New research bolsters highly targeted gastro-intestinal cancer treatment

Gastro-Intestinal Stroma Tumor (GIST) is a rare form of cancer of the stomach or small intestine. Up to now, only one effective treatment has existed for GIST: the use of Glivec. However, over time, this remedy becomes ineffective for a large percentage of the patients. Along with colleagues in Leuven, the research group of Peter Marynen of the Flanders Interuniversity Institute for Biotechnology (VIB), connected to the Catholic University of Leuven, has uncovered the process underlying the frequent ineffectiveness of Glivec. In addition, the researchers have shown that PKC412 – an experimental drug currently in the second phase of clinical research – can be effective in helping these patients once again. This possible alternative to Glivec, and the genetic understanding of the development of resistance to Glivec, should make it possible to prescribe a new highly targeted therapy for patients in the future.

GIST: a specific form of gastro-intestinal cancer

GIST is a rare form of gastro-intestinal cancer that strikes some 175 Belgians each year. Often, by the time it is discovered, there are already metastases in other organs, which make it impossible to remove the GIST tumors surgically. Furthermore, the other traditional cancer treatments – chemotherapy and radiation treatment – produce little result. Since 2002, there has been an effective treatment for GIST: Glivec. And up to now, this has been the only remedy for treating GIST effectively.

Why look for an alternative for Glivec?

To arrive at a definite diagnosis for GIST, a biopsy is needed to verify the presence of specific receptor proteins on the GIST cells. Cells contain certain receptors to which growth factors can bind, but GIST cells contain a defect in one of these receptors, the KIT receptor. The defective KIT receptor gives a continuous signal to the cancer cells to multiply, enabling the cancer cells to grow irrespective of the presence of the growth factors. However, the drug Glivec works by also binding to this KIT receptor and thus disabling its activity. As a consequence, the GIST cells stop growing and even die off. In contrast to chemotherapy or radiation treatment, Glivec is a highly targeted drug without many side effects. The problem is that often the tumor cells adapt themselves so that Glivec no longer has an effect on them. To find a solution for this problem is a great challenge in the treatment of GIST.

KIT adapts and resists

Peter Marynen, in collaboration with other Leuven researchers, set out to discover the mechanisms behind the origin of this tumor cell resistance to Glivec. By investigating tumor tissue from 26 GIST patients, their research revealed that, in most cases, KIT’s reactivation was a crucial factor in this process. Usually, the reactivation was the consequence of an additional alteration in KIT itself, but sometimes it was brought about by a change in another protein. This last finding is a new piece of information in cancer research.

PKC412: a new solution appears

The researchers in Leuven investigated whether an experimental drug, PKC412, could counteract the reactivation of KIT. They have demonstrated that PKC412 is indeed able to combat resistant tumors. So, once it’s on the market, this new medicine can be a good alternative for Glivec, or it can be used in combination with Glivec. At the moment, PKC412 is in Phase II clinical research on leukemia and other cancer patients. If all goes well, it is expected to come onto the market within a few years.

Research funding

This research was made possible through funding from VIB, the Catholic University of Leuven, the Belgian Federation Against Cancer, and the Flanders Research Fund for Scientific Research.