DKK1 is a secreted protein that acts as an inhibitor of the canonical Wnt/β-catenin pathway, which plays a critical role in embryonic development, cell proliferation, and differentiation. DKK1 also acts on non-canonical Wnt signaling pathways in cancer cells.
DKK1 expression in cancer tissue has been associated with poor prognosis in multiple cancers, including esophageal cancer, non-small cell lung cancer, and cholangiocarcinoma.
Inhibition of DKK1 has demonstrated anti-tumor activity in preclinical models. Our hypothesis is that inhibiting DKK1 reduces downstream non-canonical signaling and results in anti-tumor activity.
Recent publications have also 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 has been shown to activate the suppressive effects of myeloid-derived suppressor cells, or MDSC, a type of white blood cell that can potently block other immune system cells. Other published data has shown that metastatic tumor cells with stem cell-like features avoid the immune system by overexpressing DKK1 and secreting it out of the cell. Secreted DKK1 can then down-regulate certain molecules on tumor cells known as natural killer cell activating ligands, or NK ligands, that would activate the immune system, causing these cancer cells to remain invisible to and evade the immune system. Through these multiple activities, research has shown that DKK1 helps protect the cancer cells from being targeted by the immune system.
Immune modulation has proven to be an effective strategy in treating numerous cancers with therapies known as checkpoint inhibitors. Checkpoint inhibitors prevent cancer cells from suppressing the body’s innate immune system resulting in an immune anti-tumor response (“releasing the brakes”). However, there is a consensus that improvements in response rate and efficacy are needed, often due to an insufficient anti-tumor immune response.
A new class of therapies, immune checkpoint agonists, has been identified that amplify the immune system to attack cancer (“hitting the gas”). GITR (glucocorticoid-induced TNFR-related protein) is an important receptor expressed on a variety of lymphocytes that plays a critical role in this process. We have developed an anti-GITR agonist, TRX518, which selectively amplifies an antigen-specific immune response for use in cancer. Activation of GITR results in larger expression of anti-tumor inflammatory response, increased inflammatory cytokines, and increased resistance to immunosuppression. We believe that anti-GITR therapies will synergize with existing cancer therapies as well as with checkpoint inhibitors and cancer vaccines.
Wnt Pathway and DKK1 Biology Overview:
Wnt Inhibitor Dickkopf-1 as a Target for Passive Cancer Immunotherapy, Cancer Res. 2010;70(13); 5326-533 View Article
Secreted antagonists of the Wnt signaling pathway, Cell Sci. 2003;116(Pt 13):2627-34. View Article
DKK1 EFFECTS on IMMUNOSUPPRESSION:
Malladi, S. et al. Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165, 45-60, doi:10.1016/j.cell.2016.02.025 (2016). View Article
D'Amico, L. et al. Dickkopf-related protein 1 (Dkk1) regulates the accumulation and function of myeloid derived suppressor cells in cancer. J Exp Med 213, 827-840, doi:10.1084/jem.20150950 (2016). View Article
Chae, WJ. et al. The Wnt Antagonist Dickkopf-1 Promotes Pathological Type 2 Cell-Mediated Inflammation. Immunity Volume 44, Issue 2, p246–258, 2016, doi: http://dx.doi.org/10.1016/j.immuni.2016.01.008 (2016)
Esophagus and Lung:
Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas, Cancer Res. 2007;67:2517-2525 View Article
Clinical Significance and Prognostic Value of Serum Dickkopf-1 Concentrations in Patients with Lung Cancer. Clin Chem. 2009;55:1656-1664. View Article
Evaluation of Dickkopf-1 (Dkk-1) Expression in Non-small Cell Lung, Esophageal and Gastric Cancer. J Clin Oncol 31, 2013 (suppl; abstr e22203). View Article
High expression of dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangicarcinoma patients after surgery. Cancer 2013;119:993-1003. View Article
Multiple Myeloma and Bone Disease:
In vivo and in vitro effects of a novel anti-Dkk1 neutralizing antibody in multiple myeloma, Bone. Volume 53, Issue 2, April 2013, Pages 487–496 View Article
The role of Wnt signaling antagonist Dkk-1 in the development of osteolytic lesions in multiple myeloma, N Engl J Med. 2003;349:2483-2494. View Article
Phase 1 study evaluating safety and efficacy of DKN-01 in patients with advances NSCLC: View Article
ASCO 2014 Poster: View Poster
Modulation of GITR for Cancer Immunotherapy, Opin Immunology. 2012;24(2): 217-224. View Article
Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells, Natl Acad Sci. 2003;100(25):15059-64. View Article
Biology and Animal Studies:
Agonist anti- GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLoS ONE 2010;5(5):e10436. View Article
Agonist anti- GITR antibody enhances vaccine-induced CD8(+) T-cell responses and tumor immunity. Cancer Res 2006;66:4904-4912. View Article
Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 2005; 202:885-91. View Article
Glucocorticoid-induced TNF receptor family related gene activation overcomes tolerance/ignorance to melanoma differentiation antigens and enhances antitumor immunity. J Immunol 2006;176:6434-42. View Article
Pivotal roles of CD4+ effector T cells in mediating agonistic anti-GITR mAb-induced-immune activation and tumor immunity in CT26 tumors. J Immunol 2007;179:7365-75. View Article
Enhancement of humoral and cellular immunity with an anti-glucocorticoid-induced tumor necrosis factor receptor monoclonal antibody. Immunology 2010;(130) 231-242. View Article
Characteristics and Development of TRX518, an Aglycosyl Humanized Monoclonal Antibody (Mab) Agonist of huGITR. Clinical Immunology 2010; 135:S96. View Article
GITR Keystone Poster presentation View Poster