Combining mRNA Nanotherapy with Standard Antiangiogenic/Immuno Therapy for HCC
Abstract
The fiscal year 2022 (FY22) Peer Reviewed Cancer Research Program (PRCRP) Topic Area addressed by our research project is Liver Cancer. The objective of this Impact Award proposal is to develop a transformative treatment strategy for hepatocellular carcinoma (HCC), which is the most common type of liver cancer. Targeting the immune system of cancer patients with the so called immune checkpoint blockers has revolutionized cancer treatment, but the benefits for patients with advanced HCC have been limited so far. In part, this is because existing treatments do not directly target the cancer cells themselves, but rather target the tumor vasculature and the immune system. Consequently, the majority of HCCs still do not respond to or are likely to recur after these therapies. Our proposal specifically aims to improve the existing treatment by developing a new approach to target a widely mutated tumor suppressor gene p53 using nanoparticles to more effectively deliver the therapy to the liver cancer cells. The loss/mutation of p53 gene has a causal role in the development and progression of a wide range of cancers. Recent clinical data reveal the mutation of p53 in approximately one-third of HCC patients, ranking as the most common among the altered genes. Interestingly, increasing evidence also suggests a key role of p53 in regulating the antitumor immune responses. Our latest research work supported by Department of Defense PRCRP Idea Award with Special Focus (2019-2021) has shown that: (i) nanoparticle-mediated delivery of mRNA for p53 is feasible and restores p53 protein expression in HCC cells; and (ii) combining p53 mRNA nanotherapy with immunotherapy results in markedly extending the duration of survival as well as reduced morbidity of the disease, without eliciting any detectable toxicities in state-of-the-art models of HCC in mice. In this project, we will develop a translatable lipid nanoparticle (LNP) platform for p53 mRNA delivery to HCC and evaluate its combination with the new standard of care therapy, which targets the tumor vasculature and the immune system. The goal is to prove that this new strategy is feasible and can achieve more durable responses to treatment in HCC models. Of note, this LNP platform is similar to the LNP clinically approved for short inhibitory RNA therapy or COVID-19 mRNA vaccination. Importantly, our strategy will be more selective for HCC tissue and have much higher accumulation and retention in the liver cancer. We expect the unique combination strategy proposed herein to be rapidly advanced to clinical development upon successful completion of this project, and to have a major impact on the survival and quality of life of HCC patients with tumors driven by p53 gene mutation over the next 3 years through our network of clinical collaborators and patient advocates. A recent study demonstrates that male U.S. military Veterans had an increased frequency of HCC at autopsy compared with the general population, likely due to more exposure to different risk factors, such as transfusion of blood products, intravenous drug use, hemodialysis, ear piercing in men, and organ transplants. We expect the proposed research to benefit HCC patients in general but to have a particularly profound impact on the health of U.S. military Veterans who are impacted by the environmental exposure risk factors associated with cancer – one of the FY22 PRCRP Military Health Focus Areas. This proposal is therefore also in accordance with the following two FY22 PRCRP Overarching Challenges: (i) improve treatment and outcomes for patients in underserved or under-recognized populations, and (ii) advance immunotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310846
Entities
People
- Jinjun Shi
Organizations
- United States Army