The long-term goal of this U01 proposal is to develop Thermoresponsive (TR)-NanoVelcro circulating tumor cell (CTC) purification system that can be digitally programmed to achieve optimal performance for recovering viable CTCs in prostate cancer (PC) patients' blood, allowing seamless coupling with various downstream functional and molecular assays. Dr. Tseng (PI/UCLA) and Dr. Posadas (co-PI/Cedars Sinai Medical Center) will bring together an interdisciplinary research team to implement the proposed research activities. CTCs are regarded as a liquid biopsy of tumors, allowing non-invasive, repetitive, and systemic sampling of the disease. Although detecting and enumerating CTCs is of prognostic significance in metastatic PC, it is conceivable that performing molecular and functional characterization on CTCs will reveal unprecedented insight into the pathogenic mechanisms driving lethal PC. In order to obtain CTC-derived molecular signatures and functional readouts, it is important to develop improved methodologies that can not only detect/enumerate CTCs with high sensitivity, but also recover CTCs with minimum contamination by white blood cells and negligible disruption to CTCs' viability. Our working hypothesis, based on preliminary data gathered of temperature-dependent purification of viable CTCs using polymer brush-grafted nanosubstrates, is that the performance of the proposed TR- NanoVelcro CTC purification system can be i) optimized by rationally modulating surface chemistry, cocktail capture agents, flow rates, and heating/cooling cycles, and ii) validated using both artificial and prostate cancer patient blood samples. PC CTCs purified by TR-NanoVelcro CTC purification system will be of sufficient viability and purity, paving the way for i) short-term in vitro culture, ii) long-term i vitro maintenance, and iii) in vivo tumorigenic models as patient-derived xenografts. The ex vivo expanded CTCs will provide sufficient high-quality gDNA and mRNA that can be characterized by next-generation sequencing (NGS) for de novo identification of key molecular events in PC. Using bioinformatic approaches, we will assemble PC-specific genomic/transcriptomic panels for cross-validation by NGS using CTCs freshly isolated from multiple PC patients. We envision that TR-NanoVelcro system will enable instant purification of viable CTCs from PC patients, paving the way for performing a variety of downstream molecular and functional assays that can significantly contribute to understanding PC progression, implementation of personalized treatment, and development of new therapeutics.

Public Health Relevance

The long-term goal of this UO1 proposal is to develop Thermoresponsive (TR)-NanoVelcro circulating tumor cell (CTC) purification system that can be digitally programmed to achieve optimal performance for recovering viable CTCs in prostate cancer (PC) patients' blood. The purified CTCs will be subjected to various downstream functional and molecular assays, resulting in molecular signatures that can significantly contribute to understanding PC progression, implementation of personalized treatment, and development of new therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01CA198900-03
Application #
9336269
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Hartshorn, Christopher
Project Start
2015-08-18
Project End
2020-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Biochemistry
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Shen, Mo-Yuan; Chen, Jie-Fu; Luo, Chun-Hao et al. (2018) Glycan Stimulation Enables Purification of Prostate Cancer Circulating Tumor Cells on PEDOT NanoVelcro Chips for RNA Biomarker Detection. Adv Healthc Mater 7:
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Hou, Shuang; Chen, Jie-Fu; Song, Min et al. (2017) Imprinted NanoVelcro Microchips for Isolation and Characterization of Circulating Fetal Trophoblasts: Toward Noninvasive Prenatal Diagnostics. ACS Nano 11:8167-8177
Sho, Shonan; Court, Colin M; Kim, Stephen et al. (2017) Digital PCR Improves Mutation Analysis in Pancreas Fine Needle Aspiration Biopsy Specimens. PLoS One 12:e0170897
Ankeny, J S; Court, C M; Hou, S et al. (2016) Circulating tumour cells as a biomarker for diagnosis and staging in pancreatic cancer. Br J Cancer 114:1367-75
Cheng, Shirley; Chen, Jie-Fu; Lu, Yi-Tsung et al. (2016) Applications of circulating tumor cells for prostate cancer. Asian J Urol 3:254-259

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