Abstract 5827
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.
Clinical trial identification
Editorial acknowledgement
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. Pęczkowicz-Szyszka: Full / Part-time employment: OncoArendi Therapeutics SA. P. Wolska: Full / Part-time employment: OncoArendi Therapeutics SA. P.S. Stańczak: 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. Siwińska: Full / Part-time employment: OncoArendi Therapeutics SA. R. Błaszczyk: Full / Part-time employment: OncoArendi Therapeutics SA. B. Borek: Full / Part-time employment: OncoArendi Therapeutics SA. M. Dzięgielewski: 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. Brzezińska: Full / Part-time employment: OncoArendi Therapeutics SA. K. Jędrzejczak: Full / Part-time employment: OncoArendi Therapeutics SA. J. Chrzanowski: Full / Part-time employment: OncoArendi Therapeutics SA. A. Gołębiowski: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. J. Olczak: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. P. Dobrzański: Leadership role, Full / Part-time employment: OncoArendi Therapeutics SA. All other authors have declared no conflicts of interest.
Resources from the same session
1908 - Androgen Receptor (AR) Aberrations in Patients (Pts) With Metastatic Castration-Sensitive Prostate Cancer (mCSPC) Treated With Apalutamide (APA) Plus Androgen Deprivation Therapy (ADT) in TITAN
Presenter: Kim Chi
Session: Poster Display session 3
Resources:
Abstract
4058 - 68Ga-PSMA guided bone biopsies for molecular diagnostics in metastatic castration resistant prostate cancer patients
Presenter: Anouk de Jong
Session: Poster Display session 3
Resources:
Abstract
2226 - Spatial-Temporal Change in Quantitative Total Bone Imaging (QTBI) and Circulating Tumor Cells (CTCs) in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated With Enzalutamide (ENZA)
Presenter: Glenn Liu
Session: Poster Display session 3
Resources:
Abstract
5795 - Efficacy of Enzalutamide in Hormone-sensitive Metastatic Prostate Cancer: Clinical Utility of 18F-Choline PET and Whole Body MRI.
Presenter: Susanne Osanto
Session: Poster Display session 3
Resources:
Abstract
899 - Urine extracellular vesicle GATA2 mRNA alone and in a multigene test predicts initial prostate biopsy result
Presenter: Jungreem Woo
Session: Poster Display session 3
Resources:
Abstract
3094 - Circulating tumor cell (CTC) genomic landscape in neuroendocrine prostate cancer (NEPC) by single cell copy number analysis
Presenter: Vincenza Conteduca
Session: Poster Display session 3
Resources:
Abstract
2527 - Circulating Tumor Cells (CTC) count and Prostate-Specific Antigen (PSA) response measures in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients (pts) treated with Docetaxel (Doc)
Presenter: Rebeca Lozano Mejorada
Session: Poster Display session 3
Resources:
Abstract
6106 - Assessing the clinical relevance of drug–drug interactions (DDI) with darolutamide (DARO)
Presenter: Christian Zurth
Session: Poster Display session 3
Resources:
Abstract
2237 - KEYNOTE-921: phase 3 study of pembrolizumab (pembro) plus docetaxel and prednisone for enzalutamide (enza)- or abiraterone (abi)-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Presenter: Daniel Petrylak
Session: Poster Display session 3
Resources:
Abstract
2241 - KEYNOTE-641: Phase 3 Study of Pembrolizumab (pembro) Plus Enzalutamide for Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenter: Julie Graff
Session: Poster Display session 3
Resources:
Abstract