Review

Cite This: Chem. Rev. 2018, 118, 6893−6923 pubs.acs.org/CR

Cancer Metabolism: Current Understanding and Therapies Jessica L. Counihan, Elizabeth A. Grossman, and Daniel K. Nomura*

Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, California 94720, United States

ABSTRACT: Dysregulation of cancer cell metabolism contributes to abnormal cell growth, the biological end point of cancer. We review here numerous affected oncogenes and metabolic pathways common in cancer and how they contribute to cancer pathogenesis and malignancy. This review also discusses various pharmacological manipulations that take advantage of these metabolic abnormalities and the current targeted therapies that have arisen from this research.

CONTENTS pathogenicity.1,2 The genomic landscape of cancer is highly complex with a high level of heterogeneity.3 It has been 1. Introduction 6893 determined, however, that many of the mutational or somatic 2. Oncogenes and Tumor Suppressors 6893 ff changes in cancer cells impact commonly and fundamentally 2.1. Warburg E ect: The Link Between Onco- impact cancer metabolism. In this review, we will discuss many genesis and Metabolism 6893 aspects of altered cancer cell metabolism and the current 2.2. Tumor Suppressor Loss 6897 therapies developed to target these alterations. We will first 3. Glucose Metabolism 6899 discuss the major mutated oncogene and tumor suppressors that 3.1. Glycolysis 6899 impact cancer cell metabolism. We then discuss the major 3.2. Lactate Metabolism 6900 alterations in nutrient metabolism and changes of associated 3.3. Pyruvate Dehydrogenase Complex 6900 proteins within various metabolic pathways. Along the way, we 3.4. Tricarboxylic Acid Cycle 6901 consider current targeted therapies, either in preclinical or 3.5. Electron Transport Chain and Oxidative clinical trials that are currently being researched and developed Phosphorylation 6902 to target these metabolic dysregulations. 4. Amino Acid Metabolism 6903 4.1. Glutamine 6904 2. ONCOGENES AND TUMOR SUPPRESSORS 4.2. Asparagine 6905 4.3. Serine 6906 2.1. Warburg Effect: The Link Between Oncogenesis and 4.4. Tryptophan 6906 Metabolism 5. Additional Pathways 6907 A well-known dysregulation in cancer metabolism is Warburg’s 5.1. One-Carbon Metabolism 6907 observation that cancer cells upregulate their use of glucose and 5.2. Pentose Phosphate Pathway 6908 produce more lactic acid than normal tissues.4 Recent research 5.3. NADPH 6908 has implicated oncogenic activation as the main cause, though 6. Fatty Acid Metabolism 6908 not the only cause, of the “Warburg effect”.5,6 The Warburg Downloaded via UNIV OF CALIFORNIA BERKELEY on July 25, 2018 at 15:41:18 (UTC). 6.1. Fatty Acid Anabolism 6909 effect, also more broadly called fermentation or aerobic See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles. 6.2. Fatty Acid Oxidation 6911 glycolysis (though it takes place under anaerobic conditions in 7. Conclusion 6911 cancer cells as well), is considered a hallmark of dysregulated Author Information 6912 metabolism in many types of cancer cells. While resting cells Corresponding Author 6912 typicallyrelyonmitochondrial oxidation to meet their ORCID 6912 bioenergetic needs, cancer cells often utilize aerobic glycolysis Notes 6912 for both energy and proliferative pathogenesis. Even though Biographies 6912 mitochondrial oxidation yields much more energy for a cell per Acknowledgments 6912 glucose, tumor cells are thought to utilize aerobic glycolysis to References 6912 allow diversion of glycolytic intermediates to biosynthetic pathways to generate nucleotides, lipids, and amino acids, among others, necessary for cell growth and division.7 Though 1. INTRODUCTION this is generally how the Warburg effectiscanonically The development of cancer depends on alterations or mutations understood, recent studies of sources for biosynthesis have arising within the cell, driving aberrant behavior that can bypass revealed that glucose and glutamine, and their associated the typical checkpoints required for normal cell health. Mutations or expression changes in oncogenes and tumor Received: December 29, 2017 suppressors are known to alter cellular metabolism to fuel cancer Published: June 25, 2018

© 2018 American Chemical Society 6893 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review increase due to the Warburg effect, are not the main providers of Table 1. Drugs Targeting Oncogenes for Cancer Treatment material for mass accumulation.8 A full understanding of the and Their Stage in Clinical Development or Use Warburg effect’s impact on cancer cell metabolism is yet to be clinical elucidated. compound target trial phase relevant cancer(s) Altered metabolism is found across many different cancer cell pictilisib (GDC0941) PI3K inhibitor phase II breast, NSCLC types. Although cells that are functioning under the Warburg buparlisib (BKM120) PI3K inhibitor phase III breast, cervical, effect produce about 20 times less ATP than oxidative NSCLC, colorec- respiration does per glucose molecule, ATP is rarely limiting tal, prostate in cancer cells. Further, the building blocks needed for Temsirolimus mTOR inhibitor approved tumorigenesis, including the reducing power NADPH, nucleo- Everolimus mTOR inhibitor approved tides, lipids, and amino acids, are increased in availability NVP-BEZ235 PI3K/mTOR inhibi- phase II breast, pancreatic, tor renal, endometrial, corresponding to the increased flux through glycolysis via the glioblastoma Warburg effect. Thus, increasing glycolysis and fermentation, AZD8055 mTOR kinase inhib- phase I glioma, solid tumors while simultaneously decreasing mitochondrial oxidation, itor enables cells to balance their energetic requirements with their Lapatinib TK inhibitor approved capacity to divide. Additionally, it has been shown that the (HER2, EGFR) Iressa EGFR inhibitor approved production of lactate happens anywhere from ten to one (ZD1839, gefitinib) 9,10 hundred times faster than glucose oxidation. In order for Tarceva (OSI-774) EGFR inhibitor approved cancer cells to utilize the advantageous Warburg effect, they PKI116 EGFR inhibitor NA must undergo genetic mutations or possess some form of GW2016 EGFR inhibitor phase II breast, prostate, varying transcriptional profiles.11,12 Of note, the Warburg effect ovarian, perito- is most likely a primary event in oncogenesis and does not neal, stomach, liver EKB-569 EGFR inhibitor phase II NSCLC, colorectal happen in all cancer cells. For example, it is an immediate result CI-1033 (PD183805) EGFR inhibitor phase II breast, lung, NSCLC of an initial oncogenic KRAS mutation in pancreatic cancer and 9,13,14 Zarnestra (Tipifar- farnesyltransferase phase III pancreatic, lung, of BRAF in melanoma. nib) inhibitors breast, colorectal, One well-researched connection between tumorigenesis and thyroid, prostate glucose metabolism is the serine/threonine kinase AKT/ FTI-277 farnesyl transferase NA phosphoinositide 3-kinase (PI3K)/mammalian target of inhibitor GGTI-298 geranylgeranyl trans- NA rapamycin (mTOR) signaling pathway. PI3K signaling can ferase inhibitor directly upregulate glucose intake and metabolism via various 10058-F4 MYC/MAX interac- NA mechanisms, including increased localization of the glucose tion disruptor transporter, namely GLUT1, to the plasma membrane and KJ-Pry-9 MYC/MAX interac- NA through increasing hexokinase (HK), phosphofructokinase-1 tion disruptor 11,15−17 Omomyc MYC/MAX interac- NA (PFK-1), and phosphofructokinase-2 (PFK-2) activities. tion disruptor PI3K also phosphorylates phosphatidylinositol 4,5-bisphos- phate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 can then stimulate AKT; AKT plays numerous important biological roles within the cell. For example, AKT results, the combination of pictilisib and fulvestrant was regulates cellular growth via its effects on the tuberous sclerosis correlated to a progression-free survival that increased from (TSC1/TSC2) complex and mTOR signaling.18,19 AKT can 5.1 to 6.6 months.29 Pictilisib is also currently undergoing trials also regulate cell proliferation and survival through phosphor- to treat nonsmall cell lung cancer (NSCLC) as well. BKM120, ylation of cyclin-dependent kinase (CDK) inhibitors for the also called buparlisib (Novartis Pharmaceuticals), is another former and inhibition of pro-apoptotic proteins and signals, such − PI3K inhibitor that is more advanced in clinical development. as Bad or the transcription factor FoxO, for the latter.19 21 The BELLE-2 study (NCT01610284) is a phase III trial which AKT/PI3K’s downstream effector, mTOR, is crucial for randomized 1148 postmenopausal women with HR+/HER2- cellular proliferation and growth. mTOR belongs to two advanced breast cancer after progression on AI to fulvestrant and separate complexes, mTOR complex 1 (mTORC1) and buparlisib or fulvestrant and placebo. Another trial, the BELLE- mTOR complex 2 (mTORC2), which are structurally similar 3 study (NCT01633060), looks at the same treatment but functionally different. mTORC1 positively regulates protein combination in patients whose cancer has progressed after an translation and plays roles in lipid synthesis and glucose AI and mTOR inhibitor. metabolism,22,23 while mTORC2, on the other hand, regulates The first mTOR inhibitor in clinical use was rapamycin, which AKT phosphorylation.24 was initially given as an immunosuppressant medication after Due to altered AKT/PI3K/mTOR signaling frequently transplant surgeries. Later, Temsirolimus, a rapamycin deriva- contributing to human disease, researchers have been keen to tive, was developed and is currently approved to treat renal cell develop small molecule inhibitors for AKT, PI3K, and carcinoma (RCC). Everolimus, another rapamycin analogue − mTOR.25 27 For example, upregulation of the AKT/PI3K/ and mTOR inhibitor, is approved for treatment in post- mTOR pathway occurs in approximately 70% of breast menopausal women with HR+ breast cancer among other cancers.28 Data from a randomized phase II clinical trial, called cancer types, including RCC, pancreatic, subependymal giant the FERGI trial (NCT01437566), evaluated the role of adding cell astrocytomas, and neuroendocrine tumors26 (Figure 1). pictilisib, also called GDC-0941 (Genentech), a PI3K inhibitor, These analogues, cleverly called “rapalogues”, exert their effect to fulvestrant, a steroidal antiestrogen hormone therapy drug, to mainly as mTORC1 allosteric inhibitors. However, since only treat patients with advanced ER+, aromatase inhibitor (AI)- the mTORC1 complex is inhibited, their use is sometimes resistant or metastatic breast cancer (Table 1). In preliminary accompanied by resistance, such as negative feedback regulatory

6894 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Figure 1. Analogs of rapamycin, or “rapalogues” that have been developed as cancer therapies. mechanisms, leading to paradoxical AKT activation and The Warburg effect is positively regulated by oncogenes, such downstream proliferative effects.30 as KRAS and MYC.33 Activation of the oncogenic RAS has been mTOR is constitutively activated in some forms of cancer, shown to significantly impact various aspects of cancer cell such as acute myeloid leukemia (AML), and is currently a target malignancy, including the dysregulation of cell growth, for inhibitor development. Many mTOR kinase inhibitors can apoptosis, and invasiveness among others.34 Three canonical suppress protein translation and synthesis and induce cell members of the RAS family, HRAS, KRAS, and NRAS, have 31,32 apoptosis. For example, the mTORC1 pathway is normally been found to be oncogenic.35 The HRAS, KRAS, and NRAS rapamycin-sensitive; in AML, however, the leukemia cells are enzymes are broadly expressed; KRAS, for example, is expressed rapamycin-resistant and protein translation becomes dysregu- in nearly every human cell type. In addition to its ubiquitous lated. Treatment of AML with NVP-BEZ235 (Novartis expression, KRAS has also been shown in previous knockout Pharmaceuticals), a dual PI3K/mTOR inhibitor, has been mice studies to be essential for normal development.36 shown to inhibit protein translation, PI3K signaling, mTORC1 31 Many receptor types, including tyrosine kinases and G- signaling, and mTORC2 activity. Additionally, the prolifer- protein-coupled receptors, can activate RAS.37 For example, the ation rate in AML cells was reduced and induction of an epidermal growth-factor receptor (EGFR), through growth- apoptotic response occurred, without affecting normal factor-receptor-bound protein 2 and the Son of Sevenless CD34(+) survival, when treated with NVP-BEZ235.31 It has proteins, can activate RAS via increased exchange of GDP with additionally been shown that another inhibitor, AZD8055, ff which is a specific mTOR inhibitor, was able to block both GTP. GTP-bound RAS is then able to activate various e ector mTORC1 and mTORC2 signaling in AML cells. Significantly, enzymes, such as the serine/threonine kinase RAF (i.e., c-RAF1, AZD8055 blocked PI3K/AKT feedback activation, which is BRAF, and ARAF) which promotes cell cycle progression mTORC1-dependent, in AML cells in situ.32 Although clinical through the mitogen-activated protein kinase (MAPK) path- way,38 PI3K which promotes apoptosis evasion through the trials are not yet underway in treating AML, AZD8055 is 39,40 undergoing testing in numerous phase I clinical trials for other AKT/PI3K pathway and the RAS-related RAL proteins tumor types, including one to treat recurrent gliomas which evade cell cycle arrest and apoptosis by inhibiting 41 (NCT01316809), another to treat advanced solid tumors transcription factors of the FoxO family. These pathways, (NCT00731263), and also one to treat liver cancer among others, enable activated RAS to significantly contribute (NCT00999882). Due to the critical role of the AKT/PI3K/ to tumorigenesis. Targeting RAS and its associated downstream mTOR signaling pathway in cancer metabolism, this signaling effector pathways is, therefore, an attractive therapeutic pathway remains an important therapeutic target. objective.

6895 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Table 2. Drugs Targeting Tumor Suppressors for Cancer Treatment and Their Stage in Clinical Development or Use

compound target clinical trial phase relevant cancer(s) CP-31398 p53 reactivator NA STIMA-1 p53 reactivator NA PRIMA-1MET (APR-246) p53 reactivator phase II ovarian, esophageal, AML, melanoma MIRA-1 p53 reactivator NA NSC652287 p53 reactivator NA NSC319726 (ZMC1) p53 reactivator NA NSC87511 p53 reactivator NA Chetomin p53 reactivator NA PK7088 p53 reactivator NA SCH529074 p53 reactivator NA 17-AAG (tanespimycin) Hsp90 inhibitor phase III gastrointestinal, ovarian, pancreatic, prostate, NSCLC IPI-504 Hsp90 inhibitor phase II breast, prostate, NSCLC, lung, kidney, gastrointestinal Ganetespib Hsp90 inhibitor phase III NSCLC, breast, ovarian, lung, rectal Vorinostat HDAC inhibitor approved Gambogic acid (p53?) NA Spautin-1 (p53?) NA YK-3−237 (p53?) NA NSC59984 (p53?) NA Temsirolimus mTORC1 inhibitor approved AZD6482 PI3K/p110B inhibitor NA MK-2206 AKT inhibitor phase II colon, rectal, breast, NSCLC rapamycin mTOR inhibitor approved geldenamycin Hsp90 inhibitor NA 17-(allylamino)-17- demethoxygeldanamycin Hsp90 inhibitor phase II leukemia, lymphoma bevacizumab VEGF antibody approved sorafenib anti-VEGF tyrosine kinase inhibitor approved pazopanib anti-VEGF tyrosine kinase inhibitor approved

RAS and its effector pathways often undergo aberrant NCT00137800, and NCT00063895), ovarian cancer signaling in cancer via mutational damage, including the RAS (NCT00063895), and head and neck cancer genes. More than 20% of tumors have mutations in RAS; KRAS (NCT00063895).46 OSI-774 has been studied in combination comprises approximately 85% of the total RAS mutations.37,42 as well, including OSI-774 plus gemcitabine in pancreatic cancer These mutations all prevent GTP hydrolysis on RAS, causing (NCT00040183). Other EGFR inhibitors in clinical trials accumulation of GTP-bound (active) RAS. As mentioned include GW2016 (GlaxoSmithKline), PKI116 (Novartis), EKB- previously, overexpression of EGFR activates RAS signaling 569 (Wyeth-Ayerst/Genetics Institute), and CI-1033 (Pfizer). pathways; overexpression of HER2 is another common example. Taken together, EGFR inhibitors seem to be a promising lead EGFR and HER2 are frequently overexpressed in many types of toward the treatment of numerous carcinomas. cancers, including ovarian, breast, and stomach carcinomas.43 For RAS proteins to function normally, they must first be Receptor tyrosine kinases, such as EGFR and HER2, activate post-translationally modified via prenylation, most often by the downstream signal transduction pathways that coordinate covalent addition of a farnesyl isoprenoid group.47 Prenylation tumor cell growth.44 Lapatinib is an FDA-approved tyrosine serves to localize RAS proteins to the plasma membrane or kinase inhibitor that targets both EGFR and HER2.45 At least six another subcellular compartment. Since mislocalized RAS other EGFR small-molecule inhibitors are presently under proteins are inactive, the enzymes involved in post-translational evaluation in clinical trials. Two of these drugs have shown modification of RAS are attractive therapeutic targets.37,48 especially great potential and are at an advanced stage of Alternatively, some RAS proteins, including KRAS and NRAS, − development, ZD1839, also called Gefitinib or Iressa but not HRAS,49 51 can also undergo geranylgeranylation. By (AstraZeneca) and OSI-774, also called Tarceva or Erlotinib using high-throughput screening of compound libraries, a large (OSI Pharmaceuticals/Genentech). ZD1839 has been tested in number of highly effective farnesyl transferase inhibitors that are several phase I and II clinical trials and has shown little toxicity. specifically effective against HRAS mutations, which cannot be Encouragingly, its use in numerous cancer types, including alternatively modified via geranylgeranylation, have been advanced NSCLC (NCT00259064, NCT00770588, and identified and developed as potential cancer therapies.52,53 NCT01017679), metastatic squamous cell carcinoma (SCC; Tipifarnib, also called Zarnestra (Kura Oncology), is currently NCT00054691), and adrenocortical carcinoma (ACC; being evaluated in phase II clinical trials, including a trial that NCT00215202), has shown promising antitumor activity. targets advanced tumors with HRAS mutations, specifically Some combinatorial studies have also occurred, including HRAS-mutated thyroid and squamous head and neck cancer comparing ZD1839 with anastrozole to ZD1839 with (NCT02383927). For those RAS proteins, such as KRAS, that fulvestrant in postmenopausal women with metastatic breast can gain resistance against farnesyl transferase inhibitors via cancer (NCT00057941). Phase I, II, and III clinical trials are geranylgeranylation, geranylgeranyl transferase inhibitors are also currently underway for OSI-774 and have shown promising also being developed. For example, cotreatment with FTI-277, a results in NSCLC (NCT00036647, NCT00072631, farnesyl transferase inhibitor, and GGTI-298, a geranylgeranyl

6896 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review transferase inhibitor, inhibited KRAS prenylation in multiple NSC319726/ZMC1, NSC87511, Chetomin, PK7088, and the human cancer cell lines that were initially resistant to FTI-277 small-molecule SCH529074.70 As of current, PRIMA-1MET is alone.54,55 the only compound listed here presently undergoing clinical As mentioned previously, MYC also positively regulates the trials; it has been shown to be safe and has a favorable Warburg effect. MYC is an important transcription factor within pharmacokinetic profile thus far (NCT02999893 and cells and is involved in numerous important processes including NCT00900614).72 proliferation, cellular differentiation, metabolism, and apopto- The second main approach to drug mutant p53 relies on sis.56,57 MYC can promote activation or repression of genes that discovering and developing compounds that specifically deplete are part of the aforementioned processes on a global scale within mutant p53 while leaving wild-type p53 intact. Although the cells.58,59 In normal cells, MYC expression is tightly mechanism still remains unclear, several mutant p53-depleating regulated;60,61 in cancer cells, however, various abnormalities, compounds have been found. 17-AAG and Ganetespib, both such as gene amplification, chromosomal translocation, or Hsp90 inhibitors, are able to deplete mutant p53, along with Raf- mutations in signaling pathways, can stimulate MYC over- 1 and ErbB2, since Hsp90 has been previously shown to expression, leading to cell proliferation and tumorigenesis.62 contribute to the accumulation of mutant p53.68,73,74 An analog When MYC becomes oncogenic, it drives cancer cell growth, of 17-AAG, IPI-504, has been tested in clinical trials, mostly cell, metabolism (including promoting glutaminolysis which we looking at its use in NSCLC and gastrointestinal stromal tumors will cover later in more depth), and cell survival. Importantly, (GIST).75,76 A recent phase II clinical trial looking at IPI-504 in MYC is dysregulated in about 70% of human cancers.58 NSCLC patients with ALK mutations was terminated due to Furthermore, it has been shown tumor regression and cell slow patient accrual (NCT01228435). The GIST trials were differentiation occur when MYC activity is inhibited.63 The also terminated; there were multiple observed mortalities in widespread activation of MYC, as well as observed tumor these patients given IPI-504 (NCT00688766). Ganetespib regression when MYC is inhibited, has driven researchers to (Synta Pharmaceuticals Corp.) is also currently being studied in explore MYC as a target for cancer therapy. clinical trials, including phase II for metastatic breast cancer and Many efforts have been made to discover compounds that can phase III for NSCLC.77,78 Ganetespib was also granted Fast deliberately target MYC for cancer therapy. This has proved an Track status by the FDA in two clinical trials, GALAXY-1 immense challenge, however, since MYC lacks functional (NCT01348126) and GALAXY-2 (NCT01798485), which are binding pockets that small-molecules may bind and is localized currently examining the use of ganetespib in combination with within the nucleus, which makes it inaccessible to any antibody- Taxotere for treating advanced lung adenocarcinoma, a type of based therapies. Researchers have, thus, taken advantage of NSCLC. Unfortunately, despite positive results in the phase II MYC’s heterodimerization with MAX, which is essential for GALAXY-1 study, the phase III GALAXY-2 study did not MYC DNA-binding activity, to develop drugs that will disrupt improve overall or progression-free survival and was ultimately 79 this interaction. 10058-F4, KJ-Pyr-9, and Omomyc compounds terminated after the first interim analysis due to futility. all disrupt the MYC/MAX interaction and have shown efficacy Inhibitors of histone deacetylases (HDAC), which prevent in in vivo experiments.64 Hsp90 from complexing with p53, have also been devel- 68,80 2.2. Tumor Suppressor Loss oped. In fact, one compound, Vorinostat, is already FDA- approved for use in relapsed or refractory cutaneous T cell A well-known and well-researched tumor suppressor is p53, lymphoma. Other drugs in development to deplete mutant p53 which is integral to apoptosis and cell cycle regulation, and is include the natural product Gambogic acid, Spautin-1, YK-3- implicated in DNA damage sensing. Furthermore, p53 has also 237, and the small molecule NSC59984.70 been shown to counteract the Warburg effect, working to Another important tumor suppressor is phosphatase and stimulate respiration and reduce glycolytic flux. p53 plays an tensin homologue (PTEN). PTEN is absent in approximately integral role in blocking the formation of tumors, and, therefore, 40% of tumors, second most to p53.81 PTEN normally when a point mutation or deletion leads to loss of p53 function, antagonizes the AKT/PI3K/mTOR pathway to block tumor cancer cells are better able to evade apoptosis and gain cell growth and survival; loss of PTEN’s tumor suppressor insensitivity to antigrowth signals, leading to immortalization fi − activity activates the PI3K pathway in cancer cells. Speci cally, and cancer.65 67 Of importance, it has previously been observed the PTEN gene encodes a lipid-phosphatase that removes one that roughly 50% of cancers have p53 gene mutations.68 Two phosphate group from phosphatidylinositol (3,4,5)-trisphos- key strategies have been employed to target cancer cells with p53 phate (PIP3) and phosphatidylinositol (4,5)-bisphosphate mutation: first, developing drugs that reinstate wild-type p53 (PIP2), thereby reversing their accumulation caused by PI3K. activity and, second, developing drugs that deplete mutant p53. PTEN also promotes DNA repair and chromosome stability Most p53 mutants are no longer able to bind with p53-specific within the nucleus. response elements and, therefore, lose their transcriptional Since loss of PTEN activity leads to PIP3 accumulation, and activity and tumor suppressive functions.69 However, it has subsequently an activated AKT/PI3K/mTOR pathway,82 previously been shown that p53 transcriptional activity can be researchers are interested in finding therapeutics that target restored from mutant p53.70 For example, CP-31398 was the this pathway. For example, it has been shown in mouse models first drug identified that can restore p53 activity from mutant that genetic loss of PTEN is associated with increased sensitivity p53.69 Since then, researchers have been developing compounds to Temsirolimus (an mTORC1 inhibitor), AZD6482 (a PI3K that restore p53 activity (Table 2). CP-31398, along with inhibitor), MK-2206 (an AKT inhibitor), and 17-AAG (a another p53-reactivating compound, STIMA-1, binds to the HSP90 inhibitor).83 mutated p53 and stabilize the wild-type p53 conformation; now Deletion of the von Hippel-Lindau (VHL) tumor suppressor in its active-from conformation, p53’s transcriptional activity is gene was identified in the 1990s as the genetic source for VHL restored.71 Other p53 wild-type restoration compounds include disease.84 The VHL gene product, protein VHL (pVHL), plays PRIMA-1MET (or APR-246), MIRA-1, NSC652287, an integral role in oxygen sensing; it specifically targets hypoxia-

6897 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Figure 2. Glucose metabolism in cancer and associated dysregulations and inhibitor therapies. Glycolysis is a series of metabolic processes; it involves nine reactions, of which three are highly regulated (hexokinase (HK), phosphofructokinase (PFK), and pyruvate kinase (PK)). As indicated, this pathway also fuels several other pathways, including the pentose phosphate pathway (PPP) and the hexosamine synthesis pathway. Glucose metabolism also contributes to the biosynthesis of fatty acids (FAs) and serine, among others. In cancer cells, pyruvate’s conversion into lactate is upregulated but can also be imported into the mitochondrial matrix to fuel the tricarboxylic acid (TCA) cycle. Thicker black arrows indicate reactions that are upregulated in cancer cells. Similarly, upregulated enzymes in cancer metabolism are indicated with bolded text. Current cancer therapies in clinic or preclinic targeting enzymes associated with glucose metabolism are shown in red. Oncogenes that upregulate glucose metabolism in cancer cells are indicated in blue. Transporters: glucose transporter (GLUT); monocarboxylate transporter (MCT). Glycolytic intermediates: glucose-6- phosphate (G-6-P), fructose-6-phosphate (F-6-P); fructose-1,6-bisphosphate (F-1,6-BP); fructose-2,6-bisphosphate (F-2,6-BP); dihydroxyacetone phosphate (DHAP); glyceraldehyde-3-phosphate (G-3-P); 1,3-bisphosphoglycerate (1,3BPG); 3-phosphoglycerate (3PG); 2-phosphoglycerate (2PG); phosphoenolpyruvate (PEP). Enzymes: glucose-6-phosphate isomerase (GPI); aldoase (ALDO); glyceraldehyde 3-phosphate dehydrogenase (GAPDH); phosphoglycerate kinase (PGK); phosphoglycerate mutase (PGAM); enolase (ENO); lactate dehydrogenase (LDH); pyruvate dehydrogenase kinase (PDK); pyruvate dehydrogenase complex (PDC). Oncogenes: phosphatidylinositol-3 kinase (PI3K); mammalian target of rapamycin (mTOR). Chemical inhibitors: 2-deoxy-glucose (2-DG); 3-bromopyruvate (3BP), koningic acid (KA); dichloroacetate (DCA). inducible factors (HIF), including HIF-1α, HIF-2α, and HIF- not yet exist, multiple drugs have been reported to indirectly − 3α, for ubiquitination and proteasomal degradation.85 88 Since downregulate HIF. For example, it has been previously shown its discovery, researchers have identified that early loss of VHL that the mTOR inhibitor rapamycin can downregulate − function is frequently seen in clear-cell renal cell carcinoma HIF,87,89 91 as well as hsp90 inhibitors, such as geldenamycin (ccRCC), and patients with VHL disease are more likely to and 17-(allylamino)-17-demethoxygeldanamycin.92,93 Alterna- develop ccRCC. This finding led to the development of tively, HIF-responsive gene products, including vascular compounds that inhibit HIF, or associated downstream targets, endothelial growth factor (VEGF), can be targeted. In fact, to treat RCC. Although suitable inhibitors against HIF itself do the VEGF-neutralizing antibody bevacizumab is approved to

6898 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Table 3. Drugs Targeting Glucose Metabolism for Cancer Treatment and Their Stage in Clinical Development or Use

compound target clinical trial phase relevant cancer(s) fasentin GLUT1 inhibitor NA STF-31536 GLUT1 inhibitor NA 3-bromopyruvate HK-2 inhibitor (?) NA 2-deoxyglucose HK inhibitor phase II prostate, lung, breast, head and neck, pancreatic, gastric 3PO PFKFB3 inhibitor NA PK-158 PFKFB3 inhibitor NA LAS17 GSTP1 inhibitor NA koningic acid GSTP1 inhibitor NA AT-101 LDHA inhibitor phase II prostate, NSCLC, lung dichloroacetate (DCA) PDK-1 inhibitor phase II breast, NSCLC, glioma, head and neck, neoplasms radicicol PDK-3 inhibitor NA mitaplatin PDK-3 inhibitor NA CPI-613 PDK-1 inhibitor (?) phase II lung, pancreatic, liver AGI-6780 IDH2 inhibitor NA N-(3-iodophenyl)-2, 2-di-chloroacetamide PDK-1 inhibitor NA Mito-DCA PDK-1 inhibitor NA JQI BET inhibitor NA I-BET151 BET inhibitor NA I-BET762 BET inhibitor phase II breast, prostate, solid tumors PFI-1 BET inhibitor NA AG-221 IDH2 inhibitor approved metformin NADH dehydrogenase inhibitor phase II prostate, breast, endometrial, rectal, lung, bladder, colon phenformin NADH dehydrogenase inhibitor phase I melanoma VLX600 NADH dehydrogenase inhibitor phase I solid tumors ME-344 NADH dehydrogenase inhibitor phase I breast, solid tumors treat RCC.93,94 Bevacizumab when used in combination, often Though HK1 and HK2 operate in very similar ways, only HK2 is with interferon-α, has produced prolonged progression-free upregulated in cancers; the reason for this is unknown, but its survival in RCC patients.93,95 Sorafenib and pazopanib, anti- occurrence drives the coupling of glycolysis and oxidative VEGF tyrosine kinase inhibitors, are also approved ccRCC phosphorylation by increasing the glucose flux into a variety of drugs.93,96,97 other metabolic pathways.104 HK1 and HK2 are allosterically regulated by their product, G6P, and HK1 activity can also be 3. GLUCOSE METABOLISM regulated via PI3K. HK2, bound to the outer mitochondrial 3.1. Glycolysis membrane, has been shown to enhance glycolytic rate and impair glycolytic rate when removed.11 Targeting HK2 has been Glycolysis is the initial step in glucose metabolism and involves shown to effectively kill various cancer cell types, including nine reactions, each of which is catalyzed by a distinct enzyme. hepatocellular carcinoma, as the small molecule 3-bromopyr- Of these, three are highly regulated: hexokinase (HK), uvate (3BP) causes cell death by covalently binding to HK2, phosphofructokinase (PFK), and pyruvate kinase (PK). All 105 three enzymes have been shown to be altered in cancer (Figure causing its dissociation from the mitochondrial membrane. 2).11 Of these three rate-limiting steps in the glycolytic pathway, Interfering with HK2 activity is a viable option for cancer one may exert greater control over glycolytic flux depending on therapy, as HK2 ablation in vivo inhibited mouse tumor growth ff without noticeable physiological consequence or an induction in the context, such as the presence of the Warburg e ect or a 106 distinct lack of precursors.98 HK1 activity. Glucose uptake is regulated and facilitated by glucose 2-Deoxyglucose (2-DG), a glucose analog without the 2- transporters (GLUT), of which there are four main isoforms, hydroxyl group, is taken up into cells and phosphorylated by HK. GLUT1−4. GLUT1 is overexpressed in most cancers; though However, the phosphorylated 2-DG cannot continue through other isoforms are also present in cancer cells, GLUT1 the glycolytic pathway, and acts as a competitive inhibitor 99 107 ’ overexpression is correlated with poor prognosis. Glucose against glucose in HK. 2-DG s glycolytic blocking abilities uptake, and associated lactate production, is increased in tumors have made it a widely pursued clinical candidate. However, its regardless of hypoxia.4 GLUT1 transporters are upregulated by use in clinical trials has shown very little efficacy in solid tumors 108−110 AKT/PI3K, HIF, KRAS, and BRAF in many cancers.100,101 (NCT00633087 and NCT00096707). Attempts to target these transporters have resulted in PFK catalyzes the third reaction in glycolysis, the transfer of a identification of the cytotoxic small molecules fasentin and phosphate group from ATP to fructose-6-phosphate (F6P) to STF-31536, which inhibit GLUT1-mediated glucose transport form fructose-1,6-bisphosphate (F1,6BP). The reaction cata- (Table 3).102,103 lyzed by PFK is extremely thermodynamically favorable, with a HK catalyzes the first reaction in glycolysis, the phosphor- large negative ΔG, and is the practically irreversible “committed ylation of glucose to glucose-6-phosphate (G6P). G6P feedback step” in glycolysis. Therefore, PFK is the key biochemical valve inhibits HK. There are five hexokinases: HK1−4 and HKDC1, controlling the flow of substrate to product in glycolysis and is in which the latter is poorly characterized.104 HK1 is the most therefore a crucial regulatory point in the glycolytic pathway. ubiquitous, whereas HK2−4 are found in specific tissues. ATP allosterically regulates PFK, where a high ATP

6899 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review concentration in the cell will inhibit PFK activity by binding to cells operating under the Warburg effect, given that there is an an allosteric regulatory site. PI3K can regulate PFK-1 and PFK-2 abundance of precursor materials98 fl activity, where activation of PI3K increases glycolytic ux. PFK 3.2. Lactate Metabolism is activated by fructose 2,6-bisphosphate (F2,6BP), whose levels are regulated by bifunctional enzymes with phosphofructo-2- In a normal, nondiseased cell, under aerobic conditions, the kinase and fructose 2,6-bisphosphatase (PFKFBs) activities. Of pyruvate produced in glycolysis enters the pyruvate dehydrogen- these, PFKFB3, which is regulated by the JAK/STAT5 pathway ase complex (PDC) and the tricarboxylic acid (TCA) cycle to be and phosphorylated by various kinases, such as PTEN and HIF- oxidized completely to CO2. The NADH produced in glycolysis − 1α,111 113 is upregulated in many aggressive cancers, including and the PDC, as well as the NADH and the FADH2 produced in 114,115 the TCA cycle, are all reoxidized in the electron transport chain leukemia. fi Various inhibitors of PFKFB3 have been developed based off (ETC), where O2 is the nal electron acceptor. In anaerobic the scaffold of the weak inhibitor 3PO, with the latest iteration, conditions, however, electron transport is not functional, and PFK-158 (Advanced Cancer Therapeutics), having recently the scarce supply of NAD+ is entirely converted to NADH, thus undergone phase 1 clinical trials (NCT02044861).111,112,116 inhibiting glycolysis if there is too little NAD+ left in the cell. PFKFB3 inhibitors are of particular interest in the context of Glycolysis can continue even when O2 is absent; fermentation can regenerate NAD+ in anaerobic conditions, which is a central combinatorial therapy, as resistance to targeted cancer therapies ff can be seen in the MAPK and PI3K/AKT-mediated activation feature of the Warburg e ect. Fermentation allows pyruvate to of PFKFB3, restoring survival and proliferative defects induced accept high-energy electrons from NADH and, simultaneously, by drugs such as B-raf inhibitors.117 For example, it was found reduces pyruvate to lactate in muscle cells via lactate that treatment of ER+ breast cancer with both palbociclib and dehydrogenase (LDH) enzymes, which happens to a much PFK-158 produced a combinatorial effect, causing greater cell higher percentage of metabolized glucose in tumors. The NAD+ 118 produced by reducing pyruvate is now available for reuse in death than either drug alone. glycolysis, so more ATP and other various glucose byproducts PK catalyzes the final step of glycolysis. Of the four isoforms, can be produced. In cancerous cells, the oft-increased expression PK muscle isozyme M2 (PKM2) is the dominant isoform in of LDHA produces greater amounts of NAD+, affecting the cancer cells, as well as fetal and proliferating cells in general. opposite response and allowing glycolysis to continue.127 PKM2 activity is relatively low, attenuating the final irreversible However, cancer exploits this fermentation step in a variety of glycolytic step and creating a buildup of glycolytic intermediates ways, with one indication being that the expression of the LDHB that can be shuttled elsewhere for use in biosynthetic pathways 7 isoform is inconsistently up- or down-regulated in various necessary for proliferation. PKM2 is implicated in only some 128 − cancers. Several groups have shown that the knockdown of cancers, most notably breast and colon cancer.119 121 PKM2 is LDHA is effective in preventing cancer cell proliferation, activated by both F1,6BP and serine.120 PKM2 is also a including limiting anchorage-independent growth as well as in coactivator of HIF-1α;HIF-1α is activated by PKM2 vivo growth of breast tumors.129,130 Various inhibitors have been hydroxylation, participating in a positive feedback loop that identified; however, selectivity has caused issues for drugs in activates its own production.122 Though one might anticipate clinical trials. For example, AT-101 (Ascenta Therapeutics), an that a loss of PKM2 activity could impair the development of enantiomer of the naturally derived phenol gossypol, is also a cancer, the absence of PKM2 did not inhibit tumor BCL2 domain 3 mimetic and has only shown mild effectiveness metabolism.119 Rather, it was found that PKM2 exerts its pro- in phase I and II trials (NCT01285635, NCT00286793, and cancerous effect by becoming the dominant isoform over PKM1, 131−134 NCT00286806). Also, a class of compounds, called the which is more constitutively active, in order to control the 3-hydroxycyclohex-2-enone series (Genentech), are currently production of ATP more closely;11 this results in the production being an optimized for inhibition specific to LDHA over the B of NADPH via shuttling glycolytic intermediates into the 135 isoform. pentose phosphate pathway (PPP). One approach to cancer If lactate builds up to high enough concentrations, however, it treatment focuses on activating PKM2 to make it more similar to can act as a poison to the cell, and lactate production is a PKM1, which has been shown to inhibit tumor growth and 136 123 contributor to tumor acidity, alongside CO2 production. As sensitize cells to oxidative stress. Furthermore, PKM2 has cancer cells take in more glucose, more lactate is secreted.137 been postulated as a potential biomarker in early tumor − 124 Excess lactate is secreted by monocarboxylate transporters 1 4 detection. (MCT1−4).104 Extracellular lactate has been shown to inhibit F1,6BP can then be converted to dihydroxyacetone immune responses to tumorigenic cells by both inactivating phosphate (DHAP) or glucose-3-phosphate (G3P), to continue cytokine release in cyctotoxic T cells and increasing the downstream in toward the production of pyruvate. Glycer- extracellular pool of lactate to such a great extent that T cell aldehyde-3-phosphate dehydrogenase (GAPDH) catalyzes the glycolysis is impaired, as the imbalanced concentration gradient next step in this pathway, converting G3P to 1,3-bisphospho- does not allow for further excretion of lactate.138 Extracellular glyceric acid (1,3-BPG). GAPDH has been reported to be a lactate can also act as a signaling molecule, as several membrane mechanism of metabolic control in cancer cells exhibiting the receptors can respond to changes in H+ concentration/ Warburg effect via its precursor, glutathione S-transferase Pi 1 ff 125,126 ff extracellular pH to e ect changes within the cell. Targeting (GSTP1). GSTP1 a ects cancer pathogenicity via its these membrane receptors holds potential for drug develop- control over glycolytic metabolism; a small molecule inhibitor of ment, and researchers are looking at inhibiting the function of G- GSTP1, LAS17, lowers production of lipids and nucleotides, 125 protein coupled receptors 4, 65, 68, and 132 via knock- lowers ATP levels, and impairs oncogenic signaling. down.14,139 Inhibitors of GAPDH itself, such as the natural product koningic acid, also impair cancer cell proliferation in those cancers 3.3. Pyruvate Dehydrogenase Complex exhibiting the Warburg effect.126 Interestingly, GAPDH has also The pyruvate produced from glycolysis and not used in lactate been shown to exert control over the entirety of glycolytic flux in production is transported into the mitochondrial matrix where it

6900 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Figure 3. Variety of BET inhibitors that are in development, including the second generation analog of JQ1, I-BET762. ff is oxidized to CO2. Pyruvate does not enter the Krebs cycle e orts are also underway, including recently published directly but instead is oxidatively decarboxylated by PDC. PDC structures of two DCA derivatives, N-(3-iodophenyl)-2,2- oxidizes pyruvate to release a CO2 and produce NADH, dichloroacetamide and Mito-DCA, both with micromolar converting pyruvate into acetyl-CoA. This bond between sulfur inhibition of PDK-1 specifically.149 and the acetyl group in acetyl-CoA is high energy, making it easy 3.4. Tricarboxylic Acid Cycle for acetyl-CoA to transfer the acetyl fragment into the TCA for further oxidation. PDC also contains a thiamine pyrophosphate The enzymes of the TCA cycle, as well as the aforementioned prosthetic group at one of its active sites, which is necessary for PDC, are located in the mitochondrial matrix. The TCA cycle biological activity and is involved in the catalyzing the oxidative involves a group of reactions that take the 2-C acetyl unit from decarboxylation. PDC was recently reported to carry the acetyl-CoA and combine it with a 4-C oxaloacetate molecule to majority of pyruvate entering the TCA cycle.140,141 produce citrate, cycles through various reactions that ultimately Regulation of PDC is crucial; a high ratio of AMP or ADP to releases two CO2 molecules, three NADH, one FADH2, and one ATP will stimulate PDC, thus increasing pyruvate’s entry rate GTP, and recycles the oxaloacetate molecule for reuse. The two into the TCA. In addition, PDC is regulated by pyruvate carbons that leave as CO2 during these reactions are not the dehydrogenase 1 (PDK-1) expression, which phosphorylates same ones that entered the cycle as acetate. In this process, the PDCα subunit and inactivates PDC. Overexpression of reducing power is stored in the high-energy electron carriers pyruvate dehydrogenase kinases, including PDK-1, has been NADH and FADH2, which will eventually be reoxidized in the linked to the oncogenic activation of AKT and HIF pathways ETC to store energy as ATP. that are deeply integrated in dysregulated cancer metabolism.142 Isocitrate is converted to citrate, which can be cleaved to yield PDK-1 expression can be hijacked by cancer cells and acetyl-CoA. In reductive carboxylation conditions, glutamine continually overexpressed to inactivate PDC, which contributes provides the majority of acetyl-CoA necessary for FA synthesis, to the Warburg-identified glycolytic alterations. Further, it has which reduces the amount of acetyl-CoA that must be derived been shown that knockdown of PDK-1 restores PDC to normal from glucose. Oxaloacetate, which is used to produce a variety of activity levels and reverses these glycolytic effects.143 4-carbon intermediates, is also produced from citrate cleavage. PDK-1 inhibition is an attractive target for cancer therapy. Therefore, reductive carboxylation can be the source of an entire Dichloroacetate (DCA), long used to treat patients with pool of TCA cycle intermediates.11 mitochondrial abnormalities and used in topical cosmetics, is a Isocitrate can also be converted to α-ketoglutarate (α-KG), weak pan-PDK inhibitor whose clinical trials for treatment of and vise versa, in the mitochondria via isocitrate dehydrogenase cancer have not shown conclusive results144,145 (NCT01386632 2 (IDH2). Extremely important to driving tumorigenesis in and NCT01029925). Radicicol is also well-documented as a many types of cancer are mutations in IDH2, which results in an PDK-3 inhibitor, but targeting PDK-3 specifically has not been enzyme that readily converts α-KG to oncogenic D-2- conclusively shown to effectively kill cancer cells.146 However, in hydroxyglutarate (2-HG; Figure 2). 2-HG levels are significantly combination with cisplatin, an anticancer effect was seen. This upregulated in tumors with IDH2 mutations and can further prompted the development of mitaplatin, a DCA- competitively inhibit the targets of α-KG, which have DNA 147−149 cisplatin combination with an IC50 of 14.0 uM. Other and histone demethylase activity. Therefore, high levels of 2-HG small-molecule inhibitors include CPI-613, a lipoate derivative production can cause changes in gene expression, which − currently in phase I/II clinical trials (NCT01766219, researchers have found results in impaired differentiation.152 155 NCT01835041, and NCT03435289).150,151 A variety of other Inhibition of the mutated-IDH2 enzyme by AGI-6780 has

6901 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review shown efficacy in vitro in acute myeloid leukemia (AML) cells, are therefore expressed. HIF target genes include glucose in which 2-HG levels normalized, histone and DNA hyper- transporters and glycolytic enzymes, whose sustained expression methylation were reversed, and the cells ceased proliferating and contributes to the cell’s ability to adapt to hypoxic conditions. differentiated.154,156,157 A bromodomain-containing protein 4 Hypoxic conditions also facilitate PDK1 expression, inhibiting (BRD4) inhibitor, JQ1, has also shown promising results in vivo PDC and thus impairing the cell’s ability to produce acetyl-coA in mice with IDH2-driven AML.154 Furthermore, AG-221 and citrate from glucose. Glutamine-dependent reductive (Agios Pharmaceuticals, Inc./Celgene) has shown suppressed 2- carboxylation provides citrate and fatty acids in cultured cancer HG production and induced cell differentiation in both in situ cells lacking pVHL.11 IDH2 mutant AML cells and in vivo in xenograft mouse 158 3.5. Electron Transport Chain and Oxidative models. AG-221 is currently in active status in phase I/II Phosphorylation clinical trials targeting AML-harboring IDH2 mutations patients (NCT01915498).159 Although this study is still active, the FDA Oxidative phosphorylation is the oxidation of NADH and recently approved AG-221 for use in treating AML and will now FADH2 coupled to the phosphorylation of ADP, producing be sold as Idhifa. Comparable dose escalation studies of AG-221 ATP. The energy released via these oxidation reactions is then in patients with IDH2 mutant gliomas, other solid tumors, and used to pump protons out of the mitochondrial matrix and into angioimmunoblastic T cell lymphoma have recently completed the intermembrane space. The proton gradient that results from phase I trials (NCT02273739).159 These results further favored this can then provide the energy that drives the otherwise initiation of a phase I/II combination study looking at AG-221 unfavorable phosphorylation of ADP to ATP. The ETC is a fi with azacitidine in newly diagnosed AML patients group of ve electron carriers, all of which are bound to the inner (NCT02677922). mitochondrial membrane. Each member of the chain reduces A variety of TCA cycle enzymes (i.e., succinate dehydrogen- the next member down the line. Three of these large protein ase and fumarate hydratase) and ETC components can be complexes are cytochromes, thus containing a heme group, mutated in cancer, interfering with glutamine-derived oxaloa- while the other two are small mobile electron carriers bound cetate.11 For example, succinate dehydrogenase (SDH), a loosely to the inner mitochondrial membrane. known tumor suppressor, converts succinate to fumarate, In recent years, analysis of particularly aggressive and drug- producing FADH . SDH mutations lead to familial para- resistant cancers has shown that they rely heavily on oxidative 2 175 ganglioma and familial pheochromocytoma, and no subunit phosphorylation rather than glycolysis for survival. These mutation specificity (between B, C, and D) has been identified findings oppose the traditionally accepted, and diminished, role 176 despite their distinct functions in the complex.16,160 Mutated of the mitochondria in cancer cell metabolism. The SDH is inactive, resulting in a buildup of succinate in the importance of the ETC for cancer survival suggests that the mitochondria; excess succinate effectively stabilizes HIF-1α via current understanding of tumor metabolism is still under- HIF-1α prolyl hydroxylase inhibition, resulting in the tran- developed and lacking in nuance and underscores the potential scription of tumorigenic genes, and leads to hypermethylation of effectiveness of therapies targeting oxidative phosphoryla- 175,176 histones and DNA.161,162 SDH gene mutations are also observed tion. Developing therapies targeting components of the frequently in several types of cancer including RCC, gastro- ETC holds great potential in the goal to effectively drug all intestinal stromal tumors, colorectal cancer, and ovarian cancer types. − cancer163 167 and are associated with malignancy168 and poor The ETC is organized so that the first large carrier, NADH prognosis.169 SDHB, one if four subunits if SDH and the subunit dehydrogenase (also called complex I), receives reducing power, with the most frequently detected mutations,166,170 has recently in the form of electrons, from NADH, which is subsequently been shown to be sensitive to bromodomain and extra-terminal oxidized to NAD+. Much more interest, however, has been (BET) inhibitors, such as JQ1 and various chemotypes including focused on the use of biguanides for NADH dehydrogenase I-BET151, I-BET762, and PFI-1 (Figure 3).171 However, these inhibition in cancer, with metformin being the most commonly inhibitors are in the beginning stages; ffective drug therapies studied. Metformin, currently approved as an antidiabetic drug, have not yet been established, and the development of such is known to inhibit complex I, though the entirety of its would fulfill an unmet medical need. anticancer mechanism is yet to be understood.177 With initial Fumarate hydratase (FH), also a tumor suppressor, converts clinical trials producing promising results, subsequent trials are fumarate to malate. FH mutations lead to a buildup of fumarate, underway.178 Other biguanides, such as phenformin, have also acting as a competitive inhibitor to HIF-1α prolyl hydroxylase been put forth as potential cancer therapeutics, but a similar and stabilizes HIF-1α.6 FH mutations have been previously knowledge gaps exist for these as well. Sensitivity to biguanides identified to lead to hereditary leiomyomatosis and renal cell varies between cancers; recent work has shed light on cancer carcinoma (HLRCC).16 Some successful in vitro inhibitors have response to biguanides; determining low-glucose sensitivity can been reported,172 but similar to the SDH inhibitors, develop- help identify which cancers would respond to drugs targeting the ment of FH inhibitors remains challenging and is still in very ETC, allowing for more targeted applications of these early stages. biguanides and a more informed expectation of tumor Reductive carboxylation serves as a minor source of isocitrate, response.179 It has also been shown that NADH dehydrogenase citrate, and acetyl-CoA in many healthy tissues.173,174 This is polymorphisms correlate with breast cancer incidence, though especially important when the pathways that normally produce further research is necessary to investigate its use as a these metabolites are inactivated in cancer, often due to hypoxic biomarker.180,181 In addition, NADH dehydrogenase is conditions or dysregulated metabolism. For example, the inhibited by the small molecules VLX600 and ME-344, which − previously mentioned pVHL is implicated in the oxygen- result in cell death upon treatment.182 184 Clinical trials with dependent degradation of HIF-1α and HIF-2α, preventing the both are currently underway, and results from initial dose expression of HIF target genes. In those cancer cells lacking escalation studies with ME-344 have been positive VHL, regardless of the presence of oxygen, the HIF target genes (NCT02806817 and NCT02222363).185

6902 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Figure 4. Intersection and dysregulation of the glutaminolysis pathway and the tricarboxylic acid (TCA) cycle in cancer and their associated therapies. The catabolism of glutamine is an important feature in various cancer cells, and promotes cell survival and proliferation. Upregulation of the oncogene MYC increases both an increased uptake in glutamine into the cancer cell and an increase in glutaminolysis. Both glutaminolysis and the TCA cycle contribute to increased levels of citrate and acetyl-CoA, eventually leading to an increased fatty acid (FA) pool. Thicker black arrows indicate reactions that are upregulated in cancer cells. Similarly, upregulated enzymes are indicated with bolded text. Current cancer therapies in clinic or preclinic targeting enzymes associated with glutaminolysis, the TCA cycle, or lipogenesis are shown in red. Oncogenes that upregulate glutaminolysis, the TCA cycle, or lipogenesis in cancer cells are indicated in blue. Metabolites: alpha-ketoglutarate (alpha-KG); D-2-hydroxyglutarate (2-HG). Enzymes: glutaminase (GLS); glutamate dehydrogenase (GLDH); isocitrate dehydrogenase (IDH); ATP citrate lyase (ACL); acetyl-CoA carboxylase (ACC); fatty acid synthase (FASN); pyruvate dehydrogenase complex (PDC); fumarase (FH); succinate dehydrogenase (SDH). Oncogene: protein kinase B (AKT). Chemical inhibitors: l-γ-glutamyl-p-nitroanilide (GPNA); 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH); bis-2-[5−phenyl- acetamido-1, 2, 4-thiadiazol-2-yl] ethyl sulfide (BPTES); bromodomain-containing protein (BRD).

NADH dehydrogenase then passes its electrons to one of the RCCs, raising its potential as a biomarker.186 Cytochrome c small carriers, called coenzyme Q or ubiquinone. Ubiquinone plays a part as well, as recent studies have revealed that receives electrons from both NADH dehydrogenase as well as cancerous cells inhibit cytochrome c-mediated apoptosis by directly from FADH2 and any NADH arriving from the supplying sufficient glutathione to keep cytochrome c in a cytoplasm produced in glycolysis. Ubiquinone then passes its reduced and inactive state.187 In addition, it has been shown that electrons to the next large protein complex, cytochrome c knockdown of complex IV increases cancer aggressiveness and reductase (complex III), which then passes its electrons to has specifically been implicated in esophageal tumor pro- cytochrome c, and finally to the last large bound protein complex gression.188 called cytochrome c oxidase (complex IV). These electrons are fi nally passed to O2, reducing it to water, which is the end 4. AMINO ACID METABOLISM product of the ETC. Each of the three large, membrane-bound proteins in the ETC pumps protons from the matrix into the Cancer cells require lipids, proteins, and nucleic acids−the intermembrane space every time electrons flow past, thus standard building blocks necessary for cellular growth and producing a large proton gradient. proliferation−in addition to the maintenance of cellular redox Complexes III−IV have also been implicated in cancer status. Amino acid metabolism provides many of these pathogenicity. The ubiquinol-cytochrome c reductase hinge requirements. Amino acids play many roles in cancer cell protein (UQCRH), a protein within complex III, has been growth and survival, including supplying carbons to the TCA shown to be downregulated in ccRCC as compared to other cycle, nitrogen to nucleobase synthesis, and in regulating redox

6903 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Table 4. Drugs Targeting Amino Acid Metabolism for Cancer Treatment and Their Stage in Clinical Development or Use

compund target clinical trial phase relevant cancer(s) benzylserine SLC1A5 inhibitor NA 1γ-glutamyl-p-nitroanilide (GPNA) SLC1A5 inhibitor NA y-FBP SLC1A5 inhibitor NA 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid SLC7A5 inhibitor NA (BCH) BPTES GLS inhibitor NA CB-839 GLS inhibitor phase II colorectal, TNBC, NSCLC, ccRCC, AML compound 968 GLS inhibitor NA R162 GLDH inhibitor NA aminooxyacetate transaminase NA inhibitor L-asparaginase (Elspar, Oncaspar) asparagine hydrolase approved pediatric/ phase II adult erythrocyte-encapsulated asparaginase asparagine hydrolase phase III pancreatic, AML, ALL CBR-5884 PHGDH inhibitor NA NCT-502 PHGDH inhibitor NA NCT-503 PHGDH inhibitor NA epacadostat IDO1 inhibitor phase III NSCLC, colorectal, ovarian, head and neck, peritoneal indoximod IDO1 inhibitor phase II prostate, breast, NSCLC, pancreatic, glioblastoma BMS-986205 IDO1 inhibitor phase III NSCLC, head and neck, melanoma, gastric NLG-802 IDO1 inhibitor phase I solid tumors HTI-1090 IDO1 inhibitor phase I solid tumors balance to name a few. Much like glucose, amino acids support may also be a useful target for cancer treatment, as its inhibitor, the energy metabolism and anabolic processes that cancer cells 2-aminobicyclo(2,2,1)-heptane-2-carboxylic acid (BCH), re- require. Modern cancer therapies are now also focusing on the stricts mTOR signaling.194 importance amino acids play in cancer’s survival, and taking Inhibitors of SLC1A5 and SLC7A5 may also show promise in advantage of this knowledge to treat it. certain cancer cells as, through secondary means, inhibitors of 4.1. Glutamine mTORC1. Glutamine flux, as regulated by SLC1A5 and SLC7A5, can regulate mTOR activation, thus exerting control The notion that proliferating cells require glutamine was 194 189 over cellular growth and proliferation. Many studies support discovered by Eagle in the 1950s. Glutamine is one of the the role of amino acids, especially that of leucine and glutamine, − 11 nonessential amino acids in human metabolism, meaning it in activating mTORC1-dependent signaling.195 200 can be synthesized sufficiently endogenously. In fact, glutamine The first reaction in glutaminolysis is the initial deamination is the most abundant amino acid in circulation in human plasma. of glutamine into glutamate and ammonia through glutaminase However, under certain circumstances, such as during rapid (GLS), of which there are several human isozymes. Glutamate growth or other stresses, glutamine can become conditionally can then be oxidized, usually via the enzyme glutamate essential, meaning that the demand for glutamine overwhelms ’ dehydrogenase (GLDH), into α-KG, NAD(P)H, and ammonia. the cell s ability to produce it. In these conditions, the cell must α find other means of obtaining glutamine, such as via exogenous -KG is then used to produce ATP and anabolic carbons, which means from diet. are subsequently utilized in amino acid, nucleotide, and lipid Glutamine contains an amine functional group and plays synthesis. Glutamine itself is also utilized in nucleotide and many important biological roles within the cell, including amino acid biosynthesis, donating nitrogen to the production of purines and pyrimidines and providing for the production of involvement in various anabolic and catabolic processes. In 201 regards to the former, glutamine is a source of nitrogen and hexosamines and certain other nonessential amino acids. carbon, both of which are used in the production of Therefore, glutamine plays an integral role in respiration and macromolecule synthesis, as glutaminolysis helps regulate redox macromolecules such as nucleobases, lipids, and nucleotides. 191,202−205 Concerning the latter, glutamine is first trafficked into cells via balance, mTOR signaling, apoptosis, and autophagy. transporters (including SLC1A5 and SLC7A5) and then As previously stated, glutaminolysis is critical for cancer cell catabolized, which is called glutaminolysis; it is then converted proliferation and survival, and glutamine is conditionally into many important biological metabolites, such as glutamate, essential in rapidly proliferating malignant cells. It has been citrate, pyruvate, lactate, aspartate, alanine, and CO . Due to its previously shown that high concentrations of extracellular 2 206−208 important, often essential, role in cancer cell proliferation and glutamine fuel cancer cell growth and survival. Not survival, efforts to target glutaminolysis via small molecule surprisingly, more glutamine is utilized in both tumor and 209 inhibitors are underway (Figure 4).190,191 rapidly dividing cells alike. Mitochondrial enzymes relevant Specific inhibition of SLC1A5, the major glutamine trans- to glutamine/glutamate oxidation are also elevated in tumor porter in many cancers, has shown promise in treating cancer. cells.210,211 Moreover, many cancer cells depend on glutamine in Benzylserine, l-γ-glutamyl-p-nitroanilide (GPNA), and γ-BP all culture for cell survival, known as glutamine addiction.212 For inhibit SLC1A5 (Table 4) and some have been used to show example, it has been shown that human glioma and HeLa cells that, upon SLC1A5 inhibition, tumor growth is suppressed in die in the absence of glutamine despite the presence of excess both lung cancer and melanoma.192,193 The SLC7A5 transporter glucose.213 The resulting tumor microenvironment of this

6904 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review augmented consumption of glutamine by tumors is one in which ROS scavenging and antioxidant signaling, respec- T cell/immune cells are deprived of glutamine, which depletes tively.191,226,227 The roles of glutaminolysis in maintaining immune cell functions. redox balance are diverse and integral to cancer cell survival. In addition to the aforementioned functions of glutamine in Intriguingly, not all cancer cells are addicted to glutamine, and the context of cell proliferation, recent studies have revealed that their existence has allowed researchers to probe for oncogenic it plays additional roles in regulating drivers of proliferation. For mutations or alterations that could explain glutamine depend- instance, α-KG produced from glutamine can be used to ence in some cancers but not others. As alluded to earlier, studies produce citrate (via reductive carboxylation) in order to sustain have shown that MYC, for example, increases glutamine lipid synthesis in cells undergoing hypoxia or mitochondrial metabolism by upregulating the expression GLS, leading to dysfunction.214,215 Metabolic labeling experiments revealed that enhanced glutamate production and, eventually, elevated α-KG glutamine is metabolized via an unusual mechanism involving entry into the TCA cycle.224 Metabolomic studies have further the reversal of IDH enzyme activity. IDH typically functions as confirmed that MYC induction significantly impacts glutami- an oxidative decarboxylase; IDH3 plays this role exclusively, nolysis in cancer cells.228 Not only has MYC been shown to α converting isocitrate to -KG and CO2, while the other two induce the expression of GLS, but it has been revealed that MYC isoforms (IDH1 and IDH2) can function as oxidative upregulates glutamine transporters as well.228 Collectively, these decarboxylases (with NADP+/NADPH cofactors) or reductive studies indicate that MYC’s induction of transcription promotes carboxylases. In the case of its reductive carboxylase glutaminolysis in cancer cells. functionality, isocitrate is produced by carboxylating α-KG. Inhibiting GLS has been shown to suspend tumor growth in − This reaction converts NADPH to NADP+. As mentioned numerous models.229 231 For example, GLS inhibition has been previously, isocitrate can be used to produce citrate, whose shown to impair tumor growth in multiple cancer models, cleavage produces acetyl-CoA. including lymphoma and breast cancer.224,231 GLS is inhibited In addition to IDH2 inhibitors that were previously discussed, by several small molecules, such as bis-2-[5-phenylacetamido- mutant IDH1 inhibitors are also being developed. IDH1, a 1,2,4-thiadiazol-2-yl] ethyl sulfide (BPTES),232 CB-839,233 and cytosolic enzyme that converts isocitrate to α-KG, can be compound 968.231 The orally bioavailable inhibitor CB-839 mutated, subsequently converting α-KG to the oncogenic 2-HG. (Calithera), for example, was found to be a potent, selective, and This, ultimately, interferes with regulating cellular metabolism reversible inhibitor of GLS in preclinical trials.233,234 CB-839 and epigenetics, thus contributing to tumorigenesis and lack of allosterically inhibits the dimer-to-tetramer GLS transition, a 159 cellular differentiation. Mutated IDH1 additionally is critical step for enzyme activation.232,235 CB-839 is currently prognostically relevant for measures of overall survival in being tested in multiple phase II combination trials, including 216 patients with glioma. AGI-5198 has been shown to be a one trial designed to study CB-839 in combination with selective inhibitor of mutant IDH1 and reduced 2-HG levels and everolimus in patients with metastatic ccRCC (NCT03163667) inhibited cancer cell growth in both in vitro and in vivo glioma and another phase II clinical trial looking at CB-839 with 217 models. Another selective IDH1-mutation inhibitor, AG-120 paclitaxel in patients with TNBC (NCT03057600). Further- (Agios Pharmaceuticals, Inc.), is currently in phase I clinical more, it has been shown that CB-839 yielded positive clinical trials to investigate its use in treating advanced hematologic responses in RCC and AML (NCT02071862 and malignancies as well as in advanced solid tumors with an IDH1 NCT02071927). mutation, including gliomas, cholangiocarcinomas, and chon- In addition to GLS inhibitors, it has recently been described 159,218 drosarcomas (NCT02074839 and NCT02073994). Pre- that RNAi-mediated knockdown of GLDH, which is typically liminary results from the ongoing phase I studies demonstrated upregulated in breast and lung cancer cells, or inhibition via that AG-120, when administered as a single-agent, had a R162, a GLDH-specific inhibitor, in these cells results in favorable safety profile and produced approximately a 35% significant reductions in α-KG production and anabolic overall response rate from patients with advanced mutant- glutamine-dependent RNA biosynthesis, as well as elevated positive IDH1 hematologic malignancies. Other IDH1 inhib- ROS levels.191 Another approach to therapeutically targeting itors, such as BAY1436032, FT-2102, and AG-881, are in clinical glutaminolysis is through the use of glutamate-dependent 219−221 development as well. Phase I clinical trials are underway transaminases. Aminooxyacetate, a nonspecific transaminase for all three drugs; BAY1436032 trials are currently recruiting inhibitor, inhibited cell proliferation and overall tumor growth in (NCT02746081 and NCT03127735), a FT-2102 trial is also multiple preclinical studies.236,237 currently recruiting (NCT02719574), and trials for AG-881 are 4.2. Asparagine already running (NCT02492737 and NCT02481154). Glutaminolysis does not only promote cellular proliferation, The amino acid asparagine is required for cancer cells to make but it also plays an integral role in preventing cell death. Cancer DNA. L-Asparaginase, via Elspar (Merck & Co, Inc.), Erwinase cells encounter multifarious stress signals, including levels of (Speywood Phamaceuticals, Inc.), or Oncospar (Enzon reactive oxygen species (ROS) much higher than those Pharmaceuticals), is a successful therapeutic used against experienced by normal cells. While a slight ROS increase pediatric acute lymphoblastic leukemia (ALL), works by promotes cell proliferation and differentiation, extreme levels of hydrolyzing asparagine into aspartic acid and ammonia.199,238 ROS can negatively impact the cells, resulting in oxidative ALL cells are not able to synthesize asparagine de novo, so this damage to proteins, lipids, and nucleotides.222,223 ROS balance leaves the cells without any asparagine and, thus, unable to make is maintained via reducing agents such as glutathione (GSH) new DNA. Interestingly, asparaginase is also able to hydrolyze and NADPH, both of which are produced in part by glutamine to glutamic acid and ammonia,239 thus significantly glutaminolysis.224,225 In addition, glutamine-derived fumarate depleting glutamine levels.239,240 is integral to the regulation of oxidative stress; this fumarate Unfortunately, clinical trials looking at asparaginase treatment increases glutathione peroxidase 1 (GPx1) and activates nuclear in adults revealed substantial toxicity, including increased rates factor erythroid 2-related factor 2 (Nrf2), which are involved in of thrombosis.241,242 Although more research is still needed to

6905 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review clarify the mechanism of asparaginase against childhood versus important in mediating the immune system’s ability to destroy adult glutamine-addicted cancers, researchers have been work- pathogens and, therefore, by reducing the number of T cells, ing on developing less toxic forms of asparaginase that could upregulated tryptophan catabolites prevent the immune system − potentially be used in adult treatment for these cancers as well. from successfully destroying cancer cells.263 266 The indole- For example, asparaginase was modified by covalently amine (2,3)-dioxygenase (IDO) enzyme, which controls the conjugating it with monomethoxypolyethylene glycol to breakdown of tryptophan to later produce kynurenine,267 is increase its half-life and reduce immunogenicity.243 Further- broadly expressed in tumors, including gastrointestinal, lung, more, erythrocyte-encapsulated asparaginase, was developed by gynecological, and breast cancers.268,269 In fact, it has been researchers to decrease toxicity and improve the drug’s delivery shown that increased IDO expression is associated with a (NCT01523782).242,244,245 Lastly, it is worth noting that decrease in the survival of patients with colorectal cancer, small- asparaginase is an effective treatment for young adults with cell lung cancer (SCLC), and melanoma cancer among − ALL; however, the age cutoff for consideration is not yet others.270 273 clear.242 The IDO enzyme has two isoforms, IDO1 and IDO2, with 4.3. Serine IDO1 being the predominantly expressed and much more active isoform.274 IDO is a cytoplasmic monomeric, heme-containing Not only does serine serve as a building block for proteins, but enzyme, and its expression can suppress the body’s immune serine and glycine also contribute carbon to the serine, glycine, 269 246 responses to cancer and allow tumors to grow unchecked. It one-carbon (SGOC) metabolic network. The SGOC net- has been previously shown that overexpression of IDO1 is work plays a role in various cellular processes, including sufficient to drive immune escape via mediating immunosup- nucleotide synthesis, lipid and protein synthesis, methylation pression through T cells sensitivity to tryptophan depriva- 247 − metabolism, polyamine metabolism, and redox balance. tion.275 278 Furthermore, IDO expression decreases T cell De novo serine metabolism, which is significantly elevated in infiltration into tumor microenvironments, promotes inflam- some cancer cells and feeds into one-carbon metabolism, 248,249 mation around tumor tissues and the surrounding micro- importantly produces NADPH and glutathione. It has 279−284 environment and causes overall immune tolerance. It is been shown that breast cancer and colorectal cancer, among worthy to note that some tumor and surrounding microenviron- others, rely on serine for cellular proliferation and survival. In ment cells even express IDO to protect themselves from the fact, increased activity of the SGOC network can further drive 269,285 immune system. Lastly, kynurenine is a native ligand for the advancement of these cancers, most likely due to augmented the aryl hydrocarbon receptor that, ultimately, further promotes nucleotide synthesis rates.246 A recent study using 13C serine inflammatory carcinogenesis.286 revealed a flux of serine into nucleotides and glutathione Recently, researchers have been interested in developing IDO synthesis.249 Serine-fueled folate metabolism contributes inhibitors. It has been previously suggested that overexpression substantially to NADPH production, indicating a potential of IDO in tumors is one possible mechanism of tumor drug function in redox balancing, which could be critical to cell 287 − resistance against chemotherapy. In support of this, there has proliferation.248,250 253 Furthermore, de novo synthesis of been evidence that IDO1 inhibitors boost the effectiveness of serine from glucose is increasingly seen in serine-deprived current immunotherapies, including epacadostat (Incyte Cor- circumstances, which indicates the importance of serine to 254,255 poration) combined with anti-PD1 and indoximod (NewLink proliferating cancer cells. Genetics) combined with anti-PD1.266 The first committed reaction in serine biosynthesis is Epacadostat, previously INCB24360, is an orally available catalyzed by 3-phosphoglycerate dehydrogenase (PHGDH), tryptophan-competitive IDO1 inhibitor;288 epacadostat is which oxidizes 3-phosphoglycerate (diverted from glycolysis) to 256 currently the most advanced agent in clinical trials with 3-phosphohydroxypyruvate, a serine precursor. PHGDH is promising early phase study results, particularly in melanoma upregulated in multiple cancers, including TNBC and 257 (NCT02178722). Epacadostat combined with pembrolizumab, NSCLC. Cancer cells utilize increased PHGDH activity for proliferative benefit, as the products of its catalyzed reaction not a PD1 inhibitor, to treat advanced melanoma has entered phase only yield serine but are also used to replenish the TCA cycle’s III clinical trials (NCT02752074). Similarly, epacadostat supply of α-KG.256 combined with nivolumab, another PD1 inhibitor, has also Inhibition of PHGDH has been the subject of extended entered clinical trials and has already shown positive results in patients with melanoma (NCT02327078). Further, epacado- investigation, and multiple inhibitors, including CBR-5884, ffi NCT-502, and NCT-503, are currently undergoing preclinical stat/PD1 inhibitor combination therapies have shown e cacy in studies.258,259 These inhibitors can reduce the levels of serine in other cancer types as well, including squamous cell carcinoma of cells that have overexpressed PHGDH, and PHGDH inhibition the head and neck (SCCHN), NSCLC, urothelial cell via NCT-502 or NCT-503 treatment in in vivo tumor xenograft carcinoma, and RCC (NCT02327078 and NCT03085914). studies resulted in reduced tumor growth as compared to Indoximod (previously D-1-methyl-trytophan and NLG- controls.260 These results illustrate the potential therapeutic use 8189), a well-studied small molecule, acts directly on immune cells to reverse IDO pathway-mediated suppression, most likely of developing PHGDH inhibitors for treatment of cancer cells 266,279,285,289−292 that are addicted to serine. through derepressing mTORC1 in T cells. Indoximod also had early phase clinical trial success in treating 4.4. Tryptophan melanoma patients when used in combination with PD1 Tryptophan is another essential amino acid and its breakdown inhibitors, and just recently entered phase III as well occurs through one of two main pathways in humans, producing (NCT03301636). either NAD+ or serotonin, with the former being the dominant Other IDO1 inhibitors in development include BMS-986205 pathway.261,262 Via this dominant pathway, various tryptophan (Bristol-Myers Squibb), NLG-802 (NewLink Genetics), and catabolites, especially kynurenine, are active and block effector T HTI-1090 (Atridia Pty Ltd.).266,293 BMS-986205, which inhibits cell activation and trigger T cell apoptosis. These T cells are IDO1, has also shown promising early phase results across

6906 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Table 5. Drugs Targeting One-Carbon Metabolism, the Pentose Phosphate Pathway, or NADPH for Cancer Treatment and Their Stage in Clinical Development or Use

clinical trial compound target phase relevant cancer (s) aminopterin folate antagonist discontinued endometrial, leukemia methotrexate dihydrofolate reductase, tetrahydrofolate reductase approved inhibitor pemetrexed dihydrofolate reductase, tetrahydrofolate reductase approved inhibitor 5-fluorouracil (5-FU) thymidine synthase inhibitor approved capecitabine thymidine synthase inhibitor approved Gemcitabine ribonucleotide reductase inhibitor approved cytarabine ribonucleotide reductase inhibitor approved 2-difluoromethyl ornithine (DFMO, ornithine and SAM decarboxylase inhibitor phase III bladder, neoplasms, gastric, colorectal, eflornithine) neuroblastoma AGI-5198 IDH1 inhibitor NA AG-120 IDH1 inhibitor phase III cholangiocarcinoma, AML BAY 1436032 IDH1 inhibitor phase I neoplasms, AML FT-2102 IDH1 inhibitor phase I AML AG-881 IDH1 inhibitor phase I AML, glioma

Figure 5. Analogs of aminopterin that inhibit dihydrofolate reductase and tetrahydrofolate reductase. various advanced cancers, including melanoma, NSCLC, methionine cycle. The mTHF-sourced carbon is integrated via cervical, SCCHN, bladder, and other advanced solid tumors.266 the methylation of homocysteine, which occurs through methionine synthase, generating methionine. Methionine is 5. ADDITIONAL PATHWAYS then used to produce S-adenosylmethionine (SAM) via methionine adenyltransferase (MAT). This combination of 5.1. One-Carbon Metabolism the folate and methionine cycles is called one-carbon One-carbon metabolism is centered on the chemical reactions of metabolism. The methionine pathway is also connected to the − folate compounds and proceeds in a cyclical nature.247,294 296 trans-sulphuration pathway through homocysteine, as trans- Folic acid is a B vitamin, so it can only be obtained through diet sulphuration metabolizes serine and generates glutathione, or via production by the microbiome in the intestines. In cells, contributing greatly to redox regulation in the cell. folic acid is reduced to produce tetrahydrofolate (THF). THF As we established earlier, amino acids play an important role can then be converted to 5,10-methylene-THF (me-THF) via in cellular metabolism via providing carbon units involved in serine hydroxymethyl transferase (SHMT), which can be one-carbon metabolism. One-carbon metabolism is centered on reduced to 5-methyltetrahydrofolate (mTHF) by methylenete- the chemical reactions of folate compounds and proceeds in a − trahydrofolate reductase (MTHFR) or can be converted to 10- cyclical nature.247,294 296 This cycle functions to provide carbon formyltetrahydrofolate. Finally, the folate cycle comes to a close units to other metabolic pathways, such as nucleotide biosyn- when mTHF is demethylated and the carbon donated to the thesis. Nucleotides are made via reactions that include the folate

6907 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review cycle, while phospholipids can be constructed partially via the similarly target polyamine metabolism are also entering clinical methionine cycle. Furthermore, one-carbon metabolism is trials.329 247 implicated in maintaining redox status. The pathways of 5.2. Pentose Phosphate Pathway one-carbon metabolism exert this control through the reduction The PPP, also called the hexose monophosphate shunt, diverts of NADPH and the oxidation of NADP+. For example, one G6P from glycolysis to biosynthesize NADPH, ribose-5- molecule of NADPH is consumed for each iteration of the folate phosphate (R5P), and various glycolytic intermediates. Like cycle by the reduction of THF via MTHFR. glycolysis, this pathway takes place in the cytosol and consists of Interestingly, modern cancer therapy developed in part from an irreversible oxidative phase followed by a nonoxidative phase theideathatfolateantagonistsmightresultinreduced 297,298 consisting of a series of reversible reactions. NADPH and R5P proliferation of malignant blood cells. The merits of this are produced in the oxidative phase, while the glycolytic idea has resulted in the use of folate metabolism antagonists in − intermediates are made in the nonoxidative phase. Overall, chemotherapy for decades.299 301 Sydney Farber noted in 1947 297 glucose can be shunted out of glycolysis to generate NADPH that folic acid could stimulate ALL cell proliferation. Farber and R5P when necessary, and the glycolytic intermediates fi and colleagues were the rst to show that aminopterin, an shunted back in. intermediate of the chemical synthesis of B vitamins and The initial enzyme in the PPP is glucose-6-phosphate antagonist of folate, can induce remission in children with ALL dehydrogenase (G6PDH), and it is the primary point of 298,302 (Table 5). Still today, chemical variants of aminopterin, regulation for the PPP. As G6PDH’s substrate, G6P, is such as methotrexate and pemetrexed, are used as frontline converted to 6-phosphogluconate, and its product, NADPH, drugs for numerous cancer types, including ALL, lymphomas, acts via negative feedback to inhibit G6PDH. The conversion of 299,303−307 breast, and bladder cancer (Figure 5). These drugs 6-phosphogluconate to R5P, which is the next step of the PPP, inhibit dihydrofolate reductase and tetrahydrofolate reductase also generates NADPH alongside CO2. These two successive activity, disrupting one-carbon metabolism.308,309 oxidations make up the oxidative phase of the PPP, while the Additionally, many chemotherapies target pathways down- remaining nonoxidative reactions generate the glycolytic stream of one-carbon metabolism. 5-Fluorouracil (5-FU), for intermediates that will be shunted back to the glycolysis example, is commonly used for the treatment of a variety of pathway. cancers, including advanced colorectal cancer. 5-FU effectively Transketolase-like protein 1 (TKTL1), an enzyme associated targets nucleotide metabolism because it is an analog of uracil with the nonoxidative reactions in the PPP, has been implicated and potently inhibits thymidine synthase.310,311 5-FU’s inter- in ROS sensitivity, lactate production, and tumor prolifer- action with thymidine synthase prevents the dUMP to dTMP ation.330,331 Increased levels of TKTL1 have been associated methylation process, disrupting the folate cycle.312 The 5-FU with invasive colon and urothelial cancers, as well as poor patient and thymidine synthase inhibitor, capecitabine (brand name prognosis.332 TKTL1 has also been shown to be overexpressed Xeloda), is also approved for solo and combinatorial use; often in breast cancer, although it has not been yet shown that its used in tandem with docetaxel in breast cancer and oxaliplatin in overexpression correlates to breast cancer patients’ outcome and 333 colorectal cancer.313,314 Multiple other combinatorial applica- survival. Although it has been shown that inhibited expression tions are currently being tested, including capecitabine plus of TKTL1, via RNAi, in in vitro experiments significantly lapatinib in HER2-amplified breast cancer (NCT02650752). inhibited proliferation, successful TKTL1 inhibitors have not yet 334 Gemcitabine, which is used to treat various cancers, and been developed. cytarabine, used to treat leukemias and lymphomas, are two 5.3. NADPH 315 other inhibitors of nucleotide metabolism. Gemcitabine, also NADPH is important in cancer metabolism, and its use and called Gemzar (Eli Lilly), is FDA-approved to be used alone or generation in cancer has been discussed throughout this review; in combination to treat pancreatic cancer, ovarian cancer, it will be briefly summarized further here. NADPH is mainly NSCLC, and metastatic breast cancer. Gemcitabine, a nucleo- produced from the aforementioned serine-driven one-carbon 316,317 side analog, prevents deoxynucleotide formation. metabolism and the PPP and plays a variety of important roles in Anticancer drugs are also being developed toward targeting cancer pathogenesis. NADPH is necessary for reductive polyamine metabolism, which includes the breakdown of biosynthesis, most notably de novo lipid synthesis.7,335 In ornithine and the decarboxylation of SAM resulting in the addition, as previously mentioned, NADPH aids in the generation of spermidine.257 It has been previously established scavenging and neutralization of ROS, which are increased in that an increase in polyamines, mainly through upregulation of most cancer types. NADPH production is associated with polyamine-biosynthetic enzymes, correlate with increased enhanced cancer cell survival and apoptosis suppression. Since − cellular proliferation and tumorigenesis.257,318 321 Furthermore, glutathione biosynthesis requires NADPH, and glutathione the upregulation of polyamines are associated with colon, breast, protects cells from redox stress, apoptosis resistance oc- − − skin, and prostate cancers among others.322 325 curs.336 338 Moreover, NADPH oxidases produce hydrogen Ornithine decarboxylase (ODC), the enzyme involved in the peroxide, which inhibits tyrosine phosphatases; subsequent rate-limiting reaction in ornithine catabolism and its regulation, kinase activation further promotes cellular survival as well as is important for normal cell growth,326 is upregulated in many mitogenic signaling.338 cancers, including nonmelanoma skin cancer, breast cancer, and prostate cancer.322,324,325,327,328 2-Difluoromethyl ornithine 6. FATTY ACID METABOLISM (DFMO) inhibits ODC as well as several enzymes that are Fatty acids (FAs) provide additional substrate sources to meet competitive inhibitors of SAM decarboxylase and is currently the demanding needs of a proliferating cancer cell and, in fact, being tested in clinical trials as a potential treatment for patients are essential for proliferation. FAs play important roles in with neuroblastoma (NCT01586260, NCT02679144, synthesizing cell membranes, producing and storing energy, and NCT01349881, and NCT00003814).329 Other drugs that also in cell signaling. It has been shown that a broad increase in

6908 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Figure 6. Fatty acid (FA) anabolism and catabolism in cancer and relevant inhibitor therapies. While in certain cell types and survival situations cancer cells may perform FA catabolism through FA oxidation (FAO), more often cancer cells try to increase their FA pool. Lipogenesis via citrate and acetyl- CoA is the most common pathway to chemically target and, thus, inhibit FA biosynthesis. Metabolites and enzymes associated with FA anabolism, or lipogenesis, are shown in orange, while those associated with FAO are shown in dark blue. Thicker black arrows indicate reactions that are upregulated in cancer cells. Similarly, upregulated enzymes are indicated with bolded text. Current cancer therapies in clinic or preclinic targeting enzymes associated with FA metabolism are shown in red. Oncogenic CPT1C, which upregulates FAO lipogenesis in certain cancer cells, is indicated in light blue. Enzymes: carnitine palmitoyltransferase I (CPT1); pyruvate dehydrogenase complex (PDC); ATP citrate lyase (ACL); acetyl-CoA carboxylase (ACC); fatty acid synthase (FASN); stearoyl-CoA desaturase (SCD); long-chain acyl-CoA synthetase (ACSL). Oncogene: mammalian target of rapamycin (mTOR). endogenous FA synthesis is seen in numerous cancer cell the aforementioned metformin.348 Metformin, a drug most types.339 A cell can increase their amount of FAs by increasing known for its standard treatment for type 2 diabetes, has also biosynthesis (de novo lipogenesis), reducing the breakdown of been shown to exert anticancer properties, perhaps through its FAs (fatty acid beta-oxidation (FAO)), increasing their release previously discussed interaction with ETC complex I (Figure 6). from storage (lipolysis), and by decreasing their flux toward Metformin’s attenuation of tumor growth has also been linked to storage (re-esterification). its caloric-restriction-like affect; metformin activates sirtuin 1 6.1. Fatty Acid Anabolism (SIRT1) and AMPK while inhibiting AKT and mTOR. Overall, metformin’s mechanism of action in cancer remains contested in Cancer cells rely on heightened de novo lipogenesis to produce − the literature.349 352 the necessary FAs for proliferation, particularly at the beginning In addition, interest has risen in targeting signaling lipids for stages of the disease as compared to more advanced − tumors.340 342 When tumor cells do not need to rely on cancer therapy. Platelet-activating factor (PAF) is a phospho- increased de novo lipogenesis, however, they can obtain lipid signaling molecule cleaved by the PAF acetylhydrolases sufficient levels of FAs from their environment for growth.343 (PAFAHs), PAFAH1B1, PAFAH1B2, and PAFAH1B3. PA- FAH1B2 and PAFAH1B3 specifically have been identified as For example, it has been reported that proximity to adipocytes 353 influences malignancy and metastasis in ovarian cancers, as the metabolic enzymes upregulated in cancer. Inhibiting the adipocytes prompt metastasis to the omentum and provide function of both isoforms with small molecule P11, which blocks cancer cells with fatty acids.344 The influence of FAs in the tumor PAFAH1B2 and PAFAH1B3 activity (Table 6). Impaired microenvironment is relevant to various cancers, including cancer pathogenicity across a broad range of cancer types, 354 prostrate, ovarian, breast, and endometrial cancers, and targeting including breast and ovarian cancers. the symbiotic relationship between adipocytes and tumor cells is The synthesis of FAs takes place in the cytoplasm of cells, thought to hold great potential as an effective treatment which allows for easier regulation; the enzymes required for − strategy.345 347 Interest has risen in targeting this adipocyte synthesis and breakdown are separated, since FAO occurs in the effect for cancer therapies, and work is underway to identify mitochondria. De novo lipogenesis involves the repeated effective modulators of the tumor microenvironment, such as addition of two-carbon subunits, beginning with acetyl-CoA

6909 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Table 6. Drugs Targeting Fatty Acid Metabolism for Cancer undergoes two reductions via the oxidation of NADPH, and the Treatment and Their Stage in Clinical Development or Use resulting saturated unit is shifted to the domain with the cysteine residue. Another malonyl-CoA binds the ACP, and the process clinical trial relevant compound target phase cancer(s) repeats. FASN is highly expressed in numerous cancers, rendering it an P11 PAFAH1B2 and NA 353,372 PAFAH1B3 inhibitor attractive target for cancer therapies. Inhibiting FASN has ST1326 CPT1 inhibitor NA been shown to induce cytotoxicity in cancer cells as well as etomoxir CPT1 inhibitor NA resensitize cells that have become resistant to mainline 366,373−375 SB-204990 ACL inhibitor NA treatment, such as breast cancer cells to Herceptin. ND-646 ACC inhibitor NA Initial inhibitors of FASN, including C-75, orlistat, and C-75 FASN inhibitor NA GSK837149A, were promising indicators of the effectiveness − orlistat FASN inhibitor NA of targeting FASN for cancer therapy.376 378 However, it has GSK837149A FASN inhibitor NA taken unexpectedly longer for these inhibitors to make their way GSK2194069 FASN inhibitor NA into the clinic due to issues with toxicity and off-target effects. JNJ-54302833 FASN inhibitor NA For example, C-75’s reported interaction with CPT1A in the IPI-9119 FASN inhibitor NA hypothalamus induced hypophagia and body weight loss in TVB-2640 FASN inhibitor phase II astrocyma, mice.379 The newest generation of FASN inhibitors, including breast, colon TVB-2640, GSK2194069, JNJ-54302833, and IPI-9119, at- CVT-11127 SCD1 inhibitor NA tempts to combat these challenges, as they have been built upon MK-8245 SCD1 inhibitor NA − previous scaffolds after SAR research.380 382 The inhibitor Triacsin C ACSL inhibitor NA TVB-2640 was the first to reach clinical trials, with phase I 1a AGPS inhibitor NA studies in solid malignant tumors currently ongoing (NCT02223247).383 produced by ATP citrate lyase (ACL). Knocking down ACL has Another issue plaguing the pursuit of FASN inhibitors is an been shown to prevent the formation of FA precursors, resulting 355−357 uncertainty regarding which cancers will be most responsive, or in impaired xenograft tumor growth. A small molecule perhaps even resistant, to FASN inhibitor treatment. It has been inhibitor, SB-204990, provokes the same changes, but the previously shown that different cancers exhibit varying integral role of ACL’s products may render ACL inhibition a 356,358 sensitivities to targeting FASN, unrelated to FASN expression poor route for selective cancer therapy. 384 ff fi levels. However, the driving force behind these di erences Acetyl-CoA is rst activated, with the investment of ATP, in a has been shown to rest on a cell’s ability to maintain DAG levels carboxylation reaction to produce the three-carbon malonyl- fi and DAG-PKC signaling amidst FASN inhibition, suggesting CoA. This rst activation step is the committed reaction in FA that FASN inhibitor resistance can be overcome by synthesis and is facilitated by the enzyme acetyl-CoA combinatorial treatment with FASN and PKC inhibitors; this carboxylase (ACC) and regulated by AMPK, as phosphorylation 359 cellular ability to maintain these levels can be probed by simply of ACC inactivates it. investigating the incorporation of glucose into complex lipids.384 ACC is occasionally found to be overexpressed in several As development of FASN inhibitors advances, it will be critical tumor types and is even maintained by several tumorigenic − to understand in which contexts they will be most effective. mutations.359 361 However, its particular role in cancer cell Results from clinical trials, such as the phase II study of TVB- metabolism is not fully understood. While some groups have 2640, will be influential in further developments shown that selective inhibition of ACC activity (via inhibitors (NCT03032484). such as soraphen A) induces apoptosis in prostate and breast cancer cells, others have shown that inactivation of ACC1 Once a 16-carbon long FA is synthesized, additional enzymes − fi increased lung cell growth.362 367 Further study into the aid in further modi cation of the FA, such as the addition of differing roles of ACC isoforms will be required to understand functional groups and further elongation. These include the these effects; it has been shown that ACC2 can regulate FAO, oxygen-consuming stearoyl-CoA desaturase (SCD), which whereas ACC1 cannot.368 For instance, the breast cancer type 1 catalyzes the rate-limiting reaction in the production of susceptibility protein (BRCA1), a tumor suppressor gene, can monounsaturated FA, mainly from stearoyl-CoA. SCD exists prevent the dephosphorylation of ACC, thus stimulating FA in two isoforms in humans, SCD-1 and SCD-5. SCD has been synthesis.369 Also, aldo-keto reductase family 1 B10 shown to be upregulated in some cancers including colon, (AKR1B10), a protein often overexpressed in NSCLC and esophageal, and liver cancer; its inhibition results in the death of cancer cells, preventing tumor growth without affecting overall hepatocellular carcinoma, can protect ACC from degradation, 385−387 similarly stimulating FA synthesis.370 ND-646, an allosteric body weight. Inhibition of SCD-1 by the small molecule inhibitor of ACC, was able to suppress FA synthesis in NSCLC CVT-11127 was reported to impair proliferation in lung cancer in vitro and in vivo, resulting in markedly reduced lung tumor cells by activating AMPK and interfering with ACC 388,389 growth in several mouse models of NSCLC.371 activity. It has been shown that SCD-1 was successfully The enzyme that facilitates the synthesis of a FA chain is FA inhibited by taking advantage of overexpressed cytochrome synthase (FASN), a large enzyme with multiple catalytic P450 (CYP450), which is overexpressed in certain cancers, via domains. Acetyl-CoA first binds the acyl carrier protein developing small molecules that are metabolized by CYP450 (ACP) domain and is then shifted to another domain on the into irreversible SCD-1 inhibitors in an effort to avoid toxicity to enzyme with a cysteine residue. Malonyl-CoA now binds the sebocytes; the reported scaffolds of oxalamides and benzothia- ACP and is subsequently condensed with the already-bound zoles are yet to be built upon.390 Other attempts to inhibit SCD, acetyl group via the decarboxylation of malonyl, and the ACP such as the small molecule MK-8245, have been undertaken in domain now holds a four-carbon unit. The four-carbon unit then the context of diabetes and are untested in cancer models.391

6910 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review

Before synthesized FA is bioavailable, a CoA must be resulting in a buildup of palmitoyl-CoA and eventual cell death; appended via acyl-CoA synthetases (ACS). Of the five ACS CPT1 clears palmitoyl-CoA, but when inhibited, the remaining enzymes (ACSL1, ACSL3, ACSL4, ACSL5, and ACSL6), palmitoyl-CoA and other lipid species can be converted to toxic ACSL4 and ACSL5 have been reported to be increased in colon lipids, such as ceramide.368 Inhibition of CPT1 also increases cancer among other cancer types, and overexpression of ACSL4 flux through aerobic glycolysis.368 While increasing CPT1- in particular prevents cell apoptosis.392 Triacsin C is a reported mediated FAO could be expected to impair cancer cell inhibitor of ACSL1, 3, and 4 and induces cell death in various pathogenicity, survival is instead increased in various lympho- cancers.392,393 Various thiazolidinedione compounds have also mas and leukemias. It has also been shown that blocking FAO been shown to bind ACSL4 but are not widely studied in the reduced tumor growth in certain MYC-driven breast cancers as context of cancer treatment.394 Further elucidation of each well.405 In addition, chemical inhibition of CPT1 can kill various isoform’s role specificity is necessary before therapies can be cancer cells.403,406 Multiple CPT1 inhibitors and derivatives are developed for effective cancer treatment. currently in development, including ST1326, ranolazine, and As mentioned previously, hypoxia suppresses the production etomoxir.368,407,408 Etomoxir showed initial promise but has of acetyl-CoA from glucose by stimulating the expression of encountered some issues in the clinic due to toxicity.409,410 PDK1, which phosphorylates and, therefore, inhibits the PDH In addition, the specific roles of the various CPT1 isoforms complex. PDH complex inactivation impairs the cell’s ability to (CPT1A, CPT1B, and CPT1C) are not yet fully understood. produce glucose-derived acetyl-CoA, rendering, glutamine the CPT1A, which is ubiquitously expressed, is regulated via miR- main acetyl-CoA source in order for FA synthesis to continue. It 370 in liver cancer, where miR-370s downregulation of CPT1A 368 has been reported that hypoxic cells reduce dependence on de reduced FAO by 40%. Inhibition of CPT1A also resulted in 368 novo lipogenesis altogether, which also reduces the cell’s impaired cancer cell division in AML. It has also been reliance on SCD1.395 This phenomenon can be reproduced speculated that the CPT1C isoform is oncogenic; its expression with RAS upregulation as well, rendering both hypoxic and RAS- in cancer cells promotes FAO, tumor growth, and resistance to 411 driven cells resistant to SCD1 inhibition as a useful therapy.395 therapy. Overall, one can speculate that an increase in FAO When F1,6-BP is converted to DHAP, it results in the provides more ATP to the cell, thus providing energy for production of ether lipids, which are present in heightened levels continued cancer cell growth and proliferation. in liver cancer, though this correlation is not fully under- stood.396,397 A critical enzyme in the ether lipid synthetic 7. CONCLUSION pathway, alkyl-glycerone phosphate synthase (AGPS), has been Metabolic dysregulation, an emerging hallmark of cancer, is a shown to be upregulated in a variety of aggressive cancers, such clear focus of research today with the goal of developing as melanoma and breast cancer.398 AGPS catalyzes the treatments targeted not only to a specific cancer, but a specific conversion of acyl-glycerone-3-phosphate into alkyl-glycerone- patient. It has been shown that cancers exhibit multifarious 3-phosphate, a precursor in the production of ether lipids. It has alterations to metabolic pathways, as mutational heterogeneity is been shown that inactivation of AGPS results in a reduction of found even between cancers classified as the same type. From several oncogenic signaling lipids, impairing cancer pathoge- well-understood oncogenes, such as KRAS and MYC, to nicity.398 A selective AGPS inhibitor, 1a, caused a reduction in insufficiently understood proteins, such as ACSL3 and ether lipid levels and impacted cell migration and survival, TKTL1, cancer’s impact on the metabolic landscape is wide- showing that AGPS is an attractive target for future potential ranging and still poorly understood. Working to understand the therapies.399 variety of metabolic variations in the context of cancer will pave ff 6.2. Fatty Acid Oxidation the way for a more comprehensive understanding of the di erent iterations of the disease and enable the development of more When FAs are directed for degradation, FAO cleaves two specific therapies with lower toxicities and side effects. carbons at a time until acetyl-CoA remains, producing NADH A fuller understanding of each metabolic mutation’s and FADH2 every iteration of the cycle. Although cancer cells implication will allow for more nuanced treatments targeting are often increasing their amount of lipids, and therefore have specific alterations. Some of these steps are already being taken, decreased FAO, there are times when cancer cells are required to particularly in the realm of combinatorial therapy. Current increase FAO. Most often, FAO is increased when there is an efforts focus on designing a therapeutic cocktail targeting augmented need for ATP production; cancer cells that have mutations specific to the cancer at hand. Such efforts are spurred undergone loss of attachment (LOA) to the extracellular matrix by the discovery of increased anticancer activity upon inhibition often activate FAO to increase ATP concentration and avoid of multiple proteins (or isoforms of a protein), such as the LOA-induced anoikis.359,400 FAO has also been shown to be anticancer effect seen by tandem MCT1 and MCT4 inhibition required for cell survival in certain cancer types, such as some in colon cancer or the many examples of combinatorial lymphomas and leukemias. Although the reason for this is not therapies, including ZD1839 and anastrozole, FTI-277 and − completely clear, FAO may play a role in BAX- and BAK- GGTI-298, and CB-839 and everolimus, to name a few.412 414 dependent mitochondrial permeability transition pore forma- In addition, combinatorial therapies hold promise for those tion or via the antiapoptotic function of carnitine palmitoyl − cancers notorious for developing resistance to frontline transferase 1 (CPT1) in these cancers.359,401 403 therapies. By targeting multiple mutations in the cancer, it is Directing FAs toward FAO relies on CPT1, which converts hoped that a lower dosage can be used and full drug resistance FAs to FA carnitines outside the mitochondria.404 The role of avoided, and this is a critical goal to meet in the development of CPT1 in cancer pathogenicity is complex. Overexpression of cancer therapy.414,415 CPT1, for example, correlates with tumor progression in many As our understanding of cancer’s metabolic landscape cancer types, including breast and prostate cancer, and CPT1 expands, however, an increasing number of targets arise, and plays an integral role in cancer cell apoptosis.368 It has been with the aim to effectively drug each of them, it is necessary to shown that bcl-2-mediated apoptosis decreases CPT1 levels, reach for all possible avenues in drug discovery. Perhaps one of

6911 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923 Chemical Reviews Review the most fruitful, yet rather underutilized, approaches is to 2004 and his Ph.D. in 2008, also from the University of California, investigate the natural compounds produced by living Berkeley. From there, he pursued postdoctoral studies at The Scripps organisms. In previous decades, researchers lacked efficient Research Institute with Professor Benjamin Cravatt before returning to assays for such approaches, but the -omics era has provided Berkeley as a faculty member in 2011. He is currently an associate viable options for screening natural products and an impetus to professor in the Departments of Chemistry, Molecular and Cell do so.416 Several natural products mentioned in this review, such Biology, and Nutritional Sciences and Toxicology at the University of as soraphen A and koningic acid, have been integral to our California, Berkeley. He is also an associate adjunct professor in the understanding of particular metabolic mutations and are in the Department of Pharmaceutical Chemistry at the University of process of influencing the development of drugs for those California, San Francisco. He is also the director of the Novartis- proteins. Rapamycin is also a particularly persuasive example of Berkeley Center for Proteomics and Chemistry Technologies. Among the power of natural products, as it and several rapalogue his honors are selection as a Searle Scholar, American Cancer Society derivatives have been approved for use in the clinic. In order to Research Scholar Award, and the Department of Defense Break- continue bringing metabolism-targeting drugs to market, throughs Award. His lab is focused on developing next-generation investigation into natural products and their derivatives must transformative medicines through advancing innovative chemical continue to be pursued. technologies to overcome challenges in drug discovery. This review serves to underscore the importance of researching cancer’s metabolic alterations; the mutations ACKNOWLEDGMENTS already identified are plentiful, and the number of metabolic drugs currently in clinical trials emphasizes the potential This work was supported by grants from the National Institutes effectiveness of this strategy. However, we recognize that the of Health (R01CA172667), American Cancer Society Research current state of knowledge is vastly incomplete; though an Scholar Award (RSG14-242-01-TBE), and the National Science enzyme may be implicated in cancer pathogenicity, such as Foundation Graduate Research Fellowship (Fellow ID CPT1, simply inhibiting its activity can produce a number of 2015182321). unanticipated physiological effects resulting in toxicity.236,237 As the field continues to develop, our understanding of cancer’s REFERENCES metabolic implications is expanding beyond the simplistic, (1) Hanahan, D.; Weinberg, R. A. Hallmarks of Cancer: The Next singular cause-and-effect relationships as exemplified by the Generation. Cell 2011, 144, 646−674. development of earlier, unsuccessful inhibitors. Though that (2) Vogelstein, B.; Papadopoulos, N.; Velculescu, V. E.; Zhou, S.; Diaz, L. A.; Kinzler, K. W. Cancer Genome Landscapes. 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6923 DOI: 10.1021/acs.chemrev.7b00775 Chem. Rev. 2018, 118, 6893−6923