Identification of cancer stem cell-specific internalizing scFvs for pre-clinical antibody-drug conjugate development
Early Translational I
Cancer claims the lives of more than 7.5 million people annually worldwide and is responsible for one in four deaths in the State of California. Furthermore, incidence rates for most solid tumors are on the rise. The last few decades have witnessed significant advances in therapeutics yielding improved clinical responses measured in terms of tumor shrinkage and time to tumor recurrence; however, overall survival has failed to improve meaningfully over this time period. Recent work has demonstrated that a subpopulation with the unique capacity to fuel tumor growth (cancer stem cells; CSC) exists within the complex mixture of cells that make up solid tumors. This observation may shed light on the disconnect between clinical response and overall survival, as CSC appear responsible for initiating tumor growth, metastasis, and recurrence after chemotherapy, radiation, and other therapies fail to kill them. As such, overall survival for patients with solid tumors is unlikely to improve significantly with drugs currently on the market as these therapies generally do little to differentiate between tumor cells. In contrast, focused development of therapeutics that specifically target CSC should mitigate residual disease and metastasis, and prolong overall survival for cancer patients. Though proposed to exist in the late 1960’s, CSC remained unidentified in solid tumors until 2004 largely because the tools to identify and isolate these cells were non-existent. Recent technological advancements are enabling more accurate identification and targeting of CSC. In true collaborative fashion investigators from both academia and industry are utilizing their expertise to identify, isolate, and interrogate tumor cell populations to identify antibody-based therapeutics that target CSC. New and powerful experimental platforms consisting of human tumor cells that appear to retain the pathophysiological characteristics of patient tumors from which they were derived have been developed to evaluate the ability of these antibody-based drugs to eliminate CSC and/or reduce tumor recurrence. In taking advantage of these new platforms and focusing squarely on the cells responsible for tumor growth, recurrence, and metastasis, investigators aim to quickly develop novel therapies that truly impact overall survival of patients with solid tumors.
Statement of Benefit to California:
Of every four deaths in California, one is from cancer. Current statistics also suggest that of the more than 130,000 California residents diagnosed with cancer last year, greater than 40% will die from their disease within five years if current therapies are not improved upon. Recent scientific discoveries show that traditional therapies such as chemotherapy and radiation largely fail to target the tumor cells responsible for initiating solid tumor growth, recurrence, and metastasis (i.e. cancer stem cells; CSC). To truly impact overall survival and target the underlying root cause of cancer, the next generation of cancer drugs should target CSC. In true collaborative fashion, leading technology platforms from industrial and academic laboratories are combining to identify and target cancer stem cell populations with the intent of developing therapeutics that significantly improve overall survival for patients with solid tumors. Secondary impacts of this research with relevance to CIRM’s mission will not be limited to the identification of tools and drugs able to detect and eliminate CSC. This work will also benefit the field of regenerative medicine, as little is known about normal tissue-specific stem cells, and tools developed as part of this research should facilitate their identification and characterization. Clearly, the most desired impacts of this research is to improve both early detection of tumors and overall survival for cancer patients, but the far-reaching goal is to more generally advance stem cell research and quickly realize therapies that cure patients.
The goal of this proposal is to develop an improved strategy for delivering chemotherapeutic agents to cancer stem cells (CSC), thereby facilitating their destruction while minimizing the risk of damage to normal, unaffected tissues. To achieve these ends, the applicant plans to identify internalizing human antibodies that can be subsequently engineered to deliver toxic drug payloads to their intended targets. The applicant will first establish proof of concept by conjugating a specific toxic drug to a monoclonal antibody and testing the efficacy of this antibody/drug conjugate for reducing or eliminating tumors in xenograft models. Next, the applicant proposes to identify CSC-targeting antibodies by screening preexisting and new phage display libraries for those that react with CSCs or associated factors. Antibodies identified by this method will be conjugated to drugs and evaluated for efficacy. As a final goal, the applicant proposes to use protein arrays to identify the corresponding antigens of the most promising candidates. The reviewers agreed that the proposed effort addresses an important need for better and more selective chemotherapies for treating human cancers. The rationale for targeting CSCs or the cells that are most likely responsible for tumor generation was thought to be timely and compelling. If drugs could be delivered more effectively, the improved efficacy and decreased risk of side effects could have an enormous, positive impact on the field of cancer medicine. In addition to these potential benefits, the reviewers discussed a number of strengths in the overall application. The proposal was well written, of sound premise, and provided an admirable amount of context in which the experimental approaches could be evaluated. Moreover, the principal investigator and collaborators were considered to be extremely qualified, comprising the necessary expertise and experience to bring these studies to fruition. Reviewers also identified several significant weaknesses that threatened the overall feasibility of the proposed approach. In particular, the strategies for identifying CSC antigen targets were viewed as inadequate. For example, reviewers strongly questioned the assumption that nonessential surface proteins would represent good candidates for antibody generation. Without evidence to indicate otherwise, it seemed likely that CSCs would acquire resistance to therapies directed against such components. The reviewers also feared that the probability of identifying novel CSC targets from the preexisting phage library would be remote, as CSC would only comprise a small minority of the heterogeneous cell populations to be screened. These uncertainties, combined with the fact that no single antigens have been identified that are CSC- specific, raised doubts as to whether the therapies developed by this approach would be sufficiently selective. While these concerns were the most serious, the reviewers noted additional deficiencies that might ultimately limit success. For example, some worried that the drug payload proposed in Aim 1 would be exported by CSCs. Others commented that the applicants did not adequately address issues surrounding organ toxicity in humans, something that would be difficult to define based solely on xenograft models in rodents. In summary, the reviewers felt that the proposed research addresses an important topic, is scientifically well justified, and reflects the expertise of an extremely qualified team of investigators. While the premise was logical and convincing, a number of technical deficiencies, including some inherent limitations in the experimental design, were thought to decrease the potential impact that this effort might have.