Exploiting tumor metabolism: challenges for clinical translation

Heiden, Matthew G. Vander

doi:10.1172/jci72391

Cited by 70 publications

(60 citation statements)

References 58 publications

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“…To fuel their elevated demand for energy and macromolecular biosynthesis, cancer cells show augmented nutrient acquisition that is coupled to increased flux through downstream anabolic pathways for the biosynthesis of proteins, lipids, and nucleic acid (Dang 2012;Ward and Thompson 2012;Vander Heiden 2013;Boroughs and DeBerardinis 2015). This reprogramming of cellular metabolism to support continuous proliferation has been recognized in the updated "hallmarks of cancer" (Hanahan and Weinberg 2011).…”

Section: Pdac Metabolismmentioning

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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Section: Pdac Metabolismmentioning

confidence: 99%

Genetics and biology of pancreatic ductal adenocarcinoma

et al. 2016

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“…Pancreatic cancer is, however, very heterogeneous in its metabolic phenotypes, including the main metabolic pathways, such as KRAS signaling, glutamine-dependent metabolism, aberrant fatty acid and lipid metabolism and autophagy. Understanding aberrant signaling pathways and the complex metabolic networks of pancreatic cancer may open new possibilities for treating pancreatic cancer by selectively starving cancer cells or for the development of other types of therapies targeting tumor metabolism [130][131][132][133].…”

Section: • Targeting Cancer Metabolismmentioning

confidence: 99%

Pancreatic Cancer: Yesterday, Today and Tomorrow

et al. 2016

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Pancreatic cancer is one of our most lethal malignancies. Despite substantial improvements in the survival rates for other major cancer forms, pancreatic cancer survival rates have remained relatively unchanged since the 1960s. Pancreatic cancer is usually detected at an advanced stage and most treatment regimens are ineffective, contributing to the poor overall prognosis. Herein, we review the current understanding of pancreatic cancer, focusing on central aspects of disease management from radiology, surgery and pathology to oncology. Historical remarks & present stateThe first known description of pancreatic cancer is attributed to Giovanni Battista Morgagni in his 1761 publication 'de Sedibus Et Causis Morborum Per Anatomen Indagatis Libri Quinque' [1]. However, the lack of a microscopic evaluation makes the true diagnosis of ductal adenocarcinoma uncertain. The next important advancement in our understanding of pancreatic cancer did not come until 1858, when Jacob Mendez Da Costa revisited Morgagni's original work and also described the first microscopic diagnosis of adenocarcinoma, manifesting pancreatic cancer as a true disease entity [2].The history of pancreatic surgery is fairly recent and involves a combination of brave surgical pioneers, the development of surgical anesthesia and modern aseptic techniques. Some landmarks in the history of pancreatic surgery deserve to be mentioned. The first reported attempt at a pancreaticoduodenectomy was performed in 1898 by the Italian surgeon Alessandro Codivilla for a tumor involving the head of the pancreas [3]; however, the patient did not survive the postoperative period. In the same year, William Stewart Halsted from Johns Hopkins Hospital performed the first successful resection for ampullary cancer by excising portions of the duodenum and the pancreas [4]. The first successful pancreaticoduodenectomy is credited to the German surgeon Walther Carl Eduard Kausch, as part of a two-stage procedure [5]. In 1914, Georg Hirschel performed the first successful pancreaticoduodenectomy in one stage [6] and then in 1935, Allen Oldfather Whipple presented the results of a two-stage procedure involving the resection of the head of the pancreas and duodenum for ampullary carcinoma at the annual meeting of the American Surgical Association, which renewed interest in pancreatic surgery [7]. During his career, Whipple performed 37 pancreaticoduodenectomies, with the procedure evolving into a one-stage technique [8,9], and 1964-1968 1969-1973 1974-1978 1979-1983 1984-1988 1989-1993 1994-1998 1999-2003 2004-2008 2009-2013 Period of diagnosis Whipple is generally credited with popularizing the operation that still bears his name. In 1937, Alexander Brunschwig performed the first successful pancreaticoduodenectomy for pancreatic adenocarcinoma [10]. Today, with the concentration of experience in high-volume hospitals, pancreatic surgery has become a safe procedure associated with an operative mortality below 3% [11][12][13]. While major advances have been made ...

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“…The central role of glutamine metabolism in cancer cell growth makes glutaminolytic enzymes attractive targets for anticancer therapy (9,(16)(17)(18)(19)(20). Glutaminase catalyzes the first step of glutamine metabolism by converting glutamine to glutamate and ammonia.…”

Section: Introductionmentioning

confidence: 99%