Novel Therapeutics for Fibrolamellar Carcinoma
Abstract
FY18 PRCRP Topic Areas: Cancer in children, adolescents, and young adults Our proposal focuses on a unique form of liver cancer, fibrolamellar carcinoma (FLC). This debilitating disease affects young individuals between their teenage years and mid-30s. Importantly, this cancer afflicts young men and women in the prime of their life with none of risk factors associated with chronic liver diseases. Objective and Rationale FLC attacks healthy young people with few warning signs. Patients frequently present with general symptoms that include abdominal, shoulder, or back pain, loss of appetite, weight loss and jaundice. Hence, FLC has often progressed to an advanced stage with a large tumor before the patient receives any treatment. Consequently, the probability of surviving 5 years after the diagnosis of FLC is only around 30%, resulting in many years of potential life lost to these young patients and their families. Although there have been significant improvements in the medical management of other types liver cancer, including “targeted” drugs and immunotherapies, these treatments are not effective in FLC. In fact, currently there is no known medication that improves the survival of this form of cancer. Recent scientific breakthroughs give us reason to be optimistic toward finding clinical solutions for patients with FLC, however. This cancer was recently discovered to be caused by a mutation that brings two different proteins together to create a novel fusion protein. One of the two components of this disease-causing enzyme called protein kinase A (PKA), which, in its normal form, controls many important bodily functions. We are fortunate to have one of the world’s experts in PKA biochemistry to lead Project 1, which aims to understand why liver cells expressing mutant PKA turn cancerous. Equally important are questions related to how mutant PKA effects other cellular processes to favor the growth of this cancer (Project 2), and ways in which the cancer evades the body’s immune system to thrive (Project 3). Using state-of-the-art approaches, each Project aims to fill important gaps in our knowledge of FLC, and to develop new treatments that will combat FLC. Our Team includes basic and clinical investigators from three Institutions in Seattle, who work in unison to achieve find new treatments for FLC patients. Critical to our success are new research tools and computer-aided models of FLC. The seamless deployment of these state-of-the-art approaches forms the basis of our proposal. Whenever possible we used human-derived tissues in our analyses, as we believe this allows us to investigate FLC in its natural terrain. These include a patient-derived xenograft mouse model and an organotypic slice culture platform that allows us to test fresh human cancer samples. Hence, the results of our investigations should have direct clinical relevance. Most of our team have treated young patients with FLC. They fully appreciate the urgency and the need to develop new therapies for this deadly disease. Applicability of Research Our long-term goal is to find effective treatments through mechanistic, multi-dimensional investigations. Each Project contains a plan to translate our results from the laboratory bench to the clinic with actionable targets using available drugs. This approach will greatly expedite our findings by getting our results validated in our pre-clinical models to the bedside. We are optimistic that at least one clinical trial will come out of our work. Our goal is to improve and extend the lives of FLC patients. FY18 PRCRP Military Relevance Focus Area: Gaps in cancer treatment that impact mission readiness and the health and well-being of military members. FLC afflicts healthy adolescents and young adults during a period when they may be considering a career in the military. For example, one of our patients had his dream of becoming a US Navy SEAL shattered when his devastating diagnosis of FLC was made.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910544
Entities
People
- Raymond Yeung
Organizations
- United States Army
- University of Washington