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Purpose: Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC). Patients and Methods: Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable. Conclusion: Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

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Purpose:Devimistat (CPI-613) is a novel inhibitor of tumoral mitochondrial metabolism. We investigated the effect of devimistat in vitro and in a phase Ib clinical trial in patients with advanced biliary tract cancer (BTC).Patients and Methods:Cell viability assays of devimistat ± gemcitabine and cisplatin (GC) were performed and the effect of devimistat on mitochondrial respiration via oxygen consumption rate (OCR) was evaluated. A phase Ib/II trial was initiated in patients with untreated advanced BTC. In phase Ib, devimistat was infused over 2 hours in combination with GC on days 1 and 8 every 21 days with a primary objective to determine the recommended phase II dose (RP2D). Secondary objectives included safety, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).Results:In vitro, devimistat with GC had a synergistic effect on two cell lines. Devimistat significantly decreased OCR at higher doses and in arms with divided dosing. In the phase Ib trial, 20 patients received a median of nine cycles (range, 3–19). One DLT was observed, and the RP2D of devimistat was determined to be 2,000 mg/m2 in combination with GC. Most common grade 3 toxicities included neutropenia (n = 11, 55%), anemia (n = 4, 20%), and infection (n = 3, 15%). There were no grade 4 toxicities. After a median follow-up of 15.6 months, ORR was 45% and median PFS was 10 months (95% confidence interval, 7.1–14.9). Median OS is not yet estimable.Conclusion:Devimistat in combination with GC is well tolerated and has an acceptable safety profile in patients with untreated advanced BTC.

The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show that ETC suppression promotes resistance to proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response–dependent suppression of protein translation and ubiquitination, leading to PI resistance. ETC and protein translation gene expression signatures from the CoMMpass trial are down-regulated in patients with poor outcome and relapse, corroborating our in vitro findings. ETC-suppressed MM exhibits up-regulation of the cystine-glutamate antiporter SLC7A11 , and analysis of patient single-cell RNA-seq shows that clusters with low ETC gene expression correlate with higher SLC7A11 expression. Furthermore, erastin or venetoclax treatment diminishes mitochondrial stress–induced PI resistance. In sum, our work demonstrates that mitochondrial stress promotes PI resistance and underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic state.

The performance of immune checkpoint inhibitors, which benefit only a subset of patients and can cause serious immune-related adverse events, underscores the need for strategies that induce T-cell immunity with minimal toxicity. The gut microbiota has been implicated in the outcomes of patients following cancer immunotherapy, yet manipulating the gut microbiome to achieve systemic antitumour immunity is challenging. Here, we show, in multiple murine tumour models, that inulin — a widely consumed dietary fibre — formulated as a colon-retentive orally administered gel can effectively modulate the gut microbiome in situ, induce systemic memory-T-cell responses, and amplify the antitumour activity of the checkpoint inhibitor anti-programmed-cell-death-protein-1 (anti-PD-1). Orally delivered inulin-gel treatments increased the relative abundances of key commensal microbes and their short-chain-fatty-acid metabolites, and led to enhanced recall responses for interferon-γ+ CD8+ T cells as well as to the establishment of stem-like T-cell factor-1+ PD-1+ CD8+ T cells within the tumour microenvironment. Gels for the in situ modulation of the gut microbiome may be applicable more broadly to treat pathologies associated with a dysregulated gut microbiome., One-sentence editorial summary: An orally administered gel that is retained in the colon modulates the gut microbiome of mice with murine tumours, inducing systemic memory-T-cell responses, and amplifying the antitumour activity of a checkpoint inhibitor.

Chromosomal alterations that occur frequently in cancers confer selective advantages for tumor progression by deleting tumor-suppressing genes or amplifying oncogenic drivers. However, the collateral effect of these, i.e., deletion of essential genes or upregulation of metabolic regulators, exposes cancers to biological pressures by suppressing essential metabolic pathways. Cancer cells rely on paralogous metabolic pathways to compensate for this loss of function, which in turn opens the door to exploit metabolic vulnerabilities arising as a direct consequence of chromosomal alterations. These pathways are collateral lethal (CL) targets and offer a unique precision medicine approach for metabolic therapeutics. We have developed an integrated machine learning and systems biology platform, collateral lethal gene identification via metabolic fluxes (CLIM) to identify metabolic targets across multiple cancers. Results: In ovarian cancers with 19p13.3 deletion, a loss of Complex III subunit-encoding gene UQCR11 occurs, leading to suppressed electron transport chain (ETC) activity. CLIM predicted that MTHFD2 acts noncanonically to oxidize NADH to NAD+ to compensate for reduced NAD+ recycling via the ETC. We demonstrate selective death of ETC deficient ovarian cancers by targeting MTHFD2 and provide mechanistic validation of oxidative MTHFD2 flux. We observed significant shrinkage of ovarian tumors with ETC deficiency upon MTHFD2 knockdown in mouse models. In triple negative breast cancers (TNBC), we discovered a chromosomal amplification leading to reprogramming of the serine biosynthesis pathway. CLIM predicts a target in the tryptophan metabolism. Methods: Patients are stratified using machine learning to identify tumors with distinct chromosomal alterations. Multiobjective metabolic flux analysis is employed to predict CL pathways in curated genome-scale metabolic models. Validation of metabolic rewiring predicted by CLIM were examined using 3-2H-glucose, 4-2H-glucose and 2,3,3-2H-serine to probe the one carbon metabolism. Oxidative MTHFD2 flux was quantified using innovative combinatorial tracer study with 2H-formate and 4-2H-glucose. We utilized gain- and loss-of-function assays in multiple cell-lines to show utility of the predicted CL targets in TNBCs with chromosomal amplifications. Conclusion: Our integrated platform successfully identifies CL gene pairs to decipher novel metabolic targets specific to chromosomal alterations across many cancer types. Importantly, targets identified by CLIM are based on quantitative flux analysis. This approach reveals functional connection between CL pairs, thereby providing a mechanistic understanding of emerging lethality. This is critical in developing therapeutic interventions that selectively target cancer cells, with minimal off-target or side effects. Citation Format: Abhinav Achreja, Jin Heon Jeon, Mark Slayton, Tao Yu, Olamide Animasahun, Minal Nenwani, Fulei Wuchu, Anjali Mittal, Xiongbin Lu, Sofia D. Merajver, Deepak Nagrath. Identification of collateral lethal targets in cancers using integrated machine learning and flux analysis platform for personalized metabolic therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6037.

One of the most challenging aspects of PDAC is intense therapeutic resistance towards radiotherapy. Cellular signaling pathways are tightly regulated to protect and withstand constant DNA-damaging insults. Similarly, pancreatic cancer cells are known to activate important metabolic events in the advent of cellular stress. Fuel sources obtained via the high metabolic flexibility of PDAC cells confer on them enhanced survival and the ability to escape therapy-induced cell death. To this end, we aim to dissect the role of altered metabolic reprogramming in radioresistant PDAC cells. Investigation of systemic metabolic changes post-radiation of 8Gy in in vitro systems revealed reduced total NAD/NADH ratio and hinted at the increased dependency of PDAC cells on the one-carbon metabolic pathway. Using combinatorial stable-isotope tracing techniques, we confirmed the role of methylene tetrahydrofolate dehydrogenase (MTHFD1/2) enzymes as key regulators in maintaining total NAD/NADH ratio in irradiated cells. Moreover, inhibition of the one-carbon metabolic pathway hindered the ability of PDAC cells to resolve radiation-induced DNA damage. In summary, we propose that PDAC cells modulate the flux of MTHFD1/2 enzymes to reprogram their metabolic state and generate intermediates for DNA repair and cell survival, thus establishing MTHFD1/2 enzymes as potential therapeutic targets to tackle radioresistance. Citation Format: Minal Nenwani, Abhinav Achreja, Olamide Animasahun, Itisam Sarangi, Jyotirmoy Roy, Srinadh Choppara, Fulei Wuchu, Miya Paserba, Anjali Mittal, Sergio Quispe, Aradhana Mohan, Meredith Morgan, Theodore S. Lawrence, Deepak Nagrath. Targeting one-carbon metabolism radiosensitizes pancreatic ductal adenocarcinoma cells (PDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1092.

Cholangiocarcinoma is the second most common primary liver cancer with extremely low survival rates. However, a combination of gemcitabine and cisplatin is the only treatment for advanced unresectable cholangiocarcinoma currently, and the cancer can become resistant to the treatment, contributing to the high mortality. CPI-613 is a lipoic acid analog, which can inhibit dehydrogenases and disrupt mitochondrial metabolism. It is regarded as a promising anti-cancer drug and has been tested in multiple clinical trials. Efficacy and working mechanisms of CPI-613 have not been established in cholangiocarcinoma. In this study, we aim to evaluate the performance of CPI-613 in combination with other therapeutic drugs and unravel the metabolic underpinnings. We treated cholangiocarcinoma cell lines with different genetic backgrounds with standard of care chemotherapy (gemcitabine and cisplatin) alone, CPI-613 alone, or the combination of the two. Results from viability assay showed that CPI-613 had synergistic (not simply additive) effects with standard of care chemotherapy. CPI-613 has a relatively short half-life, so longer infusion may be more beneficial even if the total dose remains the same. To mimic longer infusion, we treated the cells with multiple times of drug addition (fractional dosing), and compared the results to single addition. Oxygen consumption rate (an indicator of mitochondrial function) of cells under fractional dosing regimen was significantly lower in both short and long term, as measured by Agilent Seahorse and Resipher respectively. The results provided mechanistic support for longer infusion in clinical practice. We also collected plasma from patients before, during and after CPI-613 treatment in a clinical trial, and global metabolomics was performed. Global metabolomic changes induced by CPI-613 were identified and specific alternations in patients with complete response could be exploited as treatment targets or prediction markers. High frequency of isocitrate dehydrogenase 1 (IDH1) mutation is a characteristic of cholangiocarcinoma. Ivosidenib, an IDH1 inhibitor, has been shown to improve survival in chemotherapy-refractory cholangiocarcinoma patients in a phase 3 clinical trial. However, ivosidenib can increase alpha-ketoglutarate concentration, hence increasing the flux of TCA cycle and boosting mitochondrial fitness of the cancer cells. We hypothesized that the combination of CPI-613 and Ivosidenib could negate this effect and have better anti-cancer activities. Indeed, results from viability assay demonstrated synergy between CPI-613 and Ivosidenib. Metabolic flux analysis and global metabolomics were performed to illustrate the metabolic mechanisms of the combination of CPI-613 and Ivosidenib. Our study provides the mechanistic support for the use of CPI-613 in combination with other therapeutic agents and the results should be translated to clinical studies. Citation Format: Fulei Wuchu, Olamide Animasahun, Srinadh Choppara, Valerie Gunchick, Minal Nenwani, Jyotirmoy Roy, Miya Paserba, Abhinav Achreja, Vaibhav Sahai, Deepak Nagrath. The role of CPI-613 in cholangiocarcinoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2236.

Branched-chain amino acids (BCAAs) supply both carbon and nitrogen in pancreatic cancers, and increased levels of BCAAs have been associated with increased risk of pancreatic ductal adenocarcinomas (PDACs). It remains unclear, however, how stromal cells regulate BCAA metabolism in PDAC cells and how mutualistic determinants control BCAA metabolism in the tumour milieu. Here, we show distinct catabolic, oxidative and protein turnover fluxes between cancer-associated fibroblasts (CAFs) and cancer cells, and a marked reliance on branched-chain α-ketoacid (BCKA) in PDAC cells in stroma-rich tumours. We report that cancer-induced stromal reprogramming fuels this BCKA demand. The TGF-β-SMAD5 axis directly targets BCAT1 in CAFs and dictates internalization of the extracellular matrix from the tumour microenvironment to supply amino-acid precursors for BCKA secretion by CAFs. The in vitro results were corroborated with circulating tumour cells (CTCs) and PDAC tissue slices derived from people with PDAC. Our findings reveal therapeutically actionable targets in pancreatic stromal and cancer cells.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle–related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT–expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Hepatocyte nuclear factor 4 alpha (HNF4α) is a transcription factor that plays a critical role in hepatocyte function, and HNF4α‐based reprogramming corrects terminal liver failure in rats with chronic liver disease. In the livers of patients with advanced cirrhosis, HNF4α RNA expression levels decrease as hepatic function deteriorates, and protein expression is found in the cytoplasm. These findings could explain impaired hepatic function in patients with degenerative liver disease. In this study, we analyzed HNF4α localization and the pathways involved in post‐translational modification of HNF4α in human hepatocytes from patients with decompensated liver function. RNA‐sequencing analysis revealed that AKT‐related pathways, specifically phospho‐AKT, is down‐regulated in cirrhotic hepatocytes from patients with terminal failure, in whom nuclear levels of HNF4α were significantly reduced, and cytoplasmic expression of HNF4α was increased. cMET was also significantly reduced in failing hepatocytes. Moreover, metabolic profiling showed a glycolytic phenotype in failing human hepatocytes. The contribution of cMET and phospho‐AKT to nuclear localization of HNF4α was confirmed using Spearman's rank correlation test and pathway analysis, and further correlated with hepatic dysfunction by principal component analysis. HNF4α acetylation, a posttranslational modification important for nuclear retention, was also significantly reduced in failing human hepatocytes when compared with normal controls. Conclusion: These results suggest that the alterations in the cMET‐AKT pathway directly correlate with HNF4α localization and level of hepatocyte dysfunction. This study suggests that manipulation of HNF4α and pathways involved in HNF4α posttranslational modification may restore hepatocyte function in patients with terminal liver failure., Although drug induced liver injury (DILI) is a rare clinical event, it carries significant morbidity and mortality, leaving it as the leading cause of acute liver failure in the United States. It is one of the most challenging diagnoses encountered by gastroenterologists. DILI is also the most common single adverse event that has led to withdrawal of drugs from the marketplace, drug attrition and failure of implicated drugs to obtain FDA approval. The development of various drug injury networks have played a vital role in expanding our knowledge regarding drug, herbal and dietary supplement related liver injury. In this review, we discuss what defines liver injury, epidemiology of DILI, it's biochemical and pathologic patterns, and management.

INTRODUCTION Proteasome inhibitors (PI) such as bortezomib (Velcade), carfilzomib (Kyprolis) and ixazomib (Ninlaro)) have been shown to be efficacious in multiple myeloma (MM) therapy. However, despite being an effective first line therapy, resistance to PI usually develops, leading to relapse and refractory disease. Previous studies have implicated a role of OXPHOS, glycolysis, antioxidants and serine metabolism in PI resistance. Mitochondrial metabolism plays a central role in malignant progression not only by generating ATP but also by providing precursors for synthesis of several biomolecules such as proteins, nucleotides, fatty acids and antioxidants that can influence the efficacy of MM therapies. We previously determined reduced mitochondrial electron transport chain (ETC) activity promotes sensitivity to the BCL-2 antagonist, venetoclax. However, the relationship between the metabolic state of the mitochondria and proteasome inhibitor (PI) sensitivity is not fully understood. Unexpectedly, we found ETC inhibition or reduced ETC activity to promote resistance to PIs. Here, we investigate the mechanistic basis for divergent effects of mitochondrial stress on sensitivity to PIs and venetoclax. METHODS We have used RNA-Seq and carbon isotope tracing using labeled U 13C-glucose or U 13C-glutamine, flow cytometry and western blot analysis in MM cell lines treated with mitochondrial Complex I inhibitor, IACS-010759 (IACS) +/- Bortezomib; and immunostaining of MM patient samples and interrogation of Multiple Myeloma Research Foundation's CoMMpass Study (NCT01454297, Interim Analysis 15). RESULTS We find that mitochondrial ETC (complex I-V) inhibition antagonizes bortezomib (BTZ) and carfilzomib (CFZ) induced cell death in MM in contrast to promoting sensitivity to venetoclax. Additionally, cell lines exhibiting intrinsically reduced ETC activity were more resistant to PI in comparison to cell lines with higher ETC activity. Evaluation of CoMMpass MM trial (NCT0145429, IA15) and serial samples from 50 patients before PI treatment and after relapse, show pathways related to OXPHOS and TCA cycle to be downregulated in poor survival patients, corroborating our in vitro observations on reduced ETC activity promoting resistance to PI. To elucidate the mechanistic basis of ETC-inhibition induced PI resistance we performed RNA-Seq and U 13C-glucose and glutamine tracing in L363 cells treated with the ETC Complex I inhibitor IACS +/- BTZ. RNA-Seq analysis and further confirmation by western blot analysis reveals integrated stress response (ISR) upregulation, ATF4 induction, and suppression of protein translation and global protein ubiquitination levels, likely responsible for resistance to proteasome inhibition in cells co-treated with IACS and BTZ compared to BTZ alone. Stable isotope tracing reveals an upregulation of reductive carboxylation; while RNA-Seq data and flow cytometry demonstrate increase in the cystine/glutamate transporter SLC7A11. The ensuing metabolic rewiring in mitochondrially suppressed MM induces several metabolic vulnerabilities including sensitivity to the SLC7A11 inhibitor, erastin. We also show that knockdown of ATF4 re-sensitizes ETC-inhibited cells to BTZ while ablating sensitivity to venetoclax (previously reported). Furthermore, examination of patient samples demonstrates inter-cellular heterogeneity in ATF4 expression. Our results thus, support the role ATF4 as key determinants of PI and BCL-2 antagonist efficacy. CONCLUSION We show mitochondrial ETC inhibition induces ISR mediated resistance to PI. These ETC-inhibited cells are however sensitive to BCL-2 antagonists and afford additional metabolic vulnerabilities that can be capitalized upon to target metabolic heterogeneity in MM. Our study underscores the need for implementing combinatorial regimens in MM cognizant of mitochondrial metabolic heterogeneity-mediated resistance. Disclosures Lonial: Janssen: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria. Boise: AstraZeneca: Consultancy, Research Funding; Abbvie: Consultancy. Jaye: Stemline Therapeutics: Honoraria. Nooka: Janssen Oncology: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Other: Travel expenses; Sanofi: Consultancy; Bristol-Myers Squibb: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Adaptive technologies: Consultancy; Karyopharm Therapeutics: Consultancy.

Large-scale chromosomal alterations, particularly chromosomal deletions in cancer genomes confer functional advantages to cancer cells via the loss of tumor suppressor genes (TSGs). However, due to the nature of these focal and arm-level deletions, essential house-keeping genes in the neighborhood of TSGs are potentially lost. We explore the emergence of metabolic adaptations and vulnerabilities that arise due to the collateral loss of essential metabolic genes. In our previous work, we showed that genomic loss in the locus containing SMAD4 and ME2 in pancreatic ductal adenocarcinomas forces these cells to rely on ME3 to compensate for the collateral loss of ME2; thereby revealing a highly selective metabolic target in these cells. Cancer cells can not only exploit such genetic redundancies but also rely on redundancies built into their complex metabolic network to compensate for the loss of metabolic function. Importantly, there is an unexplored landscape of these genomic loss events beyond well-characterized TSGs. To address these challenges, we have developed a platform to identify patient-specific metabolic vulnerabilities emerging due to distinct patterns of genomic loss events across tumors. Our platform presents opportunities for precision-based therapeutic intervention by targeting metabolic vulnerabilities in cancer patients. It uses genomic and clinical data available in cancer patient databases to obtain candidate metabolic genes that are lost to genomic deletions in an unbiased manner. To delineate metabolic redundances and tackle the complexity of genome-scale metabolic models, we employ an innovative multi-objective metabolic flux analysis approach. The utility of this platform is demonstrated via the discovery of a novel metabolic target in a cohort of ovarian cancer patients. The predicted collateral lethal target is validated in vitro using RNA interference and small-molecule inhibitors. Furthermore, we verify the metabolic mechanism of vulnerability predicted by the algorithm using deuterium tracing experiments. The target is also validated in vivo with mice containing ovarian tumors derived from cancer cells with and without the genomic deletion. Surprisingly, the collateral lethal metabolic target was also found to exist in a subset of aggressive endometrial cancers. Finally, we developed a multi-layer machine learning model to predict occurrence of the particular genomic deletion in ovarian and endometrial cancer patients with minimal molecular information to remove the need for whole-genome sequencing data. The model was trained and tested using the publicly-available molecular data from TCGA and AACR GENIE datasets. Citation Format: Abhinav Achreja, Tao Yu, Anjali Mittal, Srinadh Choppara, Noah Meurs, Olamide Animasahun, Jin Heon Jeon, Aradhana Mohan, Anusha Jayaraman, Reva Kulkarni, Justin Reinhold, Michele Cusato, Analisa Difeo, Xiongbin Lu, Deepak Nagrath. Genomic loss in cancers enable discovery of metabolic targets for precision cancer therapy via multiobjective flux analysis and machine learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 236.