Dickkopf-related protein 1 (DKK1) is a protein that regulates Wnt signaling pathways. Aberrant Wnt signaling is often implicated in cancer, enabling cancer cells to grow and divide and to suppress the immune system. Published data indicates that DKK1 is often overexpressed in many cancers and is associated with worse outcomes, more aggressive tumor growth, and suppression of immune anti-tumor responses.
Recent publications have demonstrated a role for DKK1 in maintaining an environment around a tumor that suppresses the immune system's ability to clear the tumor and to prevent metastasis. DKK1 activates the suppressive effects of myeloid-derived suppressor cells (MDSCs), a type of white blood cell that can potently block the ability of other immune cells to attack a tumor. Additional data has shown that metastatic tumor cells with stem cell-like features avoid eradication by the immune system through overexpression of DKK1. DKK1 down-regulates natural killer (NK) cell activating ligands on tumor cells allowing them to remain invisible and evade the immune system. Furthermore, neutralization of DKK1 in preclinical tumor models depends on a functioning immune system and more specifically, NK cells. Through these multiple activities DKK1 helps protect the cancer cells from being targeted by the immune system. Therefore, blocking DKK1 activity has been proposed to stimulate an immune mediated anti-tumor response. Inhibition of DKK1 has demonstrated anti-tumor activity in preclinical models. Our hypothesis is that inhibiting DKK1 can generate both a direct anti-tumor effect, as well as generate an immune anti-tumor response. Our preclinical and clinical data suggest that a DKK1 neutralizing antibody, DKN-01, is able to effectively synergize with certain chemotherapeutics and checkpoint inhibitors in their anti-tumor cytotoxicities.
Clinical trials to evaluate these combinations and investigate both tumor and infiltrated immune cells biomarkers are underway.
A new class of targets, co-stimulatory receptors, has been identified that can modulate the immune system to attack cancer. One such target is GITR (glucocorticoid-induced TNFR-related protein), an important receptor expressed on a variety of lymphocytes that plays a critical role in enhancing immune responses.
One key cell type that blocks immune responses to tumors are called regulatory T cells (Treg cells). Tregs express high levels of GITR, and our clinical data has shown that anti-GITR agonist, TRX518, blocks this suppression, allowing a potent T cell anti-tumor response. Our preclinical data also suggests that it will effectively synergize with certain chemotherapeutics and checkpoint inhibitors in their anti-tumor cytotoxicities.