Synthetic Construction of a Positive Auto-regulatory Feedback Loop in Human Cells Applied to Differentiated Anti-mitotic Cancer Therapy
Date Issued
2015
Date
2015
Author(s)
Chen, Moon-Huan
Abstract
Among treatments for the advanced-stage cancers, chemotherapy and targeted therapy are the most common ones. The targeted therapies target a specific enzyme or regulator in a specific signaling pathway in cancer cells, which has been proved to have fewer side effects. But on the other hand, this specificity of targeting has been suggested to be prone to select for preexisting secondary mutations that enable cells resistant to the drug, and acquired resistance would result in rapid cancer recurrence, thus the elevation in overall survival is limited. As for anti-mitotic chemotherapy that blocks cell mitosis, would hence influence survival of other proliferating cells, such as hematopoietic stem cells in bone marrow, and then brings more and deeper side effects. A low blood cell count, for example, would threaten patients’ lives. Therefore, the aim of our research is to inhibit cell cycle for treatment of cancer, while sparing dividing bone marrow cells. With a “synthetic biology” approach, we would construct a cell cycle-targeted molecular device in human cells that is able to sense cell states and differentiate between cancer and normal cells, delivering more specific and effective killing. In this thesis, we designed a positive auto-regulatory loop through tetracycline-controlled transcriptional activation system, using fluorescence protein as reporters to visualize device performance, with hope to induce a bimodal distribution by tuning the circuit response. It means that all cancer cells will initiate this genetic circuit effectively upon entering mitosis, ensuring to express the desired toxic proteins, and go into apoptosis, whereas all normal cells lack toxic protein expression and are able to survive. Consequently, we hope this design of molecular circuit will be applicable to cancer gene therapy in the future.
Subjects
cancer therapy
synthetic biology
positive auto-regulation
bimodality
SDGs
Type
thesis
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