RNA Medicine-Enhanced Immunotherapy and Targeted Therapy for Non-Small Cell Lung Cancer
Abstract
Scientific Objective and Rationale: Tumor relapse and spreading to secondary organs (metastasis) may occur after initial treatments, arising from minimal residual tumor cells that can survive these treatments. Treatments targeting specific genes that drive tumorigenesis and tumor progression are called targeted therapy, which is more efficient in killing fast growing tumor cells. However, a small percentage of tumor cells can transform themselves into a cell state that mimics hibernation to evade drug treatment; these are called dormant persisters. After cessation of treatment, tumor persisters regain normal growth, repopulate tumor, and metastasize. A co-mentor of this project and colleagues have identified that, after targeted therapy, tumor persisters turn on YAP1 expression to enable entering the dormant cell state to survive the treatment, which leads to tumor relapse. However, how YAP1 drives entering dormancy and eventually regrowing of persisters is not known. Downstream effector genes of YAP1 need to be identified to fully understand this cell state transition. DNA is tightly wound into a complex called chromatin, which must be opened up to enable gene expression. This process is called chromatin (epigenomic) remodeling. How YAP1 affect chromatin remodeling during the development of persisters is not clear. Immunotherapy is developed to use the power of the body’s own immune system to prevent, control, and eliminate cancer. Our preliminary single cell analyses of resected tumors from NSCLC patients who have received immunotherapy identified tumor persisters after immunotherapy that are also characterized with high expression of YAP, which is associated with suppressed immune system and diminished therapeutic efficacy. These persisters coexist and interact with the immune system in the tumor ecosystem, which is called the tumor microenvironment (TME), in a way that favors the growth of tumor cells and suppresses the immune system. In addition, tumor cells create favorable microenvironment for proliferation by continuously crosstalk with surrounding normal cells. Therefore, it is important to understand the spatial structure of TME. Most of genes regulating expression and chromatin remodeling, called transcription factors, are undruggable due to the lack of small molecule binding pocket or cellular localization. We have developed nanoparticles that can deliver small interfering RNA (siRNA) molecules to lung and tumor cells to regulate the expression of these transcription factors and thus re-sensitize tumor cells to therapy. This is call RNA therapy. Theoretically, any gene can be targeted using siRNAs for therapeutic intervention. siRNA therapy represents one of the most recent breakthroughs in medicine. FDA approval, in 2018 and 2019, of two siRNA-based therapies (Patisiran and Givosiran) for genetic diseases represents a landmark for RNA medicine. One of advantage of siRNA therapy is its long-lasting therapeutic effect. For instance, twice-yearly administration of siRNA therapeutics has been shown sufficient to achieve optimal therapeutic effect, an unprecedent achievement in the pharmaceutical history. In this study, we aim to reveal the role of YAP in the development of tumor persisters, to identify YAP- mediated alterations in gene expression and chromatin remodeling that enable tumor evasion from targeted treatment and immunotherapy, and to examine how YAP-high persisters educate immune system to avoid attacking tumor cells. We will also evaluate the therapeutic efficacy of transformative targeted therapy and immunotherapy which are enhanced by RNA medicine. This project directly addresses the FY22 LCRP Areas of Emphasis to (1) identify innovative strategies for the prevention of recurrence of or metastases from lung cancer and (2) understand mechanisms of resistance to treatment (primary and secondary). Career goals of the PI: Dr. Tang is dedicated to delineating multi-layer r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310069
Entities
People
- Yan Tang
Organizations
- United States Army