BMP-activating Antibodies for the Targeting of Colon and Breast Cancer Stem Cells
Stem cell pathways have long been recognized to be aberrantly activated in cancer (reviewed in Reya et al. 2001). These stem cell pathways play important roles in regulating self-renewal, a process by which a stem cell is able to undergo unlimited cell division. Cancer stem cells (CSC) depend upon inappropriate activation of self-renewal to mediate tumor growth and the metastatic spread of disease. It is now understood that current chemotherapeutics do not effectively eliminate CSC, leading to tumor recurrence. OncoMed was founded with the mission of developing therapeutics that target these complicated stem cell pathways in order to develop a new generation of therapeutics that target CSCs. Our research has led to new insights into the mechanisms of CSC resistance to chemotherapy (Dylla et al. 2008). In addition, our research has led to the first clinical trials of a CSC targeting therapeutic, an anti-DLL4 antibody (OMP-21M18) that inhibits Notch signaling. This antibody is currently in Phase I clinical studies for the treatment of solid tumors. We have published peer-reviewed preclinical data demonstrating the anti-cancer activity of this therapeutic approach (Hoey et al. 2009). The novel therapeutic strategy described in this grant application program could become the first therapeutic agent in its class. A large body of preclinical work shows that this therapeutic strategy has tremendous potential.
Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001 Nov 1;414(6859):105-11. PMID: 11689955
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, Pickell K, Aguilar J, Lazetic S, Smith-Berdan S, Clarke MF, Hoey T, Lewicki J, Gurney AL. Colorectal cancer stem cells are enriched in xenogeneic tumors following chemotherapy. PLoS One. 2008 Jun 18;3(6):e2428. PMID: 18560594
Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, Fitch-Bruhns M, Lazetic S, Park IK, Sato A, Satyal S, Wang X, Clarke MF, Lewicki J, Gurney A. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell. 2009 Aug 7;5(2):168-77.PMID: 19664991
Since its inception in 2004, OncoMed Pharmaceuticals has been based in California. We are located in Redwood City and are therefore among the many companies that contribute to the Bay Area’s world leading position within biotechnology. As a California company, our employees are also fellow citizens of California. OncoMed has active collaborations with researchers in area hospitals and universities. Moreover, our company also does extensive business with other local biotechnology and healthcare related firms and thereby further supports the health of the biotech industry in California. The biotechnology industry relies on highly educated, well trained employees and the jobs that are created by the success of biotechnology are good paying jobs. OncoMed Pharmaceuticals currently has 75 employees.
The research this grant will help support has great potential, and if successful it will benefit California. Developing a successful therapeutic in a major indication such as cancer is an enormous enterprise. Beyond the basic science underlying the discovery and preclinical testing of the therapeutic, there are the years of clinical trials that require people with many different types of training and experience in areas such as manufacturing, quality control, regulatory affairs, and medicine. Thus a successful therapeutic program can be anticipated to create a large number of jobs here in California. Moreover, success enables further success and allows the company to attempt additional research and discovery, develop additional therapeutics and perform additional clinical trials.
This grant is to support research on a therapeutic targeting an important stem cell pathway. Knowledge and experienced gained in this work will benefit our understanding not only of cancer stem cells, but also normal stem cells. The rapid progress that is being made in stem cell research has real potential to be the foundation of a new generation of medicines and perhaps a generation of pharmaceutical companies. California is well positioned, perhaps uniquely well positioned, to lead the new medical revolution enabled by stem cell discoveries. The work being done at OncoMed Pharmaceuticals is at the leading edge of this change. OncoMed has begun the first clinical trials of a cancer stem cell targeting therapeutic, now in Phase I clinical studies for the treatment of solid tumors. This grant will help to build OncoMed’s leading position in the cancer stem cell field, and at the same time broaden our knowledge of stem cell biology. Success in this effort will benefit California both in near term jobs at OncoMed and also in contribution to the broader goal of helping California remain a leader in the science and the opportunities of stem cell research.