Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of plasma cells localized preferentially in the bone marrow (BM). Using an in vivo model of MM, we have recently demonstrated that a population of myeloid-derived suppressor cells in the BM microenvironment is involved in the regulation of MM progression. These cells abundantly produce the pro-inflammatory protein S100A9. Function of S100A9 could be blocked with tasquinimod (ABR-215050, Active Biotech/IPSEN), a quinoline-3-carboxamide derivative that binds to S100A9 and inhibits interaction with its receptors. Here, using pre-clinical models of MM, we investigated the anti-tumor effect of tasquinimod.
The anti-tumor effect of tasquinimod was initially evaluated in vivo in a syngeneic MM model. In this model, mouse MM cells, injected intravenously, home to the BM and grow as MM that closely resembles the human disease. Tumor-bearing mice were randomly assigned to treatment or control groups. The treatment group received tasquinimod at a dose of 30 mg/kg/day in drinking water for 28 days. Administration of tasquinimod significantly improved survival of MM-bearing mice (p<0.005).
Xenograft models of human MM established in immunodeficient SCID-beige mice were utilized to exclude the involvement of B-, T- and NK cells in the pro-survival effect of tasquinimod. Treatment with tasquinimod significantly (p<0.0001) reduced growth of H929 and RPMI-8226 tumors in these mice. We next utilized S100A9 knockout (KO) mice to address the question of whether the anti-tumor effect of tasquinimod is mediated through inhibition of S100A9. Administration of tasquinimod did not improve survival of MM-bearing S100A9 KO mice. These data suggest that the anti-MM effect of tasqunimod is indeed mediated through inhibition of S100A9.
BM angiogenesis plays a critical role in MM progression. We evaluated whether inhibition of S100A9 with tasquinimod would block angiogenesis in MM. Immunohistochemical staining with anti-CD31 antibody demonstrated increased angiogenesis in the BM of MM-bearing mice compared with control tumor-free mice, and treatment with tasquinimod significantly reduced angiogenesis (p<0.005). Serum collected from tasquinimod or vehicle control treated MM- bearing mice two weeks after tumor cell inoculation, was subjected to a Mouse Angiogenesis Proteome Profiler Antibody Array (R&D). A significant decrease in serum levels of pro-angiogenic factors including VEGF, FGF2, tissue factor, and endoglin was detected in tasquinimod-treated mice.
Taken together, our data suggest that targeting S100A9 with tasquinimod results in a strong anti-tumor effect in pre-clinical models of MM. This effect is associated with reduced angiogenesis in the BM. Therefore, tasquinimod could potentially be therapeutically beneficial for patients with MM.
Citation Format: Indu Ramachandran, Cindy Lin, Dmitry I. Gabrilovich, Yulia Nefedova. Blocking of S100A9 with tasquinimod demonstrates a potent anti-myeloma activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1364. doi:10.1158/1538-7445.AM2015-1364