Targeting the myeloma bone marrow microenvironment through S100A9 inhibition with tasquinimod
Dan Vogl
MDThe Trustees of the University of Pennsylvania, Medical Center
Project Term: July 1, 2019 - June 30, 2022
We propose laboratory and clinical studies to understand the mechanisms of anti-myeloma activity of tasquinimod, a small molecule inhibitor of S100A9. This proposal is part of an ongoing collaboration between Dr. Yulia Nefedova, whose laboratory studies the myeloma bone marrow microenvironment and its immunosuppressive effects, and Dr. Dan Vogl, whose clinical and translational research program focuses on novel therapies for relapsed and refractory myeloma.
Multiple myeloma is a cancer of plasma cells, which accumulate in the bone marrow at the center of the bones and cause harm through bone lesions, low blood counts, kidney injury, and predisposition to infections. The main problem facing myeloma patients today is that although we have many effective medications for killing myeloma cells, the myeloma inevitably develops resistance to these medications. We therefore need new treatments that will overcome this resistance. We know that one way that myeloma cells develop resistance is due to other cells living next to them in the bone marrow (collectively known as the bone marrow microenvironment), which signal to the myeloma cells to stay alive and suppress anti-myeloma immune responses. Therefore, one promising approach to myeloma therapy is to try to block the bone marrow microenvironment from protecting myeloma cells. We have identified a group of cells in the bone marrow, known as myeloid-derived suppressor cells (MDSCs), and a signaling protein produced by MDSCs, known as S100A9, as particularly important for the ability of the bone marrow microenvironment to protect myeloma cells. Our laboratory work has shown increased S100A9 levels in mice with myeloma and that decreasing S100A9 levels leads to improved anti-myeloma immune responses. We therefore think that blocking S100A9 signaling will be a useful approach to treating myeloma and making other myeloma treatments work better. Tasquinimod is an experimental medication that blocks S100A9 and has had evidence of anti-cancer effects in patient trials in other cancers. Our laboratory work shows that tasquinimod has a strong anti-myeloma effect in mice with myeloma and improves the effectiveness of bortezomib (Velcade) and lenalidomide (Revlimid), two medications that form the backbone of modern myeloma treatment. We propose to better understand how blocking S100A9 can help patients with myeloma by both studying S100A9 in the laboratory and conducting a clinical trial of tasquinimod in patients with multiple myeloma. We will use mouse models to understand the effects of S100A9 on immune cells and how blocking S100A9 with tasquinimod affects the immune system. We will also conduct a clinical trial of tasquinimod in patients with relapsed myeloma to understand changes in the immune system in patients receiving tasquinimod alone and in combination with bortezomib (Velcade). We hope that the results of these studies will lead to a new way of targeting myeloma cells and improving current therapies.