Developmental Research Program Abstracts
The Developmental Research Program supports several ongoing research projects. These projects currently include:
- Targeting the Cholangiocarcinoma Epigenome
- PSMA in Hepatocellular Carcinoma
- Innovative Strategy of Targeting COX-2 and D5D To Improve Hepatocellular Carcinoma Therapy
- Rational Identification of Anti-PD Combined Therapies for Liver Cancer
Targeting the Cholangiocarcinoma Epigenome
The principal investigators of this project are Michael T. Barrett, Ph.D., a hematology-oncology researcher at Mayo Clinic's campus in Arizona, and Martin E. Fernandez-Zapico, M.D., a professor of medicine and of pharmacology at Mayo Clinic College of Medicine and Science in Rochester, Minnesota.
Cholangiocarcinoma is a lethal disease. The gene mutations in cholangiocarcinoma are now well known. These include key mutations that can be treated with specific drugs. However, treatments targeting these genetic defects have had limited success.
The sequence of DNA in each cell is the primary code that is used to make proteins. In normal cells, access to the DNA code is carefully controlled by the folding and shape of the DNA. DNA can be open to allow access of proteins that turn on genes in a cell, or it can be closed to turn off genes. This epigenome pattern of open and closed DNA is carefully controlled in normal cells and involves master protein switches that set the patterns of open and closed DNA.
It's now very clear that cancer cells reset these switches in their favor. This has prompted the search for drugs that target the epigenome switches of a cancer cell and reset them to normal. The theory is that many important cancer genes will be affected at once. Studies suggest that a cancer-promoting epigenome is a key feature of cholangiocarcinoma.
In this study, rather than focus on mutations, we focus on the epigenome of cholangiocarcinoma. The goal of our study is to describe the epigenome and its switches in this cancer and test if they can be reset to normal.
For this study, we're using a set of patient-derived models known as organoids, which are tumors grown in special tissue culture conditions. These conditions maintain the structure of the tumor tissue and allow efficient testing of drugs. Dr. Fernandez-Zapico, a co-principal investigator of this study, has developed organoids from cholangiocarcinomas.
This research project offers a unique opportunity to test whether the epigenome can be targeted to improve responses in cholangiocarcinoma.
Our first goal is to catalog the epigenome in 20 of these models. We're using a combination of DNA, RNA and protein analyses to create profiles of each tumor. This method provides a unique map of the regions of open and closed DNA in cholangiocarcinoma. We then test the effects of drugs that disrupt the epigenome in these models. The completion of this study will confirm if the epigenome is an important target for therapy in cholangiocarcinoma and help guide the design of new trials to improve patient outcomes.
PSMA in Hepatocellular Carcinoma
The principal investigators of this project are David A. Woodrum, M.D., Ph.D., and Scott M. Thompson, M.D., Ph.D., both in the Department of Radiology at Mayo Clinic in Rochester, Minnesota.
Current molecular imaging strategies to diagnose and monitor liver cancer are not very effective. There's a vital need to identify new molecular targets to more effectively diagnose and treat liver cancer. This research project should provide important information that can be used to translate new liver cancer imaging and therapies to patients.
Innovative Strategy of Targeting COX-2 and D5D To Improve Hepatocellular Carcinoma Therapy
The principal investigator of this project is Liu Yang, M.B.B.S., a gastroenterologist and transplant hepatologist at Mayo Clinic in Jacksonville, Florida.
There's an urgent need to develop novel treatment strategies for advanced and metastatic hepatocellular carcinoma. Despite improvements in treatment modalities, the prognosis for hepatocellular carcinoma is poor. Sorafenib was the first systemic therapeutic agent approved for treating patients with advanced-stage hepatocellular carcinoma, with an increased overall survival of two to three months. And even though multiple new medications, including regorafenib, lenvatinib and nivolumab, have been approved by the U.S. Food and Drug Administration (FDA), the prognosis for advanced cases remains poor.
We know that the COX enzyme, typically as its inducible isoenzyme COX-2, is overexpressed in hepatocellular carcinoma and plays an important role in cancer growth and metastasis. Although the classic research focus has been on inhibiting COX-2 and thus suppressing the formation of deleterious metabolites (prostaglandin-2, for example) from COX-2-catalyzed peroxidation of arachidonic acid (a downstream omega-6 fatty acid), many COX-2 inhibitors have critical patient safety issues.
However, our recent study showed that COX-2 can also catalyze peroxidation of dihomo-gamma-linolenic acid (DGLA) to produce a distinct free radical byproduct, 8-hydroxyoctanoic acid (8-HOA), which can inhibit the growth, migration and invasion of many types of cancer cells. This beneficial pathway is hampered by the enzyme delta 5-desaturase (D5D), which converts DGLA to arachidonic acid and subsequently leads to formation of more deleterious metabolites.
In this study, we hypothesize that knocking down D5D gene expression and taking advantage of the commonly overexpressed COX-2 in cancer (a novel COX-2 cancer treatment concept) will result in dual inhibitory effects on hepatocellular carcinoma (HCC) development, both promoting the formation of the anti-cancer metabolite 8-HOA and suppressing deleterious metabolites by inhibiting the conversion of DGLA to arachidonic acid.
Our near-term objective is to assess whether knockdown of D5D gene expression combined with DGLA-supplementation can improve the efficacy of sorafenib in both in vitro and in vivo studies. The long-term objective is to combine our new COX-2 cancer concept and the related treatment strategy with practical approaches to downregulating D5D:
- Screening or designing selective D5D inhibitors
- Delivering therapeutic gene suppression of D5D using nanoparticles (RNA nanobiotechnology and nanomedicine) that can specifically target HCC
Rational Identification of Anti-PD Combined Therapies for Liver Cancer
The principal investigator of this project is Jie Sun, Ph.D., an associate professor of immunology and medicine at Mayo Clinic College of Medicine and Science in Rochester.
Cancer immunotherapy has revolutionized the approach to anti-cancer treatment, and anti-PD therapies have shown remarkable success in the clinic. However, the durable response of current anti-PD therapies is limited to a small fraction of patients. It's hoped that combining anti-PD therapies with traditional anti-cancer methods or novel immunomodulatory strategies may be the path to achieve superior cancer control.
The current options for anti-PD combination therapies are still limited, and most of these current combination strategies lack a solid scientific rationale. It's questionable whether these strategies will truly work better than the single anti-PD therapy.
In this research project, our strategy is to rationally identify FDA-approved compounds that can potentially synergize with anti-PD therapies to boost the immune system in cancer treatment. The successful completion of this study will help develop novel promising immunotherapy modalities combined with anti-PD checkpoint therapies for patients with liver cancer.