Early Translational III
Stem cell pathways have long been recognized to be aberrantly activated in cancer. 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. They also control differentiation, a process by which stem cells give rise to cells with specialized functions. Inappropriate activation of self-renewal and/or blockage of terminal differentiation support tumor growth and metastatic spread of disease, and are the hallmark of cancer stem cells (CSCs). Thus CSCs comprise a subset of the malignant cells, but drive cancer progression. It is now understood that current chemotherapeutics do not effectively eliminate CSCs, leading to tumor recurrence, and predictably poor prognosis. Developing a new generation of therapeutics that target CSCs, therefore represents a promising novel approach to cancer treatment. Our mission is to develop such agents. We have identified and validated a therapeutic target that belongs to a stem cell pathway, and is essential for CSC maintenance in solid tumors. We propose to generate and select an antibody that will inactivate the target in primary and metastatic tumors, leading to the elimination of CSCs and control of tumor progression. The novel therapeutic strategy described in this grant application program could lead to first-in-class therapeutics targeting a CSC pathway. A large body of pre-clinical work shows that this therapeutic strategy has tremendous potential.
Statement of Benefit to California:
[Redacted] This grant is to support research on a therapeutic targeting an important stem cell pathway. Knowledge and experience gained in this work will benefit our understanding not only of cancer stem cells (CSCs), but also normal stem cells. California is well positioned to lead the new medical revolution enabled by stem cell discoveries. [Redacted] has demonstrated a capacity to discover innovative new medicines with three first-in-class novel therapeutics targeting CSCs now in clinical studies for the treatment of solid tumors. This grant will help to build [redacted]’s leading position in the CSC 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 and in helping California remain a leader in stem cell research.
This Development Candidate (DC) project proposes to develop monoclonal antibodies (mAbs) that inhibit the function of a family of secreted proteins that are implicated in self-renewal of cancer stem cells (CSC). The goal of the project is to block binding of the proteins to their cognate receptors and subsequently inhibit a cell signaling pathway required for somatic stem cell and CSC activity. By targeting CSC, these antibodies are expected to reduce tumor growth. These antibodies will be evaluated in parallel and a candidate will be selected for IND-enabling studies. Six milestones are proposed: 1) generation of antibodies that bind the mouse and human forms of the target proteins; 2) identification of the subset of antibodies that block the function of the target; 3) selection of lead antibodies based on efficacy in preclinical models; 4) analysis of mechanism of action and identification of biomarkers; 5) generation of a candidate cell line and establishment of production and purification processes; 6) establishment of pharmacokinetic and safety parameters. Objective and Milestones -It is not clear why the applicants are advancing to the IND stage a previously developed mAb against one of the protein family members while proposing to generate mAbs against each of the targeted protein family members to select the best lead mAb candidate. - It seems that a mAb that cross reacts with multiple members of the target protein family may be more effective than a mAb against a single member, since there is some co-expression and functional redundancy between protein family members in tumors. - The milestones are well defined and address key requirements to establish preclinical proof of concept and select a lead. The criteria are clear, measurable and appropriate. - The objective of the research is appropriate for a DC award and the TPP is reasonable. Rational and Significance - Targeting the relevant signaling pathway has merit but the rationale for targeting this family of proteins as the approach for cancer stem cell therapeutics is less well developed. - This proposal addresses an unmet need and has the potential for significance, but the impact of the proposed study is diminished based on the specific target being developed. Research Project Feasibility and Design - The experimental plan is feasible and the overall experimental design seems appropriate. However, the research plan is lacking in technical details or references to the procedures that are to be used. - The PI alludes to the fact that the antibodies may affect the normal somatic stem cells that require these proteins for their viability and activity but no experiments are proposed to determine whether normal stem cells will be affected. - While each member of the targeted protein family can bind to each of the cognate receptors, the possibility that the members of the targeted protein family may be functionally redundant was not addressed in the application. - It isn't clear why the applicants need to make additional mAbs against one of the targets nor whether their mAb against that target cross reacts with the other protein family members or has any toxicity associated with its administration. -It is not clear how gene expression profiling will be applied and interpreted given that treated tumors will not only have tumor cells that have responded to therapy but the composition of the tumors with regard to tumor cells and stromal cells will have changed in response to therapy. -There are no clear plans for developing and testing lead mAb candidate and no algorithms for how the large body of data will be processed. Qualification of the PI and Research Team - The principal investigator, co-investigator and their research teams have the requisite qualifications and expertise to carry out the research project and in fact have a proven track record in the field of the proposal. Collaborations, Assets, Resources and Environment - Outsourced work is well defined and appropriate and resources and skills are very good - The applicant organization is committed to this project and its collaborators have the necessary facilities for success in this project. Responsiveness to the RFA - It is really not clear what cells are being treated. They are characterized as stem cells because of their tumor-initiating qualities but tumor-initiation in some models is not confined to cells that express stem cell markers. - The proposal is responsive to the RFA. The targeted family of proteins is well validated for a role in promoting CSC based on the literature and preliminary information provided by applicant.
- A motion was made to move this application into Tier 3, Not Recommended for Funding. Although the applicants are competent and experienced, this particular proposal had several flaws in the experimental design that convinced reviewers that a recommendation for funding was not appropriate. The motion carried.