Nanoparticle-Based CRISPR Screen to Identify Genetic Regulators of Chemoresistance
Abstract
Lung cancer is the leading cause of cancer-related death in the United States, with a 5-year survival rate of 18.6%, which is lower than many other common cancers such as breast cancer (89.6%) or prostate cancer (98.2%). Moreover, lung cancer is an urgent priority among Veterans – not only is the incidence higher, but overall survival is lower than in the civilian populations according to the Lung Cancer Alliance. Currently, the first line of treatment for lung cancer patients is conventional chemotherapy. Unfortunately, this approach only provides transient survival benefits for tumor reduction and symptomatic relief due to the frequent development of acquired drug resistance. Thus, there is an immediate need to better understand how this type of resistance arises in patients and to develop new strategies to cause tumors to become more sensitive to the chemotherapy. While many attempts have been made to identify novel targets and strategies to overcome drug resistance, new technologies have emerged that make it easier to detect new therapeutic targets and understand the mechanisms that give rise to tumor resistance. Among these is the gene editing method known as CRISPR. Using this technique to alter or remove genes in tumor cells, we can now build assays that more rapidly detect vulnerable cancer proteins that can be targeted by new therapies. Commonly, the screening process to detect these vulnerabilities is performed on cells grown in culture; then the cells are subsequently implanted into animals to determine whether the altered gene has any effect on tumor growth. In contrast, our approach employs the CRISPR screen directly on tumors growing in living animals. To do this, we take advantage of small drug-delivery devices called nanoparticles that can carry the CRISPR reagents directly to tumors that are already growing in animals. This approach provides more relevance to the clinical setting because they take place in a whole animal with all the associated normal host cells, rather than just in cells in a dish. We expect that this approach will provide new insights into the nature of the genes that lead to drug resistance in patients with lung cancer that have been treated with chemotherapeutic agents such as cisplatin. As this type of resistance leads to relatively short-term gains, our approach may lead to improved recognition of genes that cause drug resistance and enable new approaches that prevent the development of such resistance, thus extending the lives of lung cancer patients. This project will explore the potential of this innovative approach in identifying physiologically relevant targets associated with cancer drug resistance and could lead potentially to new biomarkers, drug combinations, and new strategies to overcome such resistance and extend the lives of cancer patients. The completion of this project will significantly advance the field of CRISPR screening for novel drug targets to be more specific and clinically relevant. Furthermore, this novel NP-mediated CRISPR screen can be easily adapted to study other aspects of cancer, including tumor initiation and progression, as well as many different cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110329
Entities
People
- Kun Zhou
Organizations
- United States Army