Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function

Rajeshkumar, N. V.; Dutta, Prasanta; Yabuuchi, Shinichi; Wilde, Roeland F. de; Martinez, Gary V.; Le, Anne; Kamphorst, Jurre J.; Rabinowitz, Joshua D.; Jain, Sanjay; Hidalgo, Manuel; Dang, Chi V.; Gillies, Robert J.; Maitra, Anirban

doi:10.1158/0008-5472.can-15-0108

Cited by 138 publications

(124 citation statements)

References 47 publications

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“…27, 28 While HP-MRSI has not yet been explored clinically in the pancreas, hyperpolarized [1- 13 C]-pyruvate has been used previously in two pancreatic cancer mechanistic drug studies in mice and one study of pancreatic cancer diagnosis in mice. 29–31 The results of the animal studies are consistent with a marked upregulation of the pyruvate-to-lactate pathway that we observed at the level of transcriptomics and immunohistochemistry of human pancreatic cancer specimens.…”

Section: Discussionsupporting

confidence: 86%

Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms

et al. 2018

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Objective: We used transcriptomic profiling and immunohistochemistry (IHC) to search for a functional imaging strategy to resolve common problems with morphological imaging of cystic neoplasms and benign cystic lesions of the pancreas. Methods: Resected pancreatic cancer (n = 21) and normal pancreas were laser-capture micro-dissected, and transcripts were quantified by RNAseq. Functional imaging targets were validated at the protein level by IHC on a pancreatic adenocarcinoma tissue microarray and a newly created tissue microarray of resected intraductal papillary mucinous neoplasms (IPMNs) and IPMN-associated adenocarcinomas. Results: Genes encoding proteins responsible for cellular import of pyruvate, export of lactate, and conversion of pyruvate to lactate were highly upregulated in pancreatic adenocarcinoma compared to normal pancreas. Strong expression of MCT4 and LDHA was observed by IHC in >90% of adenocarcinoma specimens. In IPMNs, the pyruvate-to-lactate signature was significantly elevated in high grade dysplasia (HGD) and IPMN-associated adenocarcinoma. Additionally, cores containing HGD and/or adenocarcinoma exhibited a higher number of peri-lesional stromal cells and a significant increase in peri-lesional stromal cell staining of LDHA and MCT4. Interestingly, the pyruvate-to-lactate signature was significantly upregulated in cores containing only low grade dysplasia (LGD) from patients with histologically confirmed IPMN-associated adenocarcinoma versus LGD cores from patients with non-invasive IPMNs. Conclusion: Our results suggest prospective studies with hyperpolarized [1-13C]-pyruvate magnetic resonance spectroscopic imaging are warranted. If these IHC results translate to functional imaging findings, a positive pyruvate-to-lactate imaging signature might be a risk factor for invasion that would warrant resection of IPMNs in the absence of other worrisome features.

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Section: Discussionsupporting

confidence: 86%

Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms

et al. 2018

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“…A small pocket was prepared inside the pancreas into which one tumor cube was inserted and closed with an 8-0 nylon monofilament suture (49). Tumors were excised from the pancreas, weighed, and measured using digital calipers, and tumor volume (V) was calculated by the formula V = (largest tumor dimension) × (smallest tumor dimension) 2 × 0.52 (39,(49)(50)(51). Once a tumor volume of 50 mm 3 was reached (4 wk postimplantation), mice were treated with 12.5 mg/kg BPTES by intraperitoneal injection, 200 mg/kg CB-839 twice per d by oral gavage, 54 mg/kg BPTES-NPs (1.2 mg BPTES in 100 μL nanoparticles per mouse) by intravenous injection, blank-NPs (100 μL per mouse) by intravenous injection, 25 mg/kg gemcitabine intraperitoneally (25,26), 250 mg/kg metformin intraperitoneally daily (32,33), or a combination of BPTES-NPs with gemcitabine or metformin.…”

Section: Methodsmentioning

confidence: 99%

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

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Poore

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Targeting glutamine metabolism via pharmacological inhibition of glutaminase has been translated into clinical trials as a novel cancer therapy, but available drugs lack optimal safety and efficacy. In this study, we used a proprietary emulsification process to encapsulate bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), a selective but relatively insoluble glutaminase inhibitor, in nanoparticles. BPTES nanoparticles demonstrated improved pharmacokinetics and efficacy compared with unencapsulated BPTES. In addition, BPTES nanoparticles had no effect on the plasma levels of liver enzymes in contrast to CB-839, a glutaminase inhibitor that is currently in clinical trials. In a mouse model using orthotopic transplantation of patient-derived pancreatic tumor tissue, BPTES nanoparticle monotherapy led to modest antitumor effects. Using the HypoxCR reporter in vivo, we found that glutaminase inhibition reduced tumor growth by specifically targeting proliferating cancer cells but did not affect hypoxic, noncycling cells. Metabolomics analyses revealed that surviving tumor cells following glutaminase inhibition were reliant on glycolysis and glycogen synthesis. Based on these findings, metformin was selected for combination therapy with BPTES nanoparticles, which resulted in significantly greater pancreatic tumor reduction than either treatment alone. Thus, targeting of multiple metabolic pathways, including effective inhibition of glutaminase by nanoparticle drug delivery, holds promise as a novel therapy for pancreatic cancer.pancreatic ductal adenocarcinoma | glutaminolysis | glucose metabolism | KRAS mutation | intratumoral hypoxia P atients with pancreatic ductal adenocarcinoma (PDAC) have among the highest fatality rates of all cancers (1). Pancreatic cancer is predicted to become the second-leading cause of cancer death in the United States by the year 2030 (2). Over 90% of PDACs display mutations in oncogenic KRAS (Kirsten rat sarcoma viral oncogene homolog) (3, 4), a known regulator of glutamine metabolism that can render cancer cells dependent on glutamine for survival and proliferation (5, 6)-a state known as "glutamine addiction" (7, 8)-suggesting that dependency on glutamine could be exploited to develop new therapies for KRAS-mutated PDAC. The first step of glutamine metabolism is the conversion of glutamine to glutamate and ammonia, which is catalyzed by glutaminase (GLS). Bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), which is an allosteric, time-dependent (9), and specific inhibitor of GLS1, exhibits unique binding at the oligomerization interface of the glutaminase tetramer (10, 11). Although BPTES is more selective than other prototype glutaminase inhibitors, such as 6-diazo-5-oxo-L-norleucine (12) or ebselen (9), and can effectively inhibit GLS1 (13) and tumor growth (13-15), poor solubility (0.144 μg/mL) (16) has limited its clinical development. Recently, CB-839 (17) was tested in a phase I clinical trial. Abnormal liver and kidney function tests, lymphop...

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“…1; Racker et al 1985;Yun et al 2009;Gaglio et al 2011;Ying et al 2012). Inhibition of LDHA has shown promising effects in preclinical models (Le et al 2010;Rajeshkumar et al 2015), underscoring the important role of aerobic glycolysis in PDAC. In addition, oncogenic KRAS signaling induces the expression of monocarboxylate transporter 4 (MCT4), a lactate transporter, in PDAC cells to promote lactate efflux and thus mitigate the toxic effects of intracellular lactate accumulation due to elevated glycolysis (Baek et al 2014).…”

Section: Kras-dependent Glucose Metabolism Reprogrammingmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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With 5-year survival rates remaining constant at 6% and rising incidences associated with an epidemic in obesity and metabolic syndrome, pancreatic ductal adenocarcinoma (PDAC) is on track to become the second most common cause of cancer-related deaths by 2030. The high mortality rate of PDAC stems primarily from the lack of early diagnosis and ineffective treatment for advanced tumors. During the past decade, the comprehensive atlas of genomic alterations, the prominence of specific pathways, the preclinical validation of such emerging targets, sophisticated preclinical model systems, and the molecular classification of PDAC into specific disease subtypes have all converged to illuminate drug discovery programs with clearer clinical path hypotheses. A deeper understanding of cancer cell biology, particularly altered cancer cell metabolism and impaired DNA repair processes, is providing novel therapeutic strategies that show strong preclinical activity. Elucidation of tumor biology principles, most notably a deeper understanding of the complexity of immune regulation in the tumor microenvironment, has provided an exciting framework to reawaken the immune system to attack PDAC cancer cells. While the long road of translation lies ahead, the path to meaningful clinical progress has never been clearer to improve PDAC patient survival. Pancreatic ductal adenocarcinoma (PDAC) pathogenesisOn gross inspection, PDAC presents as a poorly demarcated, firm white-yellow mass, with the surrounding nonmalignant pancreas typically showing atrophy, fibrosis, and dilated ducts due to the obstructive effects of expanding carcinoma. Microscopically, these neoplasms vary from well-differentiated gland-forming carcinomas to poorly differentiated "sarcomatoid" carcinomas diagnosed only upon immunolabeling due to predominant mesenchymal features (Hruban et al. 2007). PDAC evolves from well-defined precursor lesions that, in the context of their genetic features, define the genetic progression model of pancreatic carcinogenesis (Yachida et al. 2010). Early disease histology manifests as several distinct types of precursor lesions-the most common are microscopic pancreatic intraepithelial neoplasia (PanIN), followed by the macroscopic cysts; namely, the intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) (Matthaei et al. 2011). Since most PDAC cases become clinically apparent at advanced stages, major opportunities to reduce mortality rest with diagnostics and treatments that would enable the reliable identification and elimination of high-risk precursor lesions. Thus, the identification of these precursor lesions has provided an essential framework to define the genomic features that drive progression to advanced disease and develop effective screening and targeted therapeutics for earlier stage disease (Eser et al. 2011).The noninvasive PanIN lesions were formerly classified into three grades according to the extent of cytological and architectural atypia: PanIN1A (flat lesion) and PanIN1B (micropapillary...

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Therapeutic Targeting of the Warburg Effect in Pancreatic Cancer Relies on an Absence of p53 Function

Cited by 138 publications

References 47 publications

Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms

Identification of a pyruvate-to-lactate signature in pancreatic intraductal papillary mucinous neoplasms

Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer

Genetics and biology of pancreatic ductal adenocarcinoma

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