Funding opportunities

BMP-activating Antibodies for the Targeting of Colon and Breast Cancer Stem Cells

Funding Type: 
Early Translational II
Grant Number: 
TR2-01760
Funds requested: 
$5 071 836
Funding Recommendations: 
Not recommended
Grant approved: 
No
Public Abstract: 
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. Literature cited: 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
Statement of Benefit to California: 
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.
Review Summary: 
This application for a Development Candidate Award focuses on a therapeutic monoclonal antibody (mAb) targeting cancer stem cells (CSCs). CSCs are defined as a relatively rare subpopulation of tumor cells which are resistant to chemotherapy and sustain tumor growth. The applicant presents preliminary data suggesting that activation of a specific cell signaling pathway reduces tumor volume and CSC frequency in preclinical tumor models of colon and breast cancer. The applicant proposes to move this work toward clinical translation by first generating hundreds of mAbs targeting this signaling pathway, then screening these mAbs for activity both in vitro and in tumor xenograft models, developing processes for the purification and manufacture of two selected mAbs, and finally, testing the pharmacokinetic and safety profiles of these two mAbs in preparation for selection of a development candidate. The reviewers agreed that, if successful, this proposal could have a significant impact on the treatment of colon and breast cancers. However, they did not find the scientific rationale for this proposal to be strongly supported by preliminary data. Reviewers noted that activation of the targeted signaling pathway did not affect the growth of all tumor xenografts tested and the applicant does not address what might account for these differential sensitivities. In addition, the reviewers found some of the reported tumor volume reductions to be modest, including that reported in the most therapeutically relevant colon cancer xenograft model. They felt that the application would have been strengthened by a more comprehensive analysis of the target tumor types to determine the frequency of responsive versus non-responsive cells and to quantify the expected reduction with the proposed treatment. Reviewers also would have appreciated comparison data with current chemotherapeutic drugs, as well as evidence that this mAb can effectively penetrate a solid tumor to target CSCs. Reviewers acknowledged that the applicant has a track record of developing therapeutic mAbs, but still raised a number of concerns about the feasibility of the research plan. They noted that the proposed mAb is agonistic and has a complex target. Reviewers felt that there are many potential pitfalls in the development of such a therapeutic which are not acknowledged in the application. They also questioned the proposed timeline and were doubtful that a development candidate could be reached within the three-year funding period. The reviewers would have appreciated a validation of the proposed milestones and a justification of the timeline based on the applicant’s experience developing two other mAbs. The reviewers found the Principal Investigator (PI), co-PI and assembled research team to be well-qualified to carry out the proposed research plan. The infrastructure and resources available are appropriate and adequate. One reviewer commented that the budget and total number of full-time employees dedicated to the project were excessive. Overall, while reviewers appreciated the potential impact of this proposal on breast and colon cancer therapy, they raised significant concerns about the preliminary data and the feasibility of completing the research plan within the three year timeline.
Conflicts: 
  • Jay Edelberg

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