In early May, the LRG Research Team held a two-day in-person meeting in Cleveland, Ohio, at the Cleveland Clinic, where I conduct my research.
Two primary aims of the meeting were to work on a manuscript describing the genetic landscape of GIST and to plan a large-scale experiment aimed at understanding and targeting quiescence therapeutically.
The manuscript on the genetic landscape of GIST has been led by Dr. Sebastian Bauer but involves virtually every member of the LRG Research Team. It is a massive undertaking, which describes the genetic makeup of Gleevec-sensitive, and Gleevec- resistant GIST in more detail than has ever been described previously. Importantly, this analysis provides a thorough understanding of how genes known as tumor suppressors, which normally act as “brakes” on cancer, are lost as GISTs become more aggressive. Surprisingly, any of three major tumor suppressors, TP53, CDKN2A, or RB1, could be lost to cause tumor progression. This paper is being resubmitted for publication at the end of May after receiving favorable reviews from the primary submission. However, it is a large and complex paper, which requires considerable effort to revise for resubmission. Hopefully we will see it in print soon.
There was also a lengthy work session on the team’s funded joint research program, which aims to lengthen the duration of therapeutic response to Gleevec in GIST patients. There are two goals of this program, which seeks effective drugs that can be combined safely with Gleevec. The first goal is to target GIST cell quiescence, the process by which some GIST cells survive Gleevec therapy. We hope these strategies can lead to a higher cure rate for GIST. The second goal is to target Gleevec-resistant GIST cells, which cause clinical progression during Gleevec therapy. The group research in the first year of the program has already identified promising approaches that will be studied in detail in the next year. We hope to expand the funding for these urgent studies.
Highlights of Ongoing Research
Finally, members of the LRG Research Team highlighted ongoing work in their individual laboratories. Several laboratories described novel mechanisms of Gleevec resistance, noting that treatment is primarily still focused on targeting KIT. New GIST models were described that will be useful in screening for new drugs against GIST. Drs. Corless and Heinrich highlighted their work in SDH-deficient GIST which is focused on genotyping these lesions and developing models for testing novel therapies. Finally, several research team members presented ideas about how to use new technologies to study GIST. Others discussed projects aimed at examining the peripheral blood (so-called “liquid” biopsies) of GIST patients to find tumor DNA in those fluids. This technology has the potential to diagnose GIST, monitor therapy, identify when patients progress, and even detect Gleevec-resistant GIST mutations before they are clinically obvious. These findings could result in less radiological studies which would be a very desirable outcome.
We would like to thank our sponsor Sanofi for supporting this meeting for researchers to come together and provide valuable updates on GIST research.