Cancer Metabolism

Otto Warburg discovered in the late 1920s that cancer cells shift their metabolism away from the highly efficient oxidative phosphorylation towards the more glucose consuming glycolysis. This “Warburg” effect was originally attributed to the lack of oxygen in the core part of ill-vascularized and fast-growing solid tumors. Recently, the Warburg effect was anew put in the spotlight, since it was found that glycolytic tumor cells maintain their metabolism pattern even under high oxygen abundance. Over the last 20 years, intensive research has led to the identification of the cellular mechanisms underlying the Warburg effect and it became clear that this specific metabolic pattern has the potential to be an Achilles’ heel of cancer. Novel drugs that target this pattern promise a directed therapy of the pathologies with negligible side effects.

Lactate in the tumor microenvironment

Phenex believes that a common denominator of the combined metabolic adaptations in cancer is the massive production of lactate by the tumor and its accumulation in the tumor microenvironment. Lactate, the end product of non-oxidative glycolysis, needs to be rapidly expelled by tumor cells to avoid detrimental intracellular enrichment and acidification.

This causes an increase in extracellular lactate and results in a pH lowering of the tumor environment at the same time. This pH lowering has immunosuppressive effects by itself. In addition, it is known that lactate has multiple effects on tumor infiltrating immune cells and prevents them from attacking cancer cells while enhancing tumor angiogenesis and malignancy.

Inhibiting MCT Lactate-Transporters

Thus, we sought to target the membrane transporters MCT1 and MCT 4 that are required to pump glycolysis-derived lactate into the extracellular fluid of the tumor microenvironment. MCT1 is the basic load lactate transporter found in many healthy tissues whereas MCT4 is a lower affinity but higher capacity lactate carrier. As an initial success we were able to identify lead compounds that inhibit MCT4 and block tumor cell growth (Publications & Posters).

As a next step we will progress these compounds into drug-like candidates and further validate them in xenograft and immune-competent mouse tumor models.

References

See References

Buck MD, Sowell RT, Kaech SM, Pearce EL. Metabolic Instruction of Immunity. Cell. 169(4):570-586. (2017).

DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7(1):11-20. (2008).

Galluzzi L, Kepp O, Vander Heiden MG, Kroemer G. Metabolic targets for cancer therapy. Nat. Rev. Drug Discov. 12(11):829-46. (2013).

Gupta S, Roy A, Dwarakanath BS. Metabolic Cooperation and Competition in the Tumor Microenvironment: Implications for Therapy. Front. Oncol. 7:68. (2017).

Kouidhi S, Ben Ayed F, Benammar Elgaaied A. Targeting Tumor Metabolism: A New Challenge to Improve Immunotherapy. Front. Immunol. 9:353. (2018).

Parks SK, Pouysségur J.Targeting pH regulating proteins for cancer therapy-Progress and limitations. Semin. Cancer Biol. 43:66-73. (2017).

Lyssiotis CA, Kimmelman AC. Metabolic Interactions in the Tumor Microenvironment. Trends Cell Biol. 27(11):863-875. (2017).

Marchiq I, Pouyssegur J. Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H symporters. J Mol Med (Berl). 94(2):155-71. (2015).

Morrot A, da Fonseca LM, Salustiano EJ, Gentile LB, Conde L, Filardy AA, Franklim TN, da Costa KM, Freire-de-Lima CG, Freire-de-Lima L. Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses. Front Oncol. 8:81. (2018).

San-Millan I, Brooks GA. Reexamining cancer metabolism: Lactate production for carcinogenesis could be the purpose and explanation of the Warburg effect. Carcinogenesis. 38(2):119-133. (2016).

Cancer Metabolism mode of action

MCT4

OUR R&D PROGRAMS

LXR / NASH

Cancer Metabolism

AHR / IDO Cancer

About Phenex