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.
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.