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.""""""""

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA170820-03
Application #
8678709
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Yovandich, Jason L
Project Start
2012-09-17
Project End
2016-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Southern California
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Fiacco, Stephen V; Kelderhouse, Lindsay E; Hardy, Amanda et al. (2016) Directed Evolution of Scanning Unnatural-Protease-Resistant (SUPR) Peptides for in Vivo Applications. Chembiochem 17:1643-51
Fang, Jinxu; Xiao, Liang; Joo, Kye-Il et al. (2016) A potent immunotoxin targeting fibroblast activation protein for treatment of breast cancer in mice. Int J Cancer 138:1013-23
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
Fang, Jinxu; Hu, Biliang; Li, Si et al. (2016) A multi-antigen vaccine in combination with an immunotoxin targeting tumor-associated fibroblast for treating murine melanoma. Mol Ther Oncolytics 3:16007
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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