Metabolomics in OncologyImmuno-Oncology

Why Cancer Metabolism?When signaling, immunity, and angiogenesis are successful contemporary targets. 

Adapted from Hanahan & Weinberg, Cell 144, March 4, 20112

Why Cancer Metabolism?

• All hallmarks engage metabolism

• Successful clinical precedent (chemotherapeutics)

• Oncogenes and tumor-suppressors reprogram metabolism

• Targeting metabolic features may circumvent genomic heterogeneity

• Metabolic adaptations shown to help drive drug resistance

When signaling, immunity, and angiogenesis are successful contemporary targets. 

Adapted from Hanahan & Weinberg, Cell 144, March 4, 20113

Metabolomics experience in oncology

Target DiscoveryLi, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature (2014).

Target validationStuart, S.D. et al. A strategically designed small molecule attacks alpha-ketoglutaratedehydrogenase in tumor cells through a redox process. Cancer & metabolism 2, 4 (2014).

MoAWatson, M. et al. The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol 29, 5872-5888 (2009).

Resistance mechanismsSun, Y. et al. Metabolic and transcriptional profiling reveals pyruvate dehydrogenase kinase 4 as a mediator of epithelial-mesenchymal transition and drug resistance in tumor cells. Cancer & metabolism 2, 20 (2014).

Immunometabolism…….

A few notable publications in immunometabolism/oncology

• Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6, 6692 (2015).

• Crompton, J.G. et al. Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 75, 296-305 (2015).

• Li, C. et al. Estradiol and mTORC2 Cooperate to Enhance Prostaglandin Biosynthesis and Tumorigenesis in TSC2-deficient LAM cells. The Journal of Experimental Medicine 211, 15-28 (2014).

• Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871-882 (2011).

From deriving greater understanding of target biology to target discovery

Case studies

Immunotherapy Targets Produce Distinct Metabolic Programs Background• PD1 is an important immunotherapy

target

• Understanding the metabolic programs of PD1 ligation may provide additional strategies for unleashing the immune system to target cancer

Objective• To understand the biology

of this target more fully to evolve new/orthogonal targeting strategies

Approach• Metabolomics on T cells treated with the ligand for PD1 and CTLA-4.

METABOLOMICSUnstimulatedStimulated + control IgGStimulated + PD-L1-Ig fusion or CTLA4 agonist ab

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Metabolomics Highlights Distinct Metabolic Programs

Indistinguishable Glucose & amino acid metabolism are (representative metabolite)

Fatty acid oxidation much more strongly upregulated by PD1 (representative metabolite and CPT1A expression)

PD1

CTLA4

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Results Summary• New directions for the mechanistic understanding of the impaired

T-cell effector function mediated by PD-1 – potential targets that can be exploited therapeutically to overcome

exhaustion– markers (lipids, CPT1A) that may define the level of exhaustion

Patsoukis N., et al. Nature Communications (2014)9

Identification Key Pathway of LAM

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Approach• ELT3 (Tsc2-deficient rat uterus-derived) cells were treated with 10 nM

estradiol for 24 hr.

Background • LAM (lymphangioleiomyomatosis) affects

women of childbearing age• Low-grade, destructive, metastasizing

neoplasm, particularly effecting the lungs• Sporadic and tuberous sclerosis complex

(TSC) mutant forms that cause mTORC1 hyperactivation

24 hrEstradiol 5Control 5

Objective• To understand the metabolic

impact of estradiol on TSC2 deficient form

METABOLOMICS

TSC2 Deficiency Stimulates COX-2 Expression

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Metabolomic insight Translating the findingsRecapitulated in patient serum

COX-2 inhibition reduced tumor volume in in vivo model

TSC2- cells have high levels of prostaglandins

COX-2 expression in LAM patient derived cells

Result Summary

• COX-2 upregulation in LAM is estradiol and TSC-genotype dependent

• Targeting COX-2 leads to efficacy in an in vivo model

• LAM patient samples exhibit COX-2 overexpression and elevated PG levels

• Ongoing clinical trial

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Li, Chenggang, et al. The Journal of experimental medicine (2014)

mTORC2

COX-2

PGE2

LAM feature

(TSC2-)

Epilogue: recent independent finding connecting COX-2 and immune evasion….

Cell 2015 162, 1257-1270DOI: (10.1016/j.cell.2015.08.015)

Immunometabolic Approach to Enhance Immunotherapy

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Approach• Cell isolated from melanoma patient, expanded for 30 days, and TILs

enriched using Miltenyi magnetic column CD8+ separation

Background • Adoptive cell therapy (ACT) using

autologous tumor-infiltrating lymphocytes (TIL) is emerging as a curative therapy for advanced cancer

• Data suggest that transfer of TIL with features characteristic of memory T cells may improve the efficacy of ACT

Objective• To explore whether inhibition of

Akt could promote features of memory in tumor-infiltrating cytotoxic T cells

METABOLOMICS24 hrAkti 5

Vehicle 5

Distinct metabolism, enhanced persistence and antitumor activity

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Metabolomic insight Key findings

Glucose metabolism unchanged but FAO is increased, consistent with memory T cell metabolism

Efficacy in tumor-bearing mice receiving adoptively transferred cells treated with Aktior control

Result Summary

• Targeting appropriate metabolic nodes can potentiate antitumor response

• Metabolomics is a key tool for identifying the metabolic nodes that accompany various stages of immune response and validating the effects of target inhibition

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Crompton, Joseph G., et al. Cancer research (2015).