Identification of cancer stem cell-specific internalizing scFvs for pre-clinical antibody-drug conjugate development
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.
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.