A Phase II Single Arm Trial Evaluating the Safety and Efficacy of Anhydrous Enol-Oxaloacetate on Improving Cognitive Complaints in Breast Cancer Survivors

This phase II trial studies how well oxaloacetate works in reducing cognitive complaints in stage 0-IIIA breast cancer survivors. Oxaloacetate is a natural substance found in the body and is available as a nutritional supplement. Giving oxaloacetate may reduce inflammation in the brain that could be contributing to cognitive complaints seen after cancer treatments.

Start Date29 Sep 2021

Sponsor / Collaborator

Jonsson Comprehensive Cancer Center

[+2]

NCT04450160 / Unknown statusPhase 2

A Phase 2, Randomized, Open-Label Study of Anhydrous Enol-Oxaloacetate in Subjects With Newly Diagnosed Glioblastoma Multiforme

This is a multicenter, Phase 2, Proof-of-concept study in subjects with newly diagnosed glioblastoma multiforme (GBM).
All subjects will receive standard of care therapy for the treatment of their GBM and any Anti-Epileptic Drug (AED) deemed necessary for their surgical resection of the GBM. Patients who are taking concomitant AEDs will be eligible for the study. Treatment with Anhydrous Enol-Oxaloacetate will be added to the Standard of Care.
This study is testing adjuvant Anhydrous Enol-Oxaloacetate (AEO) in GBM, an orally active drug candidate which in animal studies has demonstrated decreased tumor growth rate and increased survival.

Start Date01 Dec 2020

Sponsor / Collaborator

MetVital, Inc.

100 Clinical Results associated with MetVital, Inc.

0 Patents (Medical) associated with MetVital, Inc.

Literatures (Medical) associated with MetVital, Inc.

14 Nov 2022·Neuro-Oncology

TMET-06. METABOLIC FATE OF OXALOACETATE IN GLIOBLASTOMA

Author: Conway, David ; Cash, Alan ; Baskin, David ; Ijare, Omkar ; Pichumani, Kumar

AbstractOxaloacetate (OAA) inhibits the Warburg effect by reducing the glucose-derived lactate levels in human cancer cell lines. In dose ranging IC50 experiments with human hepatocellular carcinoma (HCC) cell lines, OAA inhibited cell growth in the concentration range 1.7 - 2.4 mM. Previously, we showed that in the presence of OAA, [U-13C]glucose derived lactate was reduced by 48.8% in GBM cells. OAA also increased survival in mouse models of GBM. Here, we are showing an evidence for the direct utilization of OAA by Glioblastoma (GBM) cells, using uniformly 13C-labeled oxaloacetate ([U-13C]OAA) as a metabolic tracer. Patient-derived GBM cells were grown in DMEM medium containing 11.0 mM glucose and 2.0 mM glutamine. When cells reached confluency, were treated with 4.0 mM [U-13C]OAA in the above DMEM medium. GC-MS based 13C isotopomer analysis showed that [U-13C]OAA entered the cells and get metabolized to generate distinct 13C-labeled isotopomers of aspartate, citrate, glutamate, malate and fumarate. Upon entering TCA cycle, [U-13C]OAA generated M+4 aspartate (3.0%) and citrate (3.2%), and M+3 glutamate (4.1%). During the first turn of the TCA cycle, it produced M+2 aspartate (13.9%), malate (10.5%), and fumarate (8.8%), and after multiple turns, [U-13C]OAA led to the production of the following 13C-labeled isotopomers: M+2 citrate (21.5%), M+2 glutamate (17.2%), M+1 glutamate (5.6%) and M+4 glutamate (2.2%). In addition, [U-13C]OAA also produced [U-13C]pyruvate (17.0%) through PEPCK/PK/ or malic enzyme which further generated similar amount of [U-13C]lactate (17.0%) and [U-13C]alanine (12%). These data demonstrate that GBM cells utilize [U-13C]OAA to perturb TCA cycle and glycolytic pathways, and support our previous observation that OAA-derived pyruvate lead to an increase in the total pyruvate pool and associated decrease in glycolytic flux including the glucose-derived lactate. OAA may metabolically reduce tumor growth in difficult to treat cancers.

25 Mar 2021·Neuro-Oncology Advances

FSMP-02. CHANGES IN GLUTAMINE METABOLISM INDUCED BY OXALOACETATE IN GLIOBLASTOMA

Author: Cash, Alan ; Baskin, David ; Conway, David ; Ijare, Omkar ; Pichumani, Kumar

AbstractAnhydrous Enol-Oxaloacetate (AEO) has been shown to significantly increase survival and decrease tumor growth rates in animal models of glioblastoma and hepatocellular carcinoma. In the body, AEO is metabolized to “oxaloacetate” (OAA). Earlier, we demonstrated that AEO drastically reduced Warburg glycolysis in glioblastoma cells which was determined by the increase in pyruvate to lactate ratio and a 48.8% decrease in lactate production in 13C-labeled glucose metabolism studies. We have expanded this previous work to examine 13C-labeled glutamine metabolism. Cultured solid tumor cancer cells strongly rely on both glucose and glutamine to synthesize carbon intermediates for anaplerotic reactions. With treatment of OAA, we hypothesize that glutamine-derived OAA may be reduced which can be tracked through the use GC-MS based 13C-labeled glutamine isotopomer experiments. Patient-derived glioblastoma cells were grown in 15 mM glucose and 2 mM glutamine containing DMEM medium supplemented with 2 mM OAA for 10 days. 24 hours prior to harvesting the cells, 4 mM of [U-13C]glutamine was introduced to the medium. OAA treated cells showed significant decrease in the protein levels of lactate dehydrogenase A and C which indicates the switching off of glycolysis to support the utilization of elevated OAA levels during glutamine metabolism in the TCA cycle. 13C mass distribution analysis showed significant decrease in malate, aspartate and citrate pools (malate: 8.8%, p = 0.0098; aspartate: 9.2%, p = 0.0064; citrate: 9.5%, p = 0.0036) in their M+4 isotopomer labeling in OAA treated group compared to the control group. Decrease in lactate generation may reduce cancer proliferation, migration and invasion. Together, these data provide alternative way to modulate energy metabolism in glioblastoma using AEO treatment. Similarly, AEO treatment in other solid tumors (e.g. pancreatic ductal adenocarcinoma) may produce altered glutamine metabolism which may be of therapeutic value.

11 Nov 2019·Neuro-Oncology

CBMT-49. OXALOACETATE ALTERS GLUCOSE METABOLISM IN GLIOBLASTOMA: 13C ISOTOPOMER STUDY

Author: Baskin, David ; Cash, Alan ; Conway, David ; Ijare, Omkar ; Pichumani, Kumar

AbstractAnhydrous enol-oxaloacetate (AEO) has demonstrated the ability to enhance neuronal cell bioenergetics and activate brain mitochondrial biogenesis. Since oxaloacetate has demonstrated positive effects on brain bioenergetics in neurodegenerative diseases we have begun to investigate whether AEO may also have a positive effect on the altered cellular metabolism found in cancer cells, particularly Glioblastoma multiforme. The “Warburg effect” describes an abnormal metabolic state in cancer, distinct from normal tissue, in which energy is generated through enhanced conversion of pyruvate to lactate even in the presence of oxygen during glycolysis. Oxaloacetate (OAA) is a key anaplerotic substrate that is required to maintain TCA cycle flux. The role of oxaloacetate supplementation on the energy metabolism is not known in cancer cells. Goal of this study is to investigate the changes in metabolic fluxes in glucose metabolism with and without the presence of OAA in patient-derived GBM cells. We use GC-MS based 13C isotopomer analysis for this study. GBM cells are grown in 15mM glucose containing DMEM medium supplemented with 2mM oxaloacetate for 10 days. 6 hours prior to harvesting, [U-13C]glucose is introduced to the medium. 13C isotopomer analysis of GC-MS data showed that OAA supplementation for 10 days drastically decreased Warburg glycolysis by reducing 13C labeling (M+3) by 19.7% and 48.8% in pyruvate and lactate pools respectively in comparison with cells not treated with OAA. M+3 13C labeled pyruvate entered TCA cycle via acetyl-CoA, where we also observed reduced levels of M+2 13C labeled citrate (20.5%) and glutamate (23.9%) isotopomers. Pyruvate can also enter TCA cycle via pyruvate carboxylation pathway and this activity was also found to be slightly decreased in the OAA treated cells. All the differences were statistically significant. These results indicate that OAA can be used to alter bioenergetics of GBM cells, specifically glucose oxidation.

100 Deals associated with MetVital, Inc.

100 Translational Medicine associated with MetVital, Inc.

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Drug(Targets)	Indications	Global Highest Phase

Anhydrous Enol-Oxaloacetate	Breast Carcinoma in Situ More	Phase 2
Oxaloacetate (MetVital)	Alzheimer Disease More	Phase 2
Oxaloacetic Acid (MetVital)	Amyotrophic Lateral Sclerosis More	Phase 1

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