Targeting ARG2 as a novel therapeutic approach for cancer
| Autor: | J. Nowicka, A. Gołębiowski, J. Brzezińska, J. Olczak, B. Borek, Paulina Seweryna Stanczak, Marcin Grzybowski, J. Pęczkowicz-Szyszka, M. Dzięgielewski, A.M. Siwińska, A. Gzik, P. Wolska, J. Chrzanowski, E. Nikolaev, M. Welzer, P. Dobrzański, K. Dzwonek, K. Jędrzejczak, Roman Blaszczyk |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
business.industry medicine.medical_treatment Cancer Hematology Immunotherapy medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Immune system Oncology Cell culture 030220 oncology & carcinogenesis Cancer cell Cancer research medicine ARG1 business ARG2 K562 cells |
| Zdroj: | Annals of Oncology. 30:v793-v794 |
| ISSN: | 0923-7534 |
| Popis: | Background Immunotherapies are considered the most promising therapeutic approach for cancer and the immunosuppressive activity of ARG1 has been recognized as an important mechanism of the tumor immune evasion. This prompted the development of arginase inhibitors, which in preclinical models, enhanced antitumor immunity as a monotherapy and in combination with other immune checkpoint inhibitors. On the other hand, ARG2, but not ARG1, is highly expressed in neoplastic cells in many tumors and its expression is correlated with malignant phenotype. Preclinical studies confirmed that ARG2 promotes the proliferation of cancer cells and the growth of tumor xenografts independently of its immunosuppressive activity. Generation of polyamines to facilitate the growth of hypoxic and nutrient-deprived tumors, as well as specific metabolic adaptations including increased reliance on protein catabolism are the major mechanisms underlying the tumorigenic activity of ARG2. Hence, the tumor cell intrinsic activity of ARG2 represents an attractive intracellular target for novel therapies with arginase inhibitors. Methods The compound activity was determined using human ARG1 and ARG2, and in CHO-K cells expressing ARG1 and ARG2. ARG1 and ARG2 expression in cancer cell lines and dissected tumors was assessed by WB and qPCR. CellTiter-Glo was used to assess the antiproliferative activity of the compound. In vivo antitumor activity was evaluated in murine CT26 (syngeneic) and human K562 (xenograft) subcutaneous mouse models. Results The expression of the endogenous ARG2 was confirmed in multiple human cancer cell lines and xenografts. We developed a highly potent dual ARG1 and ARG2 inhibitor, OATD-02, with a good cellular activity. We demonstrated that OATD-02 inhibited proliferation of multiple human cancer cell lines expressing ARG2 and suppressed the growth of human xenografts. OATD-02 also strongly inhibited the growth of the syngeneic CT26 tumors. Conclusions OATD-02, a potent ARG1 and ARG2 inhibitor, exerts its antitumor efficacy not only by the reactivation of the immune response but also by directly suppressing the ARG2-dependent proliferation of cancerous cells. Thus, OATD-02 is a very promising compound for the treatment of hypoxic tumors which are particularly resistant to therapies. Legal entity responsible for the study OncoArendi Therapeutics SA. Funding National Centre for Research and Development in Poland. Disclosure M.M. Grzybowski: Full / Part-time employment: OncoArendi Therapeutics SA. J. Peczkowicz-Szyszka: Full / Part-time employment: OncoArendi Therapeutics SA. P. Wolska: Full / Part-time employment: OncoArendi Therapeutics SA. P.S. Stanczak: Full / Part-time employment: OncoArendi Therapeutics SA. M. Welzer: Full / Part-time employment: OncoArendi Therapeutics SA. E. Nikolaev: Full / Part-time employment: OncoArendi Therapeutics SA. A.M. Siwinska: Full / Part-time employment: OncoArendi Therapeutics SA. R. Blaszczyk: Full / Part-time employment: OncoArendi Therapeutics SA. B. Borek: Full / Part-time employment: OncoArendi Therapeutics SA. M. Dziegielewski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gzik: Full / Part-time employment: OncoArendi Therapeutics SA. J. Nowicka: Full / Part-time employment: OncoArendi Therapeutics SA. J. Brzezinska: Full / Part-time employment: OncoArendi Therapeutics SA. K. Jedrzejczak: Full / Part-time employment: OncoArendi Therapeutics SA. J. Chrzanowski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Golebiowski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. J. Olczak: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. P. Dobrzanski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. All other authors have declared no conflicts of interest. |
| Databáze: | OpenAIRE |
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