETC) in the mitochondria appears to be crucial for both sperm motility and maintaining viability, while glycolytic enzymes in the flagella may contribute to ATP production to sustain motility and velocity. Stallion spermatozoa seemingly use diverse metabolic strategies, and in this regard, a study of the metabolic proteome showed that gene ontology (GO) terms and Reactome pathways related to pyruvate metabolism and the Krebs cycle were predominant. Following this, the hypothesis that low glucose concentrations can provide sufficient support for motility and velocity, and thus glucose concentration can be significantly reduced in the medium, was tested. Aliquots of stallion semen in four different media were stored for 48 h at 18°C; a commercial extender containing 67 mM glucose was used as a control. Stallion spermatozoa stored in media with low glucose (1 mM) and high pyruvate (10 mM) (LG-HP) sustained better motility and velocities than those stored in the commercial extender formulated with very high glucose (61.7 ± 1.2% in INRA 96 vs 76.2 ± 1.0% in LG-HP media after 48 h of incubation at 18°C P &lt; 0.0001). Moreover, mitochondrial activity was superior in LG-HP extenders (24.1 ± 1.8% in INRA 96 vs 51.1 ± 0.7% in LG-HP of spermatozoa with active mitochondria after 48 h of storage at 18°C P &lt; 0.0001). Low glucose concentrations may permit more efficient sperm metabolism and redox regulation when substrates for an efficient TCA cycle are provided. The improvement seen using low glucose extenders is due to reductions in the levels of glyoxal and methylglyoxal, 2-oxoaldehydes formed during glycolysis; these compounds are potent electrophiles able to react with proteins, lipids and DNA, causing sperm damage.

scholarly journals SUN-219 Electron Transport Chain Complex 2 in Mitochondrial Pregnenolone Synthesis

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Himangshu S Bose ◽  
Brendan Marshall ◽  
Dilip Debnath ◽  
Elizabeth W Perry ◽  
Randy M Whittal
Keyword(s):  
Electron Transport ◽  
Intermediate State ◽  
Electron Transport Chain ◽  
Molten Globule ◽  
Tca Cycle ◽  
Steroid Synthesis ◽  
Aberrant Expression ◽  
Complex Ii ◽  
The Tca Cycle ◽  
Transport Chain

Abstract The mitochondrial P450 family of enzymes (SCC), which require the electron transport chain (ETC) complexes III, IV and V, initiate steroidogenesis by cleaving the sidechain of cholesterol to synthesize steroid hormones, an essential component for mammalian survival. SCC is required for full-term gestation, and aberrant expression may cause pseudohermaphroditism, breast cancer or polycystic ovary syndrome. Complex II or succinate dehydrogenase (quinone) is shared with the TCA cycle and has no proton pumping capacity and no known role in steroid synthesis. We now show that succinate is an intermediate metabolite in the TCA cycle and plays a central role physiologically. Specifically, complex II is required for SCC activation, where the proton pump facilitates an active intermediate state conformation at the matrix, so that in the presence of succinate, ATP can add phosphate. A longer intermediate equilibrium state generates a transient stabilization to enhance the binding of phosphate anions in the presence of succinate anions, resulting in higher enthalpy and activity. An inhibition of the processing at the intermediate state stops phosphate addition and activity. We further describe that phosphate circulation brings the molten globule, an intermediate, to an active folded state. This is the first report showing that an intermediate state activated by succinate facilitates ETC complex II interaction with complexes III and IV for metabolism.

Protein hyperacylation links mitochondrial dysfunction with nuclear organization

2020 ◽  
Author(s):  
John Smestad ◽  
Micah McCauley ◽  
Matthew Amato ◽  
Yuning Xiong ◽  
Juan Liu ◽  
...  
Keyword(s):  
Chromatin Structure ◽  
Metabolic Regulation ◽  
Tca Cycle ◽  
Interphase Chromatin ◽  
Histone Octamer ◽  
The Tca Cycle ◽  
Transport Chain ◽  
Topologically Associated Domains ◽  
Biophysical Effects ◽  
Liquid Liquid Phase Separation

SummaryCellular metabolism is linked to epigenetics, but the biophysical effects of metabolism on chromatin structure and implications for gene regulation remain largely unknown. Here, using a broken tricarboxylic acid (TCA) cycle and disrupted electron transport chain (ETC) exemplified by succinate dehydrogenase subunit C (SDHC) deficiency, we investigated the effects of metabolism on chromatin architecture over multiple distance scales [nucleosomes (∼102 bp), topologically-associated domains (TADs; ∼105 – 106 bp), and chromatin compartments (106 – 108 bp)]. Metabolically-driven hyperacylation of histones led to weakened nucleosome positioning in multiple types of chromatin, and we further demonstrate that lysine acylation directly destabilizes histone octamer-DNA interactions. Hyperacylation of cohesin subunits correlated with decreased mobility on interphase chromatin and increased TAD boundary strength, suggesting that cohesin is metabolically regulated. Erosion of chromatin compartment distinctions reveals metabolic regulation of chromatin liquid-liquid phase separation. The TCA cycle and ETC thus modulate chromatin structure over multiple distance scales.

scholarly journals Higher expression of proline dehydrogenase altered mitochondrial function and increased Trypanosoma cruzi differentiation in vitro and in the insect vector

2021 ◽  
Author(s):  
Brian S Mantilla ◽  
Lisvane Paes-Vieira ◽  
Felipe Almeida Dias ◽  
Simone G. Caldeirano ◽  
Maria Carolina Elias ◽  
...  
Keyword(s):  
Trypanosoma Cruzi ◽  
Insect Vector ◽  
Mitochondrial Enzymes ◽  
Proline Dehydrogenase ◽  
Intermediate Hosts ◽  
Atp Production ◽  
Metacyclic Trypomastigotes ◽  
Transport Chain ◽  
Mitochondrial Functions

The pathogenic protist Trypanosoma cruzi uses kissing bugs as intermediate hosts that vectorize the infection among mammals. This parasite oxidizes proline to glutamate through two enzymatic steps and one nonenzymatic step. In insect vectors, T. cruzi differentiates from a noninfective replicating form to nonproliferative infective forms. Proline sustains this differentiation, but to date, a link between proline metabolism and differentiation has not been established. In T. cruzi, the enzymatic steps of the proline-glutamate oxidation pathway are catalysed exclusively by the mitochondrial enzymes proline dehydrogenase [TcPRODH, EC: 1.5.5.2] and D1-pyrroline-5-carboxylate dehydrogenase [TcP5CDH, EC: 1.2.1.88]. Both enzymatic steps produce reducing equivalents that are able to directly feed the mitochondrial electron transport chain (ETC) and thus produce ATP. In this study, we demonstrate the contribution of each enzyme of the proline-glutamate pathway to ATP production. In addition, we show that parasites overexpressing these enzymes produce increased levels of H2O2, but only those overexpressing TcP5CDH produce increased levels of superoxide anion. We show that parasites overexpressing TcPRODH, but not parasites overexpressing TcP5CDH, exhibit a higher rate of differentiation into metacyclic trypomastigotes in vitro. Finally, insect hosts infected with parasites overexpressing TcPRODH showed a diminished parasitic load but a higher percent of metacyclic trypomastigotes, when compared with controls. Our data show that parasites overexpressing both, PRODH and P5CDH had increased mitochondrial functions that orchestrated different oxygen signalling, resulting in different outcomes in relation to the efficiency of parasitic differentiation in the invertebrate host.

scholarly journals Complete Remission with Devimistat (CPI-613) in Refractory Burkitt Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4555-4555
Author(s):  
Liana Nikolaenko ◽  
Timothy Pardee ◽  
Raphel Steiner ◽  
Jeremy S. Abramson ◽  
Steven M. Horwitz ◽  
...  
Keyword(s):  
Pyruvate Dehydrogenase ◽  
Research Funding ◽  
Study Drug ◽  
Tca Cycle ◽  
Mitochondrial Enzymes ◽  
Advisory Committees ◽  
Cancer Cell Death ◽  
Redox Active ◽  
The Tca Cycle ◽  
Alpha Ketoglutarate Dehydrogenase

Abstract Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. Figure 1 Figure 1. Disclosures Nikolaenko: Pfizer: Research Funding; Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; CBM Biopharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy; Kymera: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Verastem: Research Funding; ONO Pharmaceuticals: Consultancy; Myeloid Therapeutics: Consultancy; SecuraBio: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Aileron: Research Funding; Affimed: Research Funding; Acrotech Biopharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. OffLabel Disclosure: CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis

scholarly journals A Phase II Clinical Trial of Cpi-613 (devimistat) in Patients with Relapsed or Refractory Burkitt Lymphoma/Leukemia or High-Grade B-Cell Lymphoma with Rearrangements of MYC and BCL2and/or BCL6

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4087-4087 ◽  
Author(s):  
Ariela Noy ◽  
Timothy S. Pardee ◽  
Liana Nikolaenko ◽  
Raphael Eric Steiner ◽  
Jeremy S. Abramson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tca Cycle ◽  
Mitochondrial Enzymes ◽  
High Grade ◽  
Advisory Committees ◽  
Redox Active ◽  
The Tca Cycle

Background: Patients with primary refractory or relapsed Burkitt lymphoma/leukemia (BL) or high-grade B-cell lymphoma with rearrangements of MYC and BCL2 (double hit, DHL) and/or BCL6 (triple hit, THL) have a dismal prognosis with patients rarely achieving meaningful remissions following second line therapy. No standard therapeutic approach exists for this group. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with downstream effects on both proliferation and highly glycolytic metabolism which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI 613® (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle: pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of these enzyme activities results in a shutdown of ATP and biosynthetic-intermediate production leading to cancer cell death by apoptosis or necrosis. In the initialphase I trial a patient with multiply refractory BL had a partial remission on CPI 613 sustained for over one year prior to surgical resection. Given the rarity of these types of responses in multiply relapsed BL we initiated a phase II trial to further explore efficacy. CPI-613® has FDA orphan status for BL. Study Design and Methods: NCT03793140 is a multicenter study enrolling 17 patients on each of two cohorts BL or DHL/THL. Patients must have had one prior therapy or are refusing standard of care, measurable disease or isolated bone marrow involvement, and must not be within 3 months of a prior stem cell transplant. Patients with active central nervous system (CNS) parenchymal disease are excluded, but those with leptomeningeal disease are eligible if the CSF is negative for lymphoma for more than 4 weeks and the maintenance intrathecal/intraOmmaya therapy is ongoing . CPI 613 is given by central line over 2 hours daily x 5 days for two 14-day cycles and then in 21 day cycles. With a primary objective of overall response, treatment can be used as a bridge to transplant. Secondary endpoints include duration of response, progression-free survival (PFS) and overall survival (OS). Primary and secondary outcomes will be correlated with pre-treatment biomarkers including variances in serum metabolites, immunohistochemistry staining for PDH, KGDH, PDKs1-4, SOD2 and pretreatment cytokine profiles. Biostatistics include a Simon minimax two-stage design for efficacy after the first 10 patients in each of the BL and DHL/THL cohorts separately analyzed. Additionally, an interim analysis for toxicity will be conducted after the first 10 study participants have completed two complete cycles or have come off study. Figure Disclosures Noy: Raphael Pharma: Research Funding; Pharamcyclics: Research Funding; Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding. Pardee:Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm: Research Funding; Pharmacyclics/Janssen: Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; CBM Bipharma: Membership on an entity's Board of Directors or advisory committees; Spherix Intellectual Property: Research Funding. Abramson:AbbVie Inc, Amgen Inc, Bayer HealthCare Pharmaceuticals, Celgene Corporation, EMD Serono Inc, Genentech, Gilead Sciences Inc, Janssen Biotech Inc, Juno Therapeutics, a Celgene Company, Karyopharm Therapeutics, Kite Pharma Inc, Merck, Novartis, Seattle Gen: Consultancy. Dunleavy:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Luther:Raphael: Employment. OffLabel Disclosure: CPI 613 devimistat is a is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle

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