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SOX-2 knockdown in stem cells prevents lung tumor recurrence

Institution: Scripps Research Institute
Investigator(s): Ralph Reisfeld, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19XT-0051 Award: $473,879
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
Lay Abstract: This research proposal is specifically designed to focus on a novel and innovative molecular targeted therapy for lung cancer which is one of seven primary research areas TRDRP to maintain its broad scientific portfolio. Specifically, we will develop and apply a novel and unique strategy for the treatment of lung cancer by specifically attacking cancer stem cells (CSCs) within their protective niche in the tumor microenvironment (TME). This approach is most promising because CSCs are a small subset of tumor cells that can renew themselves and constitute the only cell type that can maintain tumor growth indefinitely. In contrast, the remaining non-stem cells which make up a majority in the TME, will eventually die to be replaced by new tumor cells. The ability of CSCs for self-renewal is thus the real driving force behind lung tumor growth, spreading and recurrence. The limited number of CSCs in the TME and their unique ability to survive indefinitely are thus held responsible for tumor cell escape from such conventional treatments as chemotherapy and radiation resulting in cancer recurrence. In fact, the ability to specifically destroy lung cancer stem cells is further complicated since molecular markers expressed on their surface, that could serve as points of attack for biological/immunological therapies, are generally also expressed, to some extent, on normal stem cells that are critical for normal organ and tissue repair. Importantly, we aim to overcome this problem with a completely different approach by discovering how CSCs are maintained and protected from being killed by traditional cancer therapies within a niche in the TME. Thus, we found that this protection of CSC occurs via a factor (Sox2) that regulates genes critical for the maintenance of CSCs. When we down regulated Sox2 by genetic manipulation, we found this approach sensitized the formerly chemoresistant CSCs to being killed by drugs currently used in the clinic for the treatment of human lung cancer. Taken together, our findings will provide for an effective and novel strategy to destroy CSCs and thus lead to the suppression of lung tumor growth, spreading and recurrence in our tumor model, resulting in increased life span of experimental animals. Once such strategies will be successful in our preclinical setting, they can rapidly be translated to clinical evaluation for the improved treatment of human lung cancer.