Cancer Metabolism. Ayelet Erez, MD, PhD. Physicists working on Cancer Course July 2018

Transcription

1 Cancer Metabolism Ayelet Erez, MD, PhD Physicists working on Cancer Course July 2018

2 Overview of talk: 1. Tumors are metabolically distinct from benign tissue. 2. Reprogrammed metabolism allows enables: a. Energy formation b. Biosynthesis c. Redox control. 3. TS and oncogenes regulate metabolism and vice verse 4. Cancer metabolism presents clinical opportunities in tumor diagnosis and treatment.

3 Metabolism is complex, dynamic, and required for essential functions COMMUNICATIONS ENERGY PRODUCTION GROWTH-NUCLEIC ACIDS GROWTH-LIPIDS GROWTH- AMINO ACIDS WASTE DISPOSAL WASTE DISPOSAL WASTE DISPOSAL

4 Cancer and metabolism: historic perspective Warburg describes increased glycolysis in cancer Increased FA synthesis demonstrated in tumors Increased glutaminolysis observed in cancer HIF1a cloned mtor characterized SDHD mutations are shown to be oncogenic FH mutations are shown to be oncogenic p53 regulates cancer metabolism HG is discovered to be an oncometabolite Antimetabolites are used as chemotherapy Warburg identifies that cancer is a metabolic disease PET scan combines CT with metabolism First demonstration of loss of enzymatic activity of SDHD results in alterations in the HIF pathway IDH mutations described in gliomas Initiation of trials with IDH inhibitors cancer metabolism declared as an emerging hallmark of cancer Modified from Erez and Deberardinis, Nature Review Cancer 2015

5 Most Americans die of diseases characterized by abnormal metabolism at the cellular level

6 What is metabolic reprogramming? 1. Altered activity of normal metabolic pathways 2. Serves to improve cellular fitness 3. Prominently upregulated pathways: Glycolysis/ bioenergetics Glutaminolysis Anabolism/ growth Redox stress resistance Finley LWS et al, Cell 2013

7 Altered metabolism is a clinically important hallmark of cancer 1920s: Otto Warburg observes enhanced glucose utilization in tumor cells ~2000s: 18 FDG-positron emission tomography (PET) exploits the enhanced glucose utilization of tumors to diagnose and follow cancer in human patients. Why do tumors have unusual metabolism? How can altered metabolic states in tumors be studied and exploited?

8 Through mutation, cancer cells are selected for a stereotyped set of biological features that enable them to become malignant Hanahan and Weinberg, Hallmarks of Cancer 2000 The Next Generation, Cell 2011.

9 Cancer mutations Metabolism Cancer growth

10 Cancer arises through the cumulative effect of mutations in genes that control cell survival, growth and other processes

11 2007: Two non-overlapping disciplines Metabolic Pathways Cancer Pathways

12 Transforming vs enabling metabolic activities in cancer Vander Heiden and DeBerardinis, Cell 2017

13 Primary and secondary metabolic rewiring in cancer Secondary metabolic rewiring by mutation in oncogenes Direct metabolic rewiring by mutations

14 Oncogenes and tumour suppressors regulate metabolism Vander Heiden, Cantley, Thompson, Science 324: 1029, 2009

15 A combination of intrinsic and extrinsic influences imposes metabolic heterogeneity in tumors Intrinsic factors Genomic alterations Tissue of origin/cell lineage Histology/grade Reprogrammed pathways Metabolic heterogeneity? Extrinsic factors Access to nutrients/oxygen Cell-cell interactions Cell-matrix interactions

16 Does tumor genotype influence tumor metabolism in patients? Many tumor genotypes etc Many metabolic phenotypes etc Many tumor genotypes etc Few metabolic phenotypes 1

17 Enhanced glucose metabolism is a common endpoint of oncogene activation Science, 1987 Northern Western Akt Stimulates Aerobic Glycolysis in Cancer Cells Rebecca L. Elstrom, 1 Daniel E. Bauer, 1 Monica Buzzai, 1 Robyn Karnauskas, 3 Marian H. Harris, 1 David R. Plas, 1 Hongming Zhuang, 2 Ryan M. Cinalli, 1 Abass Alavi, 2 Charles M. Rudin, 4 and Craig B. Thompson 1 Cancer Research 2004

18 Two crucial metabolic pathways in proliferating cancer cells 1. The Warburg effect (aerobic glycolysis) 2. The truncated TCA cycle (cataplerosis/anaplerosis)

19 The Warburg effect is commonly observed in cancer cells Definition: Rapid glucose utilization and lactate production in the presence of sufficient O 2 to oxidize glucose completely ATP

20 Glycolysis intermediates support proliferation Fatty acids OXSPHOS Protein synthesis 36ATP 2ATP Glutamine

21 Cancer is an anabolic disease Stimulus Proteins: 60% Lipids: 17% RNA: 3-4% DNA: <1% Other: ~20% Embryogenesis/normal growth Wound healing Infection Tumorigenesis Yong Wan, U Pittsburgh Biosynthetic metabolism (anabolism) is required for cell growth/proliferation

22 Cancer cells hijack physiological mechanisms Nature, 1976

23 A truncated TCA cycle is often observed in cancer cells J Biol Chem, 1987

24 A truncated TCA cycle is often observed in cancer cells Parlo RA and Coleman PS, J Biol Chem 1984 During cell growth, TCA cycle intermediates leave the mitochondria and are used to build macromolecules (cataplerosis)

25 TCA cycle supplies precursors to biosynthetic pathways Efficiency (cycling for energy) Growth (anaplerosis)

26 Glutamine is the major anaplerotic nutrient in many cancer cells Glutamine provides a source of TCA cycle intermediates to replace those lost to biosynthetic pathways (anaplerosis).

27 Metabolic fluxes, not metabolite levels, indicate true metabolic activity Metabolomics Metabolic flux Mass spectrometry

28 What s the Flux? 1 6 Glucose M=0 M+4 Aspartate α-ketoglutarate Glutamate or alanine pyruvate 1 3 CoA 1 Pyruvate Acetyl-CoA 1 3 Lactate OAA 4 Citrate Malate 4 Isocitrate Fumarate Succinate CoA Succinyl-CoA 4 α-ketoglutarate aspartate alanine or OAA pyruvate 1 Glutamate

29 What can we learn from patients with IEM? Erez and DeBerardinis, Nature Review Cancer, 2015 Isolate specific consequences of genetic abnormality Humans are our target model for therapy

30 Some TCA cycle enzymes are tumor suppressors FH mutations: Hereditary leiomyomatosis & renal cell carcinoma SDH mutations: Paraganglioma, Pheochromocytoma Family with autosomal dominant paraganglioma associated with SDHD mutations; Baysal et al, J Med Genet 2002

31 Metabolites exert important biological effects beyond the metabolic network Lu and Thompson, Cell Metab 2012

32 What are oncometabolites? Oncometabolites accumulate to high levels as a result of tumorigenic mutations, and exert non-metabolic effects that promote malignancy AKG-dependent dioxygenase enzymes are inhibited by high levels of other dicarboxylic acids Dahia et al, Nat Rev Cancer 2014

33 a-ketoglutarate-dependent dioxygenases regulate epigenetics and require a-ketoglutarate and O 2 as substrates Prolyl hydroxylases Histone demethylases 5-methylcytosine hydroxylases

34 Inhibition of αkg-dependent dioxygenases collectively leads to HIF activation and global hypermethylation of target genes. X

35 Fumarate exhibits signaling effects at high concentrations Succination Nrf2 ubiquitination blocked Constitutive Nrf2 activation Antioxidants Adam et al, Cancer Cell 2011

36 Fumarate oncometabolic functions Yang et al, Frontiers in Oncology, 2012

37 Frequent mutation of isocitrate dehydrogenase-1 and -2 (IDH1, IDH2) in human gliomas (brain tumors) Yan et al, NEJM 360: (2009) IDH1/2 mutations are better prognostic markers in glioma but are common in <10% of acute myelogenous leukemia, cholangiosarcoma, fibrosarcoma, etc. Suggesting, that IDH mutation contribute to carcinogenesis.

38 IDH2-mutant tumors also produce (D)-2-HG These tumor cells also contain abundant (D)-2-HG

39 L-2-hydroxyglutaric aciduria: an inborn error of metabolism associated with brain tumors Primitive neuroectodermal tumors Glioblastoma multiforme Other brain tumors Wilms tumor From Kranendijk M et al, JIMD 2012

40 Mutant IDH1 and IDH2 retain the ability to bind a-kg, while gaining neomorphic activity to convert a-kg to D-2HG Isocitrate NADP+ Wild type IDH1/2 Wild type IDH1/2 NADPH a-ketoglutarate NADPH a-ketoglutarate 2-hydroxyglutarate Wild type IDH1/2 Mutant IDH1/2 Substrate for dioxygenases Alters dioxygenase function NADP+ (D)-2-hydroxyglutarate Dang, 2010

41 2-Hydroxyglutarate competitively inhibits a-kg dependent enzymes, leading to epigenetic alterations and impaired differentiation

42 Mutual exclusivity and functional redundancy between mutant TET2 and IDH1/2 in acute myelogenous leukemia Figueroa et al, Cancer Cell 2010 Craig Thompson, Ari Melnick, Ross Levine, MSKCC Loss of TET2 -ORmutIDH1/2 Hypermethylator phenotype Altered epigenetic state Impaired differentiation

43 Clinical importance of metabolic reprogramming in cancer Metabolic imaging 18 FDG-PET 11 C-acetate PET 18 FLT-PET 18 F-glutamine PET* 18 F-glutamate PET* MR Spectroscopy (MRS) Hyperpolarized 13 C-pyruvate* Metabolic therapies L-Asparaginase Antifolates Mutant IDH1/2 inhibitors* Glutaminase inhibitors* Fatty acid synthase inhibitors* Arginine depletion therapy* IDO1 inhibitors* 18 FDG-PET in an EGFR-mutant non-small cell lung cancer *currently in clinical trials

44 Non-invasive detection of 2-hydroxyglutarate in gliomas using 1 H MR spectroscopy Choi et al, Nat Med 2012

45 A new glutamine-based PET agent to detect gliomas Mouse 4-18 F-(2S,4R)-fluoroglutamine F-FGln Human Venneti S et al, Sci Transl Med 2015

46 Non-invasive detection of metabolic activity using hyperpolarized 13 C Pyruvate 1X MRI signal Hyperpolarization Hyperpolarized Pyruvate >10,000X MRI signal Products of pyruvate metabolism

47 13 C hyperpolarization in human cancer Prostate Nelson SJ et al, Sci Transl Med 2013 Hu et al, Cell Metabolism 2011

48 Reprogrammed pathways impose actionable vulnerabilities BLOOD LEUKEMIA CELL Asparagine uptake X X De novo synthesis

49 An inhibitor against mutant IDH1 induces blast differentiation in the bone marrow of AML patients (Agios Pharma) Screening 44% blasts Cycle 1, Day 15 3% blasts Cycle 1, Day 28 2% blasts Blasts Promyelocytes Blasts Promyelocytes Blasts Promyelocytes Myelocytes Metamyelocytes Myeloctyes Metameylocytes Myelocytes Bands Neutrophils Monocytes Bands Neutrophils Neutrophils Monocytes

50 June, 2018

51 Summary Metabolic reprogramming has biological and clinical implications. Tumor suppressors and oncogenes can regulate cancer metabolism. The Warburg effect and anaplerosis are regulated by oncogene/tumor suppressors to support cell growth and proliferation. Oncometabolites arise from mutation in or altered expression of metabolic enzymes and promote malignancy Many aspects of altered metabolism can be used for cancer diagnosis, monitoring and therapy.

52 Shiran Rabinovich, MSc Rom Keshet, MD; PhD Noa Stettner, DVM; PhD Alon Silberman, PhD Lital Adler, PhD Shaul Lerner, MSc Omer Goldman, BSc Sivan Galai, BSc Christeen Azzam, BSc Acknowledgments