The GIST Group Switzerland recently awarded its Science Prize to Dr. Anette Duensing, Assistant Professor of Pathology at the University of Pittsburgh Cancer Institute, and a member of the LRG’s Research Team.
GIST Group Switzerland, the association for the support of persons affected by GIST, has awarded the science prize for the fifth time. The 2014 GIST prize, endowed with CHF 10,000, was awarded to Dr. Duensing for the study “Unbiased Compound Screening Identifies Unexpected Drug Sensitivities and Novel Treatment Options for Gastrointestinal Stromal Tumors,” published in Cancer Research 2014; 74:1200-1213 (Boichuk et al).
The award was presented by Dr. Roger von Moos, Chief Physician of Oncology/Hematology, Kantonsspital Grisons Chur, Vice President of the Swiss Group for Clinical Cancer Research (SAKK) and Member of the GIST Group Award Committee.
The ceremony took place on November 20, 2014 during the semi-annual meeting of the Swiss Group for Clinical Cancer Research (SAKK) in St. Gallen, Switzerland.
Study to identify new GIST treatment options
In Dr. Duensing’s study, her team performed a high-throughput drug screening to identify new treatment options for GIST patients.
The panel included 89 drugs that are already approved for cancer treatment by the FDA.
The experiments successfully identified two major drug classes as being very effective in destroying GIST cells – even those that are resistant to Gleevec. This was unexpected, because most of the drugs included in the collection were “classic” chemotherapeutic agents – drugs that are traditionally known as not being effective in GIST. However, the above notion comes from studies that had been conducted before a reliable diagnosis of GIST was possible (i.e., before 1999). Hence, a number of non-GIST malignancies may have inadvertently been included. Moreover, a systematic testing of chemotherapeutic agents in GIST has not been done, in part due to the rarity of the disease.
Drugs that the study identified as being able to effectively destroy GIST cells either belonged to the group of so-called transcriptional inhibitors or to inhibitors of a DNA repair enzyme called topoisomerase II. One drug of each class was chosen for further follow-up. The transcriptional inhibitor mithramycin A blocks the first step (“gene transcription”) in a cellular process that is needed to produce proteins – such as the mutant KIT molecules that are crucial for a GIST cell to survive. The team was able to show that mithramycin A indeed kills GIST cells (at least in part) by depriving them of KIT. Inhibition of topoisomerase II by the drug mitoxantrone on the other hand leads to the introduction of DNA double-strand breaks, the most dangerous type of DNA damage for a cell. Accumulation of too many of such breaks inadvertently leads to cell death. The experiments confirmed that this is also the case in the GIST cell line models that were examined. Importantly, both drugs – mithramycin A and mitoxantrone – also showed significant anti-GIST efficacy in mouse models of GIST.
In summary, by applying the high-throughput screening study the researchers were able to successfully identify two classes of FDA-approved cancer drugs that are highly effective in GIST cell lines and GIST in vivo models. Clinical trials to test these drugs in GIST patients are currently being initiated.
This study was described at length in an article written by Dr. Duensing and Dr. Maria Debiec-Rychter of KU Leuven, Belgium, another member of the LRG Research Team in our October newsletter.
