Funding opportunities
Cancer Stem Cell Therapeutic Targets Derived from Human Embryonic Stem Cells
Funding Type:
Disease Team Planning
Grant Number:
DT1-00667
Funds Committed:
$48,950
Funding Recommendations:
Not recommended
Public Abstract:
We propose to develop and test therapeutic agents that specifically target cancer stem cells (CSC) from solid tumors that are widely believed to be responsible for recurrence and drug-resistance. The theory that most forms of cancer are stem cell disorders is gaining widespread acceptance. Thus, the emerging model of cancer is that only a minority of tumor cells can form new tumors, and the unregulated growth that is the hallmark characteristic of cancer cells is due to a disruption in regulatory mechanisms of stem cell renewal. In order to more effectively control or perhaps cure cancer, it is necessary to devise therapeutics that more effectively target CSC and prevent their capability to renew. One impediment to this goal is that CSC undergo extended periods of quiescence and have other effective molecular mechanisms for resistance and repair of damage from toxic agents. This makes them resistant to conventional chemotherapy and radiation therapies that broadly target proliferating cells. Another impediment is that the antigens expressed by CSC may not be the same as the large majority of more differentiated cells from these tumors. This may make them “invisible” to therapeutics such as monoclonal antibodies that may only target the more differentiated cells. Potentially also, these properties may be similar to the normal organ- or tissue-specific stem cells that reside in various organs of individuals that are responsible for maintenance and repair of those organs over their lifetime. Thus, agents that effectively target the cancer cells may risk damaging normal cells. Tools have recently been found to isolate CSC from breast, colorectal, head and neck, brain, pancreas and prostate tumors, but these cells have generally proved difficult to collect and maintain in abundance in cell culture for testing under non-differentiating conditions. Our approach will be based on recent accomplishments in our laboratory in deriving hundreds of highly expandable normal embryonic progenitor cell lines from human embryonic stem cells under controlled GLP culture and differentiation conditions. Through extensive characterization by gene expression and antigen profiling, we have found that many of these normal cell lines express very similar antigenic phenotypes to those ascribed to the above solid CSC types. This will enable us to develop an important diagnostic platform for testing the safety of CSC-targeted therapeutics. This will also provide a major new resource of molecular targets from which to develop more specific therapeutics. Under this grant, we propose to assemble a team to expand our derivation and characterization of these lines. We will include in this team effort technical, preclinical and clinical expertise for producing new monoclonal antibodies and other targeting ligands, testing these in vitro and in vivo using tumor xenograft models, and ultimately evaluating the efficacy of potential therapeutics in patients.
Statement of Benefit to California:
Cancer is a leading cause of death and healthcare-related expense. One of the most significant breakthroughs in the paradigm for cancer treatment is that a small subset of cells with unique properties – cancer stem cells (CSC) – resists conventional therapies and is responsible for recurrences. The CSC field is still in its infancy. The number of different types of cancer yet to be investigated is very large, and CSC with different properties may exist even among sub-types of the same form of cancer. Thus, a significant challenge ahead will be to design therapies that selectively target CSC while sparing the normal tissue stem cells that they closely resemble that maintain and repair organs throughout life. In our laboratories we have discovered and are able to reproducibly derive and manufacture in culture abundant quantities of progenitor cell lines from normal human embryonic stem cells that may represent the normal tissue homologues of certain types of CSC. This represents a resource that to our knowledge exists nowhere else for developing in vitro diagnostic assays to test the safety of therapeutics that target CSC. This could be used advantageously both by our organization and by other organizations. In addition, by comparing differences in the molecular expression patterns between normal stem cells and CSC grown in culture under the same conditions, we may discover an abundant source of novel molecular targets for more specific therapies.
California is rapidly emerging as the hub for research and development of therapeutics targeting CSC. In recent years, thought-leaders in this field from around the country have relocated to California universities and biotech companies. Major investments in early-stage companies by venture capital firms and pharmaceutical companies have been announced to rapidly exploit and develop discoveries made by academic researchers. If CIRM-funded research continues to spur progress, this area of biotechnology has the potential to grow substantially. This will help to fulfill CIRM’s goals of increasing the availability of new stem cell-based therapies and diagnostics to citizens, create new jobs and keep the state at the forefront of the biotech industry.
Review Summary:
Executive Summary
The applicant proposes a Disease Team effort with a focus on solid epithelial tumors that will carry forward a project to develop potentially therapeutic monoclonal antibodies against cancer stem cells. The concept proposed relies on the hypothesis that solid epithelial tumors arise and recur as a result of deregulation within a small population of tissue progenitor cells (cancer stem cells, CSC). The applicant has generated over one hundred partially differentiated cell lines, derived from normal human embryonic stem cell lines that s/he believes represents a spectrum of normal progenitor/stem cell populations. The applicant proposes that these lines be utilized to generate and test antibodies that could be used therapeutically to treat epithelial tumors.
Reviewers noted that the nature of tumor-initiating cells or cancer stem cells in various solid tumors has not yet been fully worked out. The suggestion that the partially differentiated lines identified by the applicants are a representation of cancer stem cells was the crux of the proposal, but was insufficiently supported and viewed as a weakness. The applicant did not make it clear how use of these cell lines would address the question of what a cancer stem cell is in a solid tumor or why these cells are a better alternative for generating therapeutic antibodies specific for CSC. Most importantly, the reviewers also felt that the Disease Team would not have a clearly identified therapeutic target that would make it to the clinic in 5 years.
The PI has leadership and management qualities that are appropriate and has worked for several companies. The PI has experience in development of monoclonal antibodies and in the field of embryonic stem cell biology.
Reviewers thought the planning approach was not well-defined and involved mostly a continuation of cell line development and recruitment of experts in the field of tumor biology and microenvironments.
Reviewer Synopsis
The concept proposed is an antibody based therapeutic against cancer stem cells of solid epithelial tumors. According to applicant, rare cell populations are the ones that form new tumors and are responsible for recurrence. The hypothesis is that normal stem cell pathways are disrupted in cancer. In order to “cure or control” cancer it is necessary to devise therapeutics that target cancer stem cells. The applicant points out that this is an important problem since director of NCI announced trans-NIH group and pharmaceutical company 1.4 billion to generate mAbs. They made under GLP conditions 140 different ES cell derived cell lines that they claim represent different normal stem cell populations, some of them are similar to described cancer stem cells. They want to make even more lines for molecular comparison (RNA, DNA, surface antigens etc. and to include) and generate mAbs.
Reviewer Comments
Concept:
- The problem with this concept is the question of what cancer stem cells really are in epithelial tumors. There is uncertainty about their origin, significance and role in the process of tumor formation
- It is not clear how hundreds of GLP cell lines will help to solve the problem
- There are no defined goals in terms of specific diseases that will be targeted in 5 years
Principal Investigator:
- PI is director of technical process deveopment at ACT, has experience in the field of ES cells and the creation of monoclonal antibodies.
- The PI has leadership qualities and management expertise, and worked for a number of companies.
- The PI does not hold an MD or have clinical experience.
Planning Approach:
- The approach is the generation of more cell lines and the recruitment of experts in the field of tumor biology / microenvironment
Conflicts:
