Patient dosing has begun in a Phase I clinical trial of OMP-59R5 in patients with advanced solid tumor cancers. OMP-59R5 is a monoclonal antibody that binds selected Notch receptors and is the first antibody to specifically block these targets to enter human studies.
The compound is a one of the drug candidates in OncoMed Pharmaceuticals, Inc. pipeline of product candidates targeting multiple validated cancer stem cell pathways.
Notch receptors and cancer
Notch proteins belong to a family of four transmembrane receptors (Notch1 ? 4) that play a fundamental role in cell proliferation, differentiation, and apoptosis. Notch receptors are crucial for stem cell maintenance and for the differentiation of cells during fetal and postnatal development. However, research has shown that amplified Notch signaling, via the overexpression of Notch ligands or the constitutive activation of the receptors, may result in the development of cancers such as leukemia and lymphoma derived from the T cells of the human immune system.
Research has revealed that Notch has multiple facets. Depending on the cellular context and cross talk with other signal transduction pathways it may either promote or suppress tumor growth. In contrast to the previously established role of Notch-1 as an oncogene in the hematopoietic system, for example, Notch-1 was also identified as a tumor suppressor in mouse skin. Inactivation of Notch-1 in the skin led first to hyperproliferation of the epidermal cells, which was then followed by the development of skin tumors.
In order to devise strategies that interfere with this pathway, scientists are now working to uncover ? and understand – the mechanisms which lead to these apparently contradictory functions of Notch signaling.
Cancer Stem Cells
Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells. Cancer stem cells (CSCs), a small, resilient subset of cells found in tumors, have the capacity to self-renew and differentiate, leading to tumor initiation and driving tumor growth, recurrence and metastasis. Also referred to as tumor-initiating cells, these cells were first discovered in breast cancer and have subsequently been identified in many other types of solid tumor cancers, including cancer of head and neck, lung, prostate, pancreas and glioblastoma. Cancer stem cells appear to be preferentially resistant to both standard chemotherapy and radiotherapy.
Cancer Stem Celles use many of the same signaling pathways that are found in normal stem cells, including Notch and development of agents that target critical steps in these pathways is complicated by signaling cross-talk.
The objective of this phase 1 study is to evaluate the safety of escalating doses of OMP-59R5 as a single-agent in patients who have received prior treatment with standard chemotherapeutics. The study will also assess pharmacokinetics, biomarkers and initial indications of efficacy. The Phase 1 trial is being conducted at leading U.S. cancer treatment centers. Preclinical studies have demonstrated that OMP-59R5 decreases the frequency of tumor-initiating cells across a variety of tumor types.
“The advancement of our second antibody into the clinic represents an important milestone for OncoMed, demonstrating our robust and productive drug discovery capabilities and steady execution on our objectives for our programs,” said Paul Hastings, President and Chief Executive Officer of OncoMed Pharmaceuticals. “In just a few short years, we have established a rich pipeline of first-in-class anti-cancer stem cell therapeutics with the potential to dramatically transform cancer treatment by directly targeting tumor-initiating cells.”
The development of OMP-59R5 is part of OncoMed’s collaboration with GlaxoSmithKline (GSK) and its advancement to the clinic triggers a milestone payment from GSK for the company. In December 2007, OncoMed and GSK entered into a strategic alliance valued at up to $1.4 billion to develop cancer stem cell antibody therapeutics targeting the Notch signaling pathway.
For more information:
– Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2010 Dec 14. [Epub ahead of print];
– Radtke F. and Raj K. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nature Reviews in Cancer 10:756-767, 2003;
– Radtke F.,Wilson A., Stark G., Bauer M., van Meerwijk J., MacDonald H.R., Aguet M. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10:547-558, 1999;
– Wilson A., MacDonald H.R. and Radtke F. Notch 1-deficient common lymphoid precursors adopt a B cell fate in the thymus. Journal of Experimental Medicine 194:1003-12, 2001;
– Wolfer, A., Wilson, A., Nemir, M., MacDonald, H.R. and Radtke, F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity 16:869-79, 2002;
– Wolfer A., Bakker T., Wilson A., Nicolas M., Ioannidis V., Littman D.R., Lee P.P., Wilson C.B., Held W., MacDonald H.R., Radtke F. Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8 T cell development. Nature Immunology 2:235-41, 2001;
– Rangarajan A., Talora C., Okuyama R., Nicolas M., Mammucari C., Oh H., Aster J.C., Krishna S., Metzger D., Chambon P., Miele L., Aguet M., Radtke F., Dotto G.P. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. EMBO Journal 20:3427-36, 2001;
– Nicolas, M., Wolfer A., Raj K., Kummer J.A., Mill P., van Noort H., Hui C.C., Clevers H., Dotto G.P., Radtke F. Notch1 functions as a tumor suppressor in mouse skin.Nature Genetics 33:416-21, 2003;