Albumin-Bound siRNA Therapeutics for Synergistic Targeting of KRAS and MCL-1L in Cholangiocarcinoma
Abstract
Cholangiocarcinoma (CCA), or cancer arising from the bile ducts, is a rare but aggressive cancer that is diagnosed in around 9,200 Americans every year. Patients with CCA currently face limited treatment options when surgical removal of the tumor is not feasible. State-of-the-art chemotherapy and immune therapy regimens only result in typical patient survival of about one year. Recent advances have revealed mutations in these cancers’ DNA - the blueprints of cancer cells – that contribute to CCA tumor growth and may be exploited to create new targeted treatments. However, many of these mutations do not have a corresponding U.S. Food and Drug Administration-approved drug therapy, including the majority of mutations in a cancer growth gene called KRAS. Furthermore, research suggests that blocking KRAS on its own is often insufficient, and combination therapies may be needed to unlock the full potential of KRAS-targeted treatment. A promising strategy that we have identified in cancer cell lines is to block both KRAS and a second target called MCL-1. MCL-1 allows cancer cells to evade self-destruction (apoptosis), so blocking it can result in increased cancer cell death. Blocking both targets simultaneously appears to be synergistic, meaning they work better together than would be expected based on how they perform individually. In this project, we propose to create a treatment regimen that simultaneously targets the combination of KRAS and MCL-1 by using small interfering ribonucleic acid (siRNA) therapeutics. siRNA therapeutics use short, customized RNA molecules to eliminate perfectly matching messenger RNA inside cells, blocking the function of genes like KRAS that help the cancer grow. However, to use siRNA as cancer treatment, measures must be taken to keep it from coming out in the urine, guide it to the sites of cancer, and help it enter cancer cells. Our research group has pioneered siRNA modifications that enable hitchhiking on albumin, the most common protein in blood. Albumin normally remains in the bloodstream but is taken up by cancers that are scavenging for nutrients to drive their abnormal growth. Our innovative albumin-binding siRNA modifications therefore lead to longer blood circulation and better accumulation in the cancer compared to healthy organs. Using albumin-bound siRNA, we propose to (1) determine what biological factors are involved in the observed synergy between KRAS and MCL-1 treatment and (2) test the therapeutic potential and safety of this combination in animal models of CCA. This project will therefore address the Therapy Focus Area of the Rare Cancers Research Program. Our ultimate goal is to establish new targeted treatment strategies that extend survival compared to conventional chemotherapy in KRAS-mutated CCA. This would most directly impact the roughly 22%-42% of CCA patients who have KRAS mutations, although the delivery technology could further be developed for other molecular targets in the future. We aim to have mouse model results regarding safety and effectiveness of this treatment strategy in the next year of this project, although several more years of preclinical development are anticipated to be necessary before direct human impact. In the interim, our biological findings regarding the interaction between different targets like KRAS and MCL-1 in CCA will help advance our understanding of how we can more effectively attack CCA from different angles to maximize the treatment effect.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310717
Entities
People
- Craig Duvall
Organizations
- United States Army
- Vanderbilt University