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Adenosine Triphosphate (ATP), Energy for Your Cells, but Inflammatory Towards Cancer

Adenosine triphosphate (ATP) is that all-important organic compound that we first learn about in biology class back in secondary school, and we revisit countless times in our college and medical school biochemistry courses.  It is found in all known forms of life, is utilized for intracellular energy transfer, and is often loosely referred to as the “molecular unit of currency.”1  In eukaryotes, ATP is produced through the process of cellular respiration, which oxidizes glucose to carbon dioxide via glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation.  Additionally, the breakdown of fatty acid molecules, or beta-oxidation, can also produce ATP.  In the absence of oxygen, anaerobic respiration can produce ATP, albeit less efficiently.


ATP has multiple functions, most notably aiding intracellular signaling by serving as a substrate for kinases and donating phosphate groups to other proteins, triggering downstream signaling cascades.2  Additionally, ATP is a precursor to DNA and RNA synthesis and is used as a coenzyme.  Yet, there are many other roles ATP may play that extend outside of our remote college and medical school biology and biochemistry course coverage.

In the realm of cancer immunity, ATP may serve a positive effect by initiating pro-inflammatory responses.3  High levels of ATP may be released through tissue damage or immunogenic cell death into the extracellular environment.  These high levels of ATP facilitate inflammation, acting as a chemoattractant for innate immune cells, which subsequently induce the adaptive immune response.  However, this process is dynamic, as ATP does not remain an extracellular constant.  ATP is eventually reduced to adenosine diphosphate (ADP), then adenosine monophosphate (AMP), and finally to adenosine.  This hydrolysis of ATP leads to extracellular accumulation of adenosine, which subsequently has pro-tumorigenic potential, an opposite and undesired effect.  Extracellular adenosine may result in many consequences, facilitating tumor immune escape, angiogenesis induction, and metastasis.4  Adenosine in tumors can also mediate immunosuppression by inhibiting CD3+ T cell and natural killer (NK) cell function.5

The process of reducing ATP in the tumor microenvironment to ADP and AMP, and further to adenosine, is dependent on the enzymatic activity of 2 distinct ectonucleotidases.  Specifically, CD39 catalyzes the hydrolysis of ATP and ADP to AMP, while CD73 further hydrolyzes AMP to adenosine.  Adenosine then inhibits activation and expansion of T cells by binding to G-protein coupled receptors.  Although there are multiple receptors (e.g., A1, A2A, A2B and A3), the A2A receptor upregulates immune checkpoints like CTLA4 and PD-1,6 while stimulation of A2B receptor suppresses dendritic cells and macrophages.  Preclinical evidence shows mice lacking A2A receptor have reduced tumor growth, implying tumor protection from T cells in the presence of the adenosine-A2A receptor interaction.7

Prostate cancer is a solid tumor that has FDA-approved cellular immunotherapy in sipuleucel-T.8  Yet, attempts with single-agent CTLA49, 10 and PD-(L)111, 12 checkpoint inhibition have not been very successful.  This is likely due to the presence of an immune-exclusive tumor microenvironment.  Relevant to the adenosine pathway, it has been shown that CD39 is strongly expressed in the stromal compartment of tumors.  Prostatic acid phosphatase (PAP) is obviously upregulated in prostate cancer, and it also has ectonucleotidase activity which leads to conversion of AMP to adenosine.13, 14  Finally, A2B receptor is upregulated in prostate cancer,15-17 leading more support to the concept of adenosine-mediated immune exclusion.

Altogether, the above evidence offers potential for targeting the adenosine pathway to reduce the immune exclusive microenvironment in many solid tumors, including the prostate and other genitourinary malignancies.  Manipulation of the microenvironment to retain ATP and avoid adenosine production and activation of specific adenosine receptors can be accomplished via multiple different mechanisms.  This may include inhibiting the reduction of ATP through inhibition of CD39 and/or CD73, resulting in decreased adenosine accumulation.  Additionally, inhibition of the adenosine receptors has the potential to minimize the impact of adenosine in the tumor microenvironment, by limiting immune checkpoint upregulation and suppression of innate immune system components.  Hence, a tumor like prostate cancer, with an immune exclusive microenvironment, may be ideal for induction of anti-tumor inflammation, initiated by manipulation of the adenosine pathway.  Clinical trials with novel therapeutics that manipulate the various components of the adenosine pathway are currently ongoing and in development.  Below, I list relevant trials that are inclusive of patients with prostate cancer and other genitourinary malignancies.

Select trials that target the adenosine pathway

  • Phase 2 trial of AZD4635 (A2A receptor antagonist) with durvalumab or with durvalumab and cabazitaxel for metastatic castration resistant prostate cancer (mCRPC) (AARDVARC) (NCT04495179)
  • Phase 1/2 trial of etrumadenant (A2A and A2B receptor antagonist) plus zimberelimab (PD-1 antibody) combinations with or without standard of care treatments or etrumadenant plus AB680 (CD73 inhibitor) with or without zimberelimab for mCRPC (NCT04381832)
  • Phase 1 trial of TTX-030 (CD39 inhibitor) with budigalimab (PD-1 inhibitor) with and without chemotherapy for solid tumors (including mCRPC and renal cell carcinoma) (NCT04306900)
  • Phase 2 trial of AZD4635 (A2A receptor antagonist) with durvalumab, oleclumab (CD73 inhibitor) or both for mCRPC (NCT04089553)
  • Phase 1/1b trial of NZV930 (anti-CD73 antibody) alone and in combination with PDR001 (PD-1 antibody) and/or NIR178 (A2A receptor antagonist) in advanced malignancies (including mCRPC and renal cell carcinoma) (NCT03549000)
  • Phase 1 trial of CPI-006 (CD73 inhibitor) alone and in combination with ciforadenant (A2A receptor antagonist) and with pembrolizumab in advanced cancers (including mCRPC, bladder cancer and renal cell carcinoma) (NCT03454451)
  • Phase 2 trial of NIR178 (A2A receptor antagonist) in combination with PDR001 (PD-1 antibody) in non-hodgkins lymphoma and solid tumors (including mCRPC, urothelial carcinoma and renal cell carcinoma) (NCT03207867)
  • Phase 1/1b trial of ciforadenant (A2A receptor antagonist) alone and in combination with atezolizumab in advanced cancers (including mCRPC and renal cell carcinoma) (NCT02655822)
Written by: Evan Yu, MD, Professor, Department of Medicine, Division of Oncology, University of Washington School of Medicine, Member, Clinical Research Division, Fred Hutchinson Cancer Research Center, Clinical Research Director, Genitourinary Oncology, Seattle Cancer Care Alliance, Medical Director, Clinical Research Service, Fred Hutchinson Cancer Research Consortium, Seattle, Washington


References:

  1. Knowles JR. "Enzyme-catalyzed phosphoryl transfer reactions." Annu Rev Biochem 1980; 49:877-919.
  2. Mishra N, Tuteja R, Tuteja N. "Signaling through MAP kinase networks in plants." Arch Biochem Biophys 2006; 452:55-68.
  3. Di Virgilio, et al. "Extracellular ATP and P2 purinergic signalling in the tumour microenvironment." Nat Rev Cancer 2018; 18:601-18.
  4. Spychala J. "Tumor-promoting functions of adenosine." Pharmacol Ther 2000; 87:161-73.
  5. Blay J, White TD, Hoskin DW. "The extracellular fluid of solid carcinomas contains immunosuppressive concentrations of adenosine." Cancer Res 1997; 57:2602-5.
  6. Hasko G, Linden J, Cronstein B, Pacher P. "Adenosine receptors: therapeutic aspects for inflammatory and immune diseases." Nat Rev Drug Discov 2008; 7:759-70.
  7. Ohta A, et al. "A2A adenosine receptor protects tumors from antitumor T cells." Proc Natl Acad Sci USA 2006; 103:13132-7.
  8. Kantoff PW, et al. "Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer." N Engl J Med 2010; 363:411-22.
  9. Kwon ED, et al. "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial." Lancet Oncol 2014; 15:700-12.
  10. Beer TM, et al. "Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer." J Clin Oncol 2017; 35:40-7.
  11. Antonarakis EA, et al. "Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study." J Clin Oncol 2020; 38:395-405.
  12. Sweeney CJ, et al. "Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study."Cancer Res 2020 (80) (16 Suppl) CT014.
  13. Kirschenbaum A, et al. "The Association Between Psychiatric Disorders and Telomere Length: A Meta-Analysis Involving 14,827 Persons." Ann NY Acad Sci 2011; 123:64-70.
  14. Xu H, et al. "Prostatic Acid Phosphatase (PAP) Predicts Prostate Cancer Progress in a Population-Based Study: The Renewal of PAP?." Dis Markers 2019; 7090545.
  15. Vecchio EA, et al. "Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation." J Pharmacol Exp Ther 2016; 357:36-44.
  16. Wei Q, et al. "Purinergic signaling in inflammatory cells: P2 receptor expression, functional effects, and modulation of inflammatory responses." Purinergic Signal 2013; 9:271-80.
  17. Li S, Huang S, Peng S. "The Anti-tumoral Properties of Orexin/Hypocretin Hypothalamic Neuropeptides: An Unexpected Therapeutic Role." Int J Oncol 2005; 27:1329-39.