Novel Agents Aimed at Disrupting Cancer Metabolism Gain Ground

Almost a century ago, Otto Warburg, MD, PhD, demonstrated that cancer cells prefer to obtain energy via glycolysis, taking in large amounts of glucose and producing lactic acid at high levels, even in the presence of oxygen and healthy mitochondria.¹

Figure 1. Differences in the Process of Glycolysis

The process through which cancer cells generate energy, however, differs from that of healthy cells. Normal, healthy cells produce adenosine triphosphate (ATP), which transports energy for metabolism, mainly though oxidative phosphorylation. Cancer cells exhibit a propensity for using aerobic glycolysis to produce ATP over the more efficient oxidative phosphorylation process. This preference, termed the Warburg effect, has since been observed in many tumor types and has emerged as one of the hallmarks of cancer (Figure 1).² Despite its importance, the mechanisms behind the Warburg effect are not well understood. Nevertheless, due to its presence in a wide range of cancers, the Warburg effect has become an intriguing target for anticancer therapeutics. Although most antitumor therapies are designed to treat a specific cancer type, therapeutics that target the Warburg effect have the potential to treat a broad range of cancers.

Drug development efforts have aimed at exploiting the aberrant metabolic processes of cancer cells by interfering with energy generation and metabolite production, but this strategy has been challenging. Recently, however, the combination therapy SM-88, which works through the Warburg effect, has been showing promise in prostate and other cancers.

The Warburg Effect and Cancer Metabolism

The development of these types of therapies has the potential to provide broad-range treatment with minimal adverse effects, leading to better patient care and favorable outcomes.Glycolysis is a stage of cellular respiration through which glucose is converted into growth and survival.⁶ It has since been established that malignant cells reprogram their metabolic pathways to support uncontrolled cell growth, maintaining oxidative phosphorylation processes while ramping up glycolysis. Several hypotheses exist to explain the pyruvate to release energy in the form of ATP. Although aerobic glycolysis is less efficient than oxidative phosphorylation, producing fewer molecules of ATP per unit of glucose, malignant cells may favor it because the process can be executed significantly faster.³ Cancer cells that favor glycolysis can quickly generate energy by increasing glucose uptake. Increased uptake results in an increase in glycolytic rate, facilitating the generation of ATP that can meet the demands of uncontrolled cell growth.

Initially, cells that exhibited the Warburg effect were hypothesized to have defective mitochondrial metabolism, but this theory has since been disproved.^4,5 Most cancer cells not only have functioning mitochondria, but mitochondrial respiration is required for tumor growth and survival.⁶ It has since been established that malignant cells reprogram their metabolic pathways to support uncontrolled cell growth, maintaining oxidative phosphorylation processes while ramping up glycolysis.

Several hypotheses exist to explain malignant cell’s preference for glycolysis.⁷ In addition to generating ATP, the carbon sources obtained from the increase in glucose flux fuel the demands for the synthesis of building blocks like amino acids, nucleotides, and lipids.⁸ Although these metabolic alterations are a well-established cancer phenomenon, the signals that mediate the Warburg effect initiation and persistence remain unclear.⁷

In addition to increasing the supply of ATP and carbon, the production and export of high levels of lactate acidify the tumor microenvironment.⁹ Such an acidic environment is toxic to normal, healthy cells and can even inactivate therapeutics, but malignant cells thrive. The acidic microenvironment also appears to enhance tumor cell invasion.¹⁰

The Warburg effect also disrupts reactive oxygen species (ROS) signaling. By converting pyruvate into lactate in excess, malignant cells generate a surplus of the coenzyme NAD+, altering the redox balance of the cell. In addition, fewer ROS are produced by cells exhibiting the Warburg effect, insulating themselves from oxidative stress—induced damage and apoptosis.^11,12 Cancer cells also upregulate the expression of transmembrane mucin proteins to protect themselves from ROS.^13,14 Mucins, particularly MUC1, regulate ROS levels by upregulating antioxidant enzymes. As a result, malignant cells are protected from self-imposed toxicity.

Targeting Metabolic Pathways

In addition to the Warburg effect, cancer cells can exhibit other metabolic alterations including increased glutamine and serine consumption, genetic abnormalities in metabolic enzymes, and de novo lipid synthesis capabilities to fuel the metabolic demands of malignant cells. Cancer metabolism research is being aided by advancements in metabolomics that increase our understanding of the mechanisms behind metabolic aberrations in cancer and open new avenues for therapeutic development. Finding ways to target and exploit cancer metabolism is expected to pave the way for the development of better and more effective therapeutics.The unique metabolic profile of malignant cells is attractive for the development of targeted therapies, but the idea of targeting cancer metabolism is not new. Commonly used therapeutics like methotrexate and gemcitabine, for example, target metabolism.¹⁵ These therapies have been successfully applied to the treatment of many cancers, but their variable efficacy, toxicities, and off-target effects limit their potential as treatment options.¹⁵ New therapies are emerging that aim to exploit malignant metabolism without damaging healthy cells.

In an interview with OncLive^®, Howard Fine, MD, director of the Brain Tumor Center in the Sandra and Edward Meyer Cancer Center and chief of the Division of Neuro-Oncology at Weill Cornell Medicine, explained, “Metabolism is … a very complex series of biochemical pathways that appear to be, in many respects, quite different in tumor tissue than in normal tissue. It offers, at least theoretically, a very promising new area to therapeutically target.”

Since the Warburg effect has been observed in the majority of cancer types, many studies have focused on developing therapies that target metabolic pathways. In May 2017, an industry report found that 48 molecules were under study, including 20 agents in clinical development. The most prevalent signaling networks under study are those that modify the activity of key enzymes or transporters implicated in metabolic pathways involving glycolysis, amino acids, and the tricarboxylic acid (TCA), or Krebs, cycle.¹⁶

IDH Inhibitors

Figure 2. First-in-Class Mechanism for Attacking Cancer

Thus far, advancing the development of drugs that target cancer metabolism into later stage trials has proved challenging.¹⁷ The field scored its first success in August 2017 when the FDA approved enasidenib (Idhifa) for the treatment of adults with relapsed or refractory acute myeloid leukemia (r/r AML) with an IDH2 mutation.¹⁸ In July 2018, ivosidenib (Tibsovo) gained FDA approval for adults with r/r AML with an IDH1 mutation. The isocitrate dehydrogenases (IDHs) have several metabolic functions in healthy cells, including regulating lipid synthesis and defending cells against oxidative stress through ROS and other mechanisms. IDH1 and IDH2 have different roles in these processes: IDH1 helps control lipid metabolism and glucose sensing, while IDH2 modulates the TCA cycle. Both are involved in ROS.¹⁹

Mutations in these genes have been observed at varying frequencies across multiple cancer types. IDH1 aberrations are frequently reported in adult gliomas, with study findings ranging from 3% to 16% in grade IV primary glioblastoma to 50% to 94% of grade II oligoastrocytomas. Investigators also have observed these mutations in up to 8% of acute myeloid leukemia (AML) cases and 10% of grade IV primitive neuroectodermal tumors. IDH2 mutations have been found in up to 15% of AML cases and in low frequencies in gliomas, ranging from 0.9% of grade II diffuse and grade III anaplastic astrocytomas to 3.4% of grade III anaplastic oligodendrogliomas and oligoastrocytomas.¹⁹

Novel Targets

Several strategies for targeting glucose-related metabolism are being explored. The compound 2-deoxy-D-glucose, for example, blocks glucose metabolism by competitive hexokinase inhibition and has exhibited antitumor effects in preclinical and early-phase studies.^20-22 Developing therapies that interfere with glucose uptake or lactate production has been difficult, particularly because critical organs like the brain also exhibit high levels of glucose uptake and the off-target effects are too disruptive.²³ Metabolic enzymes are naturally an attractive target for therapeutic development, particularly those that are commonly upregulated in cancer cells, including pyruvate kinase, hexokinase, phosphoglycerated dehy-drogenase, lactate dehydrogenase A, and the glucose transporter, GLUT1.²⁴ In addition to the development of new therapies, ongoing research is evaluating the role of existing drugs like lonidamine, 6-diazo-5-oxo-i-nor-leucine, and metformin for their efficacy as anticancer therapies.^25,26

SM-88

SM-88 is a first-in-class combination therapy containing a dysfunctional tyrosine analogue, a CYP3A4 inducer (phenytoin), an mTOR inhibitor (rapamycin), and a catalyst that stimulates oxidative stress (methoxsalen). The combination therapy elevates ROS levels while simultaneously disrupting protein synthesis in tumor cells. SM-88 is showing promise for the treatment of several cancer types (Figure 2).

Tyrosine is a nonessential amino acid, so healthy cells are able to synthesize functional tyrosine without absorbing it from the environment.²⁷ Tumor cells take up SM-88’s faulty analogue from the environment through LAT1, an amino-acid transporter that is often upregulated in cancer.²⁸ Rapamycin increases the expression of LAT1, thereby increasing tyrosine analogue uptake. Phenytoin and methoxsalen simultaneously increase ROS levels via different pathways.

Protein expression, particularly that of proteins with a high tyrosine content like MUC1, is halted by the dysfunctional tyrosine analogue. As a result, malignant cells lose the ability to mitigate rising ROS levels through MUC1 activity. The increased toxicity ultimately triggers apoptotic signaling and leads to cell death.

SM-88 is being evaluated in 4 clinical trials for the treatment of patients with prostate, pancreatic, breast, and bone cancers.²⁹ A phase I/II study is under way in nonmetastatic prostate cancer (NCT02796898), and a phase II trial is recruiting patients with pancreatic cancer (NCT03512756). Trials are planned in metastatic breast cancer (NCT02562612) and sarcoma (NCT03778996).

In prior research, findings from a phase II trial in patients with prostate cancer demonstrated that SM-88 was less toxic than traditional androgen deprivation therapy and also reduced the level of circulating tumor cells.^30-32 A phase III clinical trial is planned to further evaluate the efficacy of this therapy in patients with prostate cancer. Phase I and compassionate use cases indicated potential efficacy in breast cancer, and a retrospective chart review of SM-88 treatment in patients with pancreatic cancer indicated a favorable toxicity profile compared with existing therapies.^33,34

SM-88 is the only therapeutic that exploits the Warburg effect in this manner, combining a tyrosine analogue with repurposed therapies at low doses. Additional therapies directed toward MUC1, particularly anti-MUC1 vaccines, are also in development.³⁵

Nontherapeutic approaches

Summary

In addition to pharmaceutical approaches, metabolic intervention via nutritional management is being explored through diet alterations in patients with cancer. Caloric restriction is actively being explored for the treatment and prevention of cancer.³⁶ Carbohydrate-reduction diets, such as ketogenic diets, are of particular interest in this space.^37,38Although the Warburg effect has been known for almost 100 years, efforts to understand and target it have been challenging. The broad spectrum of cancer types exhibiting similar metabolic alterations are nonetheless appealing targets for the development of antitumor therapies, and encouraging progress is being made. In particular, SM-88 is showing promise in a variety of cancers with few off-target effects. The emergence of new therapies and research tools are aiding our understanding of the complexities of cancer cell metabolism, which will lead to the development of more effective treatment and improved patient outcomes across a wide range of cancers.

References

1. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8(6):519-530.
2. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. doi: 10.1016/j.cell.2011.02.013.
3. Locasale JW, Cantley LC. Metabolic flux and the regulation of mammalian cell growth. Cell Metab. 2011;14(4):443—451. doi: 10.1016/j.cmet.2011.07.014.
4. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314.
5. Zu XL, Guppy M. Cancer metabolism: facts, fantasy, and fiction. Biochem Biophys Res Commun. 2004;313(3):459-465.
6. Viale A, Pettazzoni P, Lyssiotis CA, et al. Oncogene ablation-resistant pancreatic cancer cells depend on mitochondrial function. Nature. 2014;514(7524):628-632. doi: 10.1038/nature13611.
7. Liberti MV, Locasale JW. The Warburg effect: how does it benefit cancer cells. ncbi.nlm.nih.gov/pmc/articles/PMC4783224/? [erratum in Trends Biochem Sci. 2016;41(3):287]. Trends Biochem Sci. 2016;41(3):211-218. doi: 10.1016/j.tibs.2015.12.001.
8. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009 May 22;324(5930):1029-1033. doi: 10.1126/science.1160809.
9. Estrella V, Chen T, Lloyd M, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013;73(5):1524-1535. doi: 10.1158/0008-5472.CAN-12-2796.
10. Gatenby RA, Gillies RJ. Why do cancers have high aerobic glycolysis? Nat Rev Cancer. 2004;4(11):891-899. doi: 10.1038/nrc1478.
11. Brand KA, Hermfisse U. Aerobic glycolysis by proliferating cells: a protective strategy against reactive oxygen species. FASEB J. 1997;11(5):388-395.
12. Spitz DR, Sim JE, Ridnour LA, Galoforo SS, Lee YJ. Glucose deprivation-induced oxidative stress in human tumor cells. A fundamental defect in metabolism? Ann N Y Acad Sci. 2000;899:349-362.doi: 10.1111/j.1749-6632.2000.tb06199.x.
13. Yin L, Li Y, Ren J, Kuwahara H, Kufe D. Human MUC1 carcinoma antigen regulates intracellular oxidant levels and the apoptotic response to oxidative stress. J Biol Chem. 2003;278(37):35458-35464. doi: 10.1074/jbc.M301987200.
14. Kufe DW. Mucins in cancer: function, prognosis and therapy. Nat Rev Cancer. 2009;9(12):874-885. doi: 10.1038/nrc2761.
15. Luengo A, Gui DY, Vander Heiden MG. Targeting metabolism for cancer therapy. Cell Chem Biol. 2017;24(9):1161-1180. doi: 10.1016/j.chembiol.2017.08.028.
16. Cancer metabolism based therapeutics, 2017-2030 [press release]. London, England: ReportBuyer; May 31, 2017. prnewswire.com/news-releases/cancer-metabolism-based-therapeutics-2017-2030-300466186.html. Accessed December 17, 2018.
17. Mullard A. Cancer metabolism pipeline breaks new ground. Nat Rev Drug Discov. 2016;15(11):735-737. doi: 10.1038/nrd.2016.223.
18. Mullard A. FDA approves first-in-class cancer metabolism drug. Nat Rev Drug Discov. 2017;16(9):593. doi: 10.1038/nrd.2017.174.
19. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J Natl Cancer Inst. 2010;102(13):932-941. doi: 10.1093/jnci/djq187.
20. Zhang D, Li J, Wang F, Hu J, Wang S, Sun Y. 2-Deoxy-D-glucose targeting of glucose metabolism in cancer cells as a potential therapy. Cancer Lett. 2014;355(2):176-183. doi: 10.1016/j.canlet.2014.09.003.
21. Raez LE, Papadopoulos K, Ricart AD, et al. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013;71(2):523-530. doi: 10.1007/s00280-012-2045-1.
22. Stein M, Lin H, Jeyamohan C, et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate. 2010;70(13):1388-1394. doi: 10.1002/pros.21172.
23. Berti V, Mosconi L, Pupi A. Brain: normal variations and benign findings in fluorodeoxyglucose-PET/computed tomography imaging. PET Clin. 2014;9(2):129-140. doi: 10.1016/j.cpet.2013.10.006.
24. Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer. 2013;12:152. doi: 10.1186/1476-4598-12-152.
25. Cervantes-Madrid D, Romero Y, Dueñas-González A. Reviving lonidamine and 6-diazo-5-oxo-L-norleucine to be used in combination for metabolic cancer therapy. Biomed Res Int. 2015;2015:690492. doi: 10.1155/2015/690492.
26. Pierotti MA, Berrino F, Gariboldi M, et al. Targeting metabolism for cancer treatment and prevention: metformin, an old drug with multi-faceted effects. Oncogene. 2013;32(12):1475-1487. doi: 10.1038/onc.2012.181.
27. Matthews DE. An overview of phenylalanine and tyrosine kinetics in humans. J Nutr. 2007;137(6 suppl 1):1549S-1555S; discussion 1573S-1575S. doi: 10.1093/jn/137.6.1549S.
28. Fuchs BC, Bode BP. Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? Semin Cancer Biol. 2005;15(4):254-266. doi: 10.1016/j.semcancer.2005.04.005.
29. US National Library of Medicine. SM-88. ClinicalTrials.gov website. clinicaltrials.gov/ct2/results?cond=&term=SM-88&cntry=&state=&city=&dist=. Accessed December 19, 2018.
30. Roach M, Gostout Z, Zawisny P et al. Phase II trial of SM 88 in non-metastatic biochemical recurrent prostate cancer. J Clin Oncol. 2018;36(suppl 6; abstr 175). ascopubs.org/doi/abs/10.1200/JCO.2018.36.6_suppl.175.
31. Del Priore G, Sokol GH, Chen W, Tsao C, Hoffman S. SM88 in non-metastatic rising PSA-recurrent prostate cancer. J Clin Oncol. 2017;35(suppl 15; abstr e16567). ascopubs.org/doi/abs/10.1200/JCO.2017.35.15_suppl.e16567.
32. Chen W, Friedlander TW, Dong H, Zhao Q, Del Priore G. Prospective comparison of invasive circulating tumor cells (iCTCs) vs PSA and mpfs in prostate cancer (PC) treated with SM-88. J Clin Oncol. 2018;36(suppl 15; abstr e24072). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.e24072.
33. Zhu X, Noel MS, Zawisny P, et al. SM-88 efficacy and safety in metastatic breast cancers. J Clin Oncol. 2018;36(suppl 15; abstr e13100). ascopubs.org/doi/abs/10.1200/JCO.2018.36.15_suppl.e13100.
34. Hoffman S, Stega J, ZAwinsy P, et al. SM-88 therapy in patients with advanced or metastatic pancreatic cancer. Poster presented at: Gastrointestinal Cancers Symposium; January 20, 2018; San Francisco, CA. Abstract 457. ascopubs.org/doi/abs/10.1200/JCO.2018.36.4_suppl.457.
35. Torres MP, Chakraborty S, Souchek J, Batra SK. Mucin-based targeted pancreatic cancer therapy. Curr Pharm Des. 2012;18(17):2472-2481. doi: 10.2174/13816128112092472.
36. Hursting SD, Lavigne JA, Berrigan D, Perkins SN, Barrett JC. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med. 2003;54:131-152. doi: 10.1146/annurev.med.54.101601.152156.
37. Verrax J, Pedrosa RC, Beck R, Dejeans N, Taper H, Calderon PB. In situ modulation of oxidative stress: a novel and efficient strategy to kill cancer cells. Curr Med Chem. 2009;16(15):1821-1830. doi: 10.2174/092986709788186057.
38. Klement RJ, Kämmerer U. Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab (Lond). 2011;8:75. doi: 10.1186/1743-7075-8-75.