Targeted Combination Therapy in a Novel In Vivo Model of Fibrolamellar Carcinoma
Abstract
Our long-term goal is to provide treatment breakthroughs for patients with advanced or recurrent fibrolamellar carcinoma (FLC) and improve the outcomes for patients with this devastating cancer. FLC is a rare but deadly liver cancer that afflicts young individuals, and is often diagnosed at advanced stages. While surgery can offer the best chance for long-term survival, many patients experience cancer recurrence after tumor resection. Unfortunately, patients with advanced or recurrent cancer face formidable odds due to the lack of effective therapy. As a result, overall survival is only 30%-45% at 5 years, which underscores the deadly nature of this cancer and emphasizes the urgent need for new therapy. Much progress has been made in recent years related to the understanding of FLC, yet advancements in therapy have been slow. A significant barrier to developing new treatments is the rarity of this cancer, which limits the ability to perform human studies. Hence, there is a need to generate compelling data from highly relevant pre-clinical models. Unfortunately, there remains a deficiency in applicable pre-clinical models that could drive discovery of therapeutic breakthroughs. Thus, the objectives of this proposal, which address the Fiscal Year 2021 Rare Cancers Research Program Focus Areas of Research Model and Therapy, are to (i) characterize a novel pre-clinical mouse model that will closely mimic human FLC, and (ii) identify new potent combination treatments for FLC to yield effective treatment options. Existing models of FLC have several key limitations that restrict clinical translation. For instance, patient derived xenografts (PDX) have been extraordinarily difficult to derive and success in propagating the tumor cells has been quite low. Furthermore, given the significant rarity of this cancer, few laboratories have access to the tumor samples (i.e., not a widely applicable model). Another model introduces the gene mutation responsible for FLC (DNAJB1-PRKACA gene fusion) indiscriminately into liver cells. While tumors form, the random integration (i.e., targeting incorrect cell) of DNAJB1-PRKACA into cells results in tumors that lack key features of human FLC. The cell of origin for FLC is presently unknown, but is likely a biliary tree or progenitor cell, which emphasizes the need for a model system in which precise cell targeting of the DNAJB1-PRKACA gene fusion can be achieved to better represent human FLC (i.e., tumor initiation in the correct cell). Thus, we have designed our innovative model to mimic the key components in human FLC, whereby the FLC gene mutation occurs in a specific liver cell population at a young age. Furthermore, we deliberately have constructed the model for widespread applicability and coordinated use by other investigators, to amplify the impact of the proposal, help advance knowledge of this rare cancer, and drive meaningful discoveries. In conjunction, we will use an FLC cell line model to determine lethal treatment combinations that target abnormal pathways in FLC. Several recent studies have identified cancer-promoting pathways caused by the FLC driver- mutation (DNAJB1-PRKACA gene fusion). Despite these discoveries, the optimal combination of therapies that inhibit these aberrant pathways in the cancer cells has not been identified. We will therefore perform a drug screen analysis to identify potent multi-drug therapies that cause cancer cell death. In future studies, the newly discovered lethal drug combinations will be tested in a novel pre-clinical mouse model, which serves as a critical step that must be achieved prior to consideration for clinical trial. The seamless transition from screening cancer cells to the in vivo testing of potent drug combinations (follow-up studies) would enable completion of pre-clinical testing in the 2-3 years after concluding the current experimental aims and should provide a substantive basis for clinical studies. Consequently, we can ac
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210847
Entities
People
- Sean Ronnekleiv-kelly
Organizations
- United States Army
- University of Wisconsin–Madison