Pancreatic cancer is one of the most aggressive forms of cancer and one of the most difficult to treat. Its high resistance to treatment is a major problem, particularly in the advanced stages. Researchers at Klinikum rechts der Isar University Hospital of the Technical University of Munich (TUM) have joined forces with a team from Stanford University to investigate a conceptually new approach to therapy which primarily takes epigenetic mechanisms into consideration. The impact of this approach in both pancreatic and lung cancer was demonstrated in animal experiments. The results have now been published .
Pancreatic cancer is a highly aggressive tumor for which there have been few successful therapy approaches until now. One of the reasons for this is its extremely high resistance to chemotherapy or radiation therapy of any kind. Recent studies on genetic changes in the tumor cells indicate that it is not just a question of mutations in known cancer genes such as RAS und MYC; epigenetic factors that modify chromosomes and DNA and, as a result, affect the activity of genes without changing the DNA sequence are also increasingly being identified as key hubs for a number of tumor properties also in pancreatic cancer.
Important role of epigenetic mechanisms
In the study just published, a team of scientists from several clinics and institutes from Klinikum rechts der Isar University Hospital and Stanford University headed by Jens Siveke from Medical Clinic II and Pawel Mazur and Julien Sage from Stanford University conducted research on a particular protein by the name of BRD4 in relation to pancreatic cancer. This protein regulates the so-called histone code of cells which determines which areas of the DNA are read. The scientists were keen to find out whether BRD4 is a target structure for therapies in pancreatic cancer.
As a first step, the researchers were able to show that BRD4 is upregulated in pancreatic cancer, before going on to test whether a therapy aimed at combating BRD4 with the API JQ1 can have a therapeutic effect. The scientists used both cell culture studies and various animal experiment model systems to do this, examining tumors using non-invasive methods including imaging systems that they had developed jointly in the "Collaborative Research Center 824". Although JQ1 therapy demonstrated an effect on the growth in size of the tumors, there was no clear indication of any survival effect as a result of it.
Combined therapy produces results
In a second step, the scientists examined whether the therapy aimed at combating BRD4 can potentially be more effectively combined with chemotherapy or other targeted therapies using drug screens. Surprisingly, it was found that a combination of JQ1 and another epigenetic therapy principle - preventing histone deacetylation using so-called HDAC inhibitors - produced an increase in the programmed cell death of cancer cells. Combining the two created improved effectiveness and a clear survival advantage.
Since pancreatic cancer is almost always caused by a mutation in the RAS gene for which there is currently no specific treatment, the team asked themselves the question of whether this combined therapy could also be effective with other types of cancer driven by the RAS gene. It also showed activity against lung cancer caused by RAS.
The next goals - higher accuracy and fewer side-effects
"The hope is that these results will help to further evaluate this therapy principle as quickly as possible in clinical studies," explains Jens Siveke, who tends to large numbers of patients in oncological studies. "Unfortunately, until now we have had little in the way of effective means of treating advanced stages of the disease. So for our patients, a rapid translation to clinical studies and a better understanding of the action mechanisms for even more carefully-targeted therapies are our main concern."
With this in mind, the scientists are keen to among other things make further improvements in the substances for greater accuracy in inhibiting proteins and reducing side-effects. The research team is also planning to use so-called biomarkers to better identify patients who will benefit from this type of therapy. In their work, the authors were able to identify the first candidates, such as the apoptosis gene p57, using a new method based on so-called CRISPR technology.
Mazur PK*, Herner A*, Mello SS, Wirth M, Hausmann S, Sanchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noel PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Hessmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT, Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma , Nature Medicine, 2015.