Welcome to study of the week, a new series from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Triptolide targets super-enhancer networks in pancreatic cancer cells and cancer-associated fibroblasts
We previously published a story about this research in a story titled “How Thunder God Vine Could Improve Pancreatic Cancer Outcomes,” which can be found here. The study was originally published in the cancer research journal Oncogenesis. You can view the full text of it here.
This study was undertaken by the research team at the Translational Genomics Research Institute (TGen).
Triptolide is a naturally occurring epoxide that naturally occurs in a plant known as the thunder god vine. Previous research has demonstrated that triptolide has the potential to be a treatment for pancreatic cancer. However, it’s physical properties and toxicity means that triptolide itself has only limited potential. In order to circumvent these disadvantages, a prodrug of triptolide, a synthetic called minnelide, is being investigated instead. A prodrug is compound that is converted into a biologically active therapy only when it has entered the body.
Aside from limited therapy options and insufficient early diagnostic methods, pancreatic cancer (more specifically pancreatic ductal adenocarcinoma, that most common form of this cancer) is difficult to treat because of properties that are unique to this tumor. The environment of this tumor includes a desmoplastic reaction, or stroma, that forms a barrier that drastically reduces the impact of conventional treatments. This stroma is hypovascularized and highly fibrotic (scar tissue). The reaction is maintained in large part due to the presence of cancer-associated fibroblasts (CAFs). Circumventing the barrier effect of the stroma is key to enhancing the impacts of treatment for pancreatic cancer. Elements of the DNA called super enhancers have been identified as maintaining gene expression networks in a given type of cell.
The scientists first mapped networks of super enhancers in CAFs and epithelial tumor cells. With these cells having distinct super enhancer profiles, the researcher then sought to investigate if minnelide could have an effect on super enhancers. The investigation revealed that the prodrug was capable of suppressing the activation marks of super enhancers and was also capable of triggering downregulation of the genes associated with them in both cells from the pancreatic cancer tumor and in CAFs. This downregulation occurred at the level of proteins. A mouse model treated with chemotherapy and minnelide showed improved antitumor activity. Overall, the scientists concluded that the triptolide-derived prodrug minnelide could significantly increase the effectiveness of pancreatic cancer treatment.
About The Thunder God Vine
The thunder god vine, also known as the thunder duke vine (Tripterygium wilfordii), is a plant known for its use in traditional Chinese medicine. It was historically used for a variety of ailments, such as fevers, joint pain, and swelling. In modern times, it has been touted as a treatment for illnesses including psoriasis and rheumatoid arthritis, as well as a form of birth control for men. While triptolide, the active substance in the vine, displays a number of medicinal effects (including against cancer), its use is not generally recommended in Western medicine due to toxicity and side effects, such as immunosuppression.
About Pancreatic Cancer
Pancreatic cancer is one of the most dangerous forms of cancer. The disease affects the pancreas, which is a glandular organ that is situated behind the stomach. Part of the reason that pancreatic cancer is so dangerous is that it rarely produces noticeable symptoms until it has reached an advanced stage and begun to spread. However, even when detected earlier, it is difficult to treat effectively. Risk factors for pancreatic cancer include being male, old age, African-American ancestry, family history, smoking, obesity, diabetes, chronic pancreatitis, and a diet heavy in red meat, processed meat, or meat cooked at very high temperatures. Symptoms include depression, upper abdominal pain, jaundice, diabetes, constipation, weight loss, and appetite loss. Treatment approaches for this cancer include surgery, chemotherapy, and radiation therapy. Even with heavy treatment, pancreatic cancer almost always returns. The five year survival rate is just five percent. To learn more about pancreatic cancer, click here.
Why Does it Matter?
Pancreatic cancer, despite its relative rarity, is the third-leading cause of death due to cancer in the US. As rates of this cancer appear to be increasing, it is expected to take the number two position in the near future. Over 47,000 people in the US die each year as a result of this disease. With five year survival rates sitting in the single digit percentages, a diagnosis is effectively a death sentence in most cases.
There is an urgent, clear need for more effective therapies for pancreatic cancer. While triptolide and its prodrug derivative minnelide are not ready to be used in the treatment of this cancer just yet, the findings from this study have revealing a potentially promising route of development that could help improve outcomes and survival rates in this disease. More research will be critical in determining the future of triptolide’s role in pancreatic cancer, but these findings are a cause for hope that some time in the future pancreatic disease can be managed much more effectively or even cured.
Check back the Monday of each week for the next installment in this series.