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Transformative GPCR Approach for Tomorrow’s Cancer Immunotherapies

G-protein-coupled receptors (GPCRs) are the most commonly utilized target in today’s treatment paradigm with more than 700 approved therapies, however, their potential in immuno-oncology has yet to be realized. GPCRs control a broad range of cellular processes vital to the formation and progression of tumors. GPCRs’ role in modulating both tumor-generating signal transduction pathways as well as interactions with immune system defense mechanisms opens the door to more novel GPCR-directed therapies aimed at the tumor microenvironment.

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Targeting Unexploited Metabolic Pathways in the Tumor Microenvironment to Restore Anti-Tumor Immunity

The immunosuppressive state of the tumor microenvironment (TME) is directed by the metabolic activity of cancer cells. Rapidly proliferating cancer cells require high levels of energy and other key metabolites. Metabolic reprogramming is the key driver for cancer survival under hypoxia, stress and limited nutrient availability.

Our focus is to develop highly selective and potent antagonists in the glucose, lipid and adenosine pathways to restore anti-tumor immunity and directly halt tumor cell growth.

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Targets That Matter

Cannabinoid Receptors: Regulates Inflammation and Immune Response

Novel Immune Response Modifier Selectively Targeting Cannabinoid CB2 Receptor

The cannabinoid CB2 receptor is a peripheral receptor found predominantly in the immune system and regulates inflammation and the immune response. Elevated CB2 receptor expression is associated with worse overall patient survival[1-5] and aggressiveness of cancer. [6,7]

Our novel, oral, small molecule antagonist, TT-816, enhances innate and adaptive immunity; synergizes antitumor effect with current novel immune response modifiers and directly promotes immune cell penetration into solid tumors.

This could overcome one of the most important resistance pathways and provide new options for patients.”

 

– Expert Oncologist
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Adenosine: Suppresses Immune Cells and Promotes Cancer Cell Proliferation in the Tumor Microenvironment (TME)

First-in-Class A2B Selective Adenosine Receptor Antagonist

The A2B receptor is overexpressed on various types of tumor cells and immune cells. A2B receptor expression and activation are regulated by hypoxia in the TME which promotes tumor growth and causes immune suppression by inhibiting the activity of essential immune cells. Inhibiting A2B receptor prevents cancer cell proliferation in many solid tumor types including prostate and breast cancers.[8-12]

Our first-in-class candidate, TT-702, works by fighting cancer’s ‘cloaking’ strategy and exposing it to the immune system so it can be destroyed.

TT-702 has a unique mechanism of action, and the inhibition of both hot and cold tumor growth would be transformative.”

 

– Expert Oncologist

References:

  1. Chen L, Chen H, Li Y, Li L, Qiu Y, Ren J. Endocannabinoid and ceramide levels are altered in patients with colorectal cancer. Oncol Rep. 2015 Jul;34(1):447-54. doi: 10.3892/or.2015.3973. Epub 2015 May 12. PMID: 25975960. 
  2. Martínez-Martínez E, Calvier L, Fernández-Celis A, Rousseau E, Jurado-López R, Rossoni LV, Jaisser F, Zannad F, Rossignol P, Cachofeiro V, López-Andrés N. Galectin-3 blockade inhibits cardiac inflammation and fibrosis in experimental hyperaldosteronism and hypertension. Hypertension. 2015 Oct;66(4):767-75. doi: 10.1161/HYPERTENSIONAHA.115.05876. Epub 2015 Aug 3. PMID: 26238446.
  3. Pérez-Gómez E, Andradas C, Blasco-Benito S, Caffarel MM, García-Taboada E, Villa-Morales M, Moreno E, Hamann S, Martín-Villar E, Flores JM, Wenners A, Alkatout I, Klapper W, Röcken C, Bronsert P, Stickeler E, Staebler A, Bauer M, Arnold N, Soriano J, Pérez-Martínez M, Megías D, Moreno-Bueno G, Ortega-Gutiérrez S, Artola M, Vázquez-Villa H, Quintanilla M, Fernández-Piqueras J, Canela EI, McCormick PJ, Guzmán M, Sánchez C. Role of cannabinoid receptor CB2 in HER2 pro-oncogenic signaling in breast cancer. J Natl Cancer Inst. 2015 Apr 8;107(6):djv077. doi: 10.1093/jnci/djv077. PMID: 25855725. 
  4. Tsoukalas N, Kiakou M, Tolia M, Kostakis ID, Galanopoulos M, Nakos G, Tryfonopoulos D, Kyrgias G, Koumakis G. Mucinous breast carcinoma with tall columnar cells. Ann R Coll Surg Engl. 2018 May;100(5):e132-e135. doi: 10.1308/rcsann.2018.0060. Epub 2018 Apr 16. PMID: 29658333; PMCID: PMC5956608.
  5. Xu S, Ma H, Bo Y, Shao M. The oncogenic role of CB2 in the progression of non-small-cell lung cancer. Biomed Pharmacother. 2019 Sep;117:109080. doi: 10.1016/j.biopha.2019.109080. Epub 2019 Jun 5. PMID: 31176172.
  6. Fraguas-Sánchez AI, Martín-Sabroso C, Torres-Suárez AI. Insights into the effects of the endocannabinoid system in cancer: a review. Br J Pharmacol. 2018 Jul;175(13):2566-2580. doi: 10.1111/bph.14331. Epub 2018 May 22. PMID: 29663308; PMCID: PMC6003657.
  7. Śledziński P, Zeyland J, Słomski R, Nowak A. The current state and future perspectives of cannabinoids in cancer biology. Cancer Med. 2018 Mar;7(3):765-775. doi: 10.1002/cam4.1312. Epub 2018 Feb 23. Erratum in: Cancer Med. 2018 Nov;7(11):5859. PMID: 29473338; PMCID: PMC5852356.
  8. Gao T, Xu Z, Song X, Huang K, Li Y, Wei J, Zhu X, Ren H, Sun C. Hybrid Sequencing of Full-Length cDNA Transcripts of the Medicinal Plant Scutellaria baicalensis. Int J Mol Sci. 2019 Sep 9;20(18):4426. doi: 10.3390/ijms20184426. PMID: 31505762; PMCID: PMC6770217.
  9. Mousavi SR, Wang H, Hesabgar SM, Scholl TJ, Samani A. A novel shape-similarity-based elastography technique for prostate cancer assessment. Med Phys. 2015 Sep;42(9):5110-9. doi: 10.1118/1.4927572. PMID: 26328962.
  10. Daniel DiRenzo, Dana Piovesan, Joanne Tan, Dillon H. Miles, Manmohan R. Leleti, Timothy Park, Ferdie Soriano, Bryan Handlos, Jenna L. Jeffrey, Ehesan U. Sharif, Brandon R. Rosen, Ulrike Schindler, Jay P. Powers, Matthew J. Walters; Abstract A162: AB928, a dual antagonist of the A2aR and A2bR adenosine receptors, relieves adenosine-mediated immune suppression. Cancer Immunol Res 1 February 2019; 7 (2_Supplement): A162. https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-A162.
  11. Mittal D, Caramia F, Michiels S, Joensuu H, Kellokumpu-Lehtinen PL, Sotiriou C, Loi S, Smyth MJ. Improved Treatment of Breast Cancer with Anti-HER2 Therapy Requires Interleukin-21 Signaling in CD8+ T Cells. Cancer Res. 2016 Jan 15;76(2):264-74. doi: 10.1158/0008-5472.CAN-15-1567. Epub 2016 Jan 7. PMID: 26744522.
  12. Horigome E, Fujieda M, Handa T, Katayama A, Ito M, Ichihara A, Tanaka D, Gombodorj N, Yoshiyama S, Yamane A, Yamada K, Horiguchi J, Shinozuka K, Oyama T, Nishiyama M, Rokudai S. Mutant TP53 modulates metastasis of triple negative breast cancer through adenosine A2b receptor signaling. Oncotarget. 2018 Oct 2;9(77):34554-34566. doi: 10.18632/oncotarget.26177. PMID: 30349649; PMCID: PMC6195371.

Our Pipeline

Teon’s rich pipeline targets unexploited metabolic pathways backed by well-validated science and a track record developing first- and best-in-class GPCR-directed therapies.

View Our Pipeline