This application aims to demonstrate that Scanning Unnatural Protease Resistant (SUPR) peptides provide a general solution to the problem of targeting traditionally undruggable proteins. To do this, we will use mRNA display with an expanded genetic code to create a new class highly stabilized, membrane-permeant peptides that can block or modulate protein-protein interactions for two of the most important intracellular proteins conferring the oncogenic phenotype-the activated form of Ras and the Stat3 protein. Our three Specific Aims are: 1) To design stabilized SUPR peptides targeting intracellular "undruggable" proteins involved in cancer transformation or maintenance, 2) To characterize and enhance selected SUPR peptide functions towards cancer drug applications, and 3) To evaluate in vivo characteristics and assess the therapeutic potential of optimized SUPR peptide drug candidates for cancer treatment in mice. Overall, this project is intended to develop novel molecules as well as a general approach to target cancer-relevant proteins that have proved challenging up to this point-so much so that the proteins may be called "undruggable."
The development of novel technologies to inhibit undruggable therapeutic cancer targets is an important public health priority. It can expand our abilities to discover new cancer drugs and improve our abilities to manage cancer. Successful completion of the proposed studies will not only offer many new treatment opportunities for cancer, but also provide new tools for cancer drug discovery.
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|Jalali-Yazdi, Farzad; Lai, Lan Huong; Takahashi, Terry T et al. (2016) High-Throughput Measurement of Binding Kinetics by mRNA Display and Next-Generation Sequencing. Angew Chem Int Ed Engl 55:4007-10|
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|Jalali-Yazdi, Farzad; Takahashi, Terry T; Roberts, Richard W (2015) General, Label-Free Method for Determining K(d) and Ligand Concentration Simultaneously. Anal Chem 87:11755-62|
|Kim, Yu Jeong; Liu, Yarong; Li, Si et al. (2015) Co-Eradication of Breast Cancer Cells and Cancer Stem Cells by Cross-Linked Multilamellar Liposomes Enhances Tumor Treatment. Mol Pharm 12:2811-22|
|Jalali-Yazdi, Farzad; Corbin, Jasmine M; Takahashi, Terry T et al. (2014) Robust, quantitative analysis of proteins using peptide immunoreagents, in vitro translation, and an ultrasensitive acoustic resonant sensor. Anal Chem 86:4715-22|
|Zhang, Chupei; Hu, Biliang; Xiao, Liang et al. (2014) Pseudotyping lentiviral vectors with lymphocytic choriomeningitis virus glycoproteins for transduction of dendritic cells and in vivo immunization. Hum Gene Ther Methods 25:328-38|
|Howell, Shannon M; Fiacco, Stephen V; Takahashi, Terry T et al. (2014) Serum stable natural peptides designed by mRNA display. Sci Rep 4:6008|
|Liu, Yarong; Fang, Jinxu; Kim, Yu-Jeong et al. (2014) Codelivery of doxorubicin and paclitaxel by cross-linked multilamellar liposome enables synergistic antitumor activity. Mol Pharm 11:1651-61|
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