Jonathan Fletcher, Maria Debiec-Rychter, Anette Duesning, & Matt van de Rijn
The LRG research team met in New Jersey recently. In 2006, the Life Raft Group initiated a strategic research plan – Pathway to a Cure –that emphasized cooperation, coordination and accountability and brought together some of the finest GIST researchers in the world. Utilizing four years of garnered expertise, the Research Team morphed into Project D-Day a four-pronged approach to finding the cure involving Sequencing, Gene Knockdown, Drug Screening and Validation.
The Team meets four times a year, with at least one in-person meeting per year. This year, the team held its in-person meeting at the LRG office in New Jersey March 22-24, 2013. Attending research team members were Drs. Maria-Debiec Rychter, Anette Duensing, Jonathan Fletcher, Matt van de Rijn, Christopher Corless, Brian Rubin, and Sebastian Bauer. The LRG was represented by Norman Scherzer, Jerry Call and Roger Campbell. Objectives for the meeting were to report progress on Research Team projects as well as to discuss future directions and unmet needs. It is important to note that the two-day meeting provides a chance to share the progress of each lab in a more detailed manner than is possible any other way. There are some major differences in the way that the LRG Research Team operates compared to traditional research. First, they are not focused on 10 or 20 different cancers; the focus of each lab is on GIST. In addition, the research labs share data on an ongoing basis. This is much different than the traditional model in which researchers operate in more isolation and data is not distributed until the publication cycle is complete. This makes the data a year or more old before it is distributed.
Highlights from this year’s LRG Research meeting:
Brian Rubin, Sebastian Bauer, Jerry Call, Chris Corless, Jonathan Fletcher
Dr. Jonathan Fletcher’s lab, working with Drs. Suzanne George, George Demetri and colleagues at Dana-Farber Cancer Institute, as well as with Dr. Michael Heinrich at Oregon Health and Science University, has identified resistance mutations (secondary mutations) associated with resistance to Stivarga (regorafenib). Stivarga was approved February 25, 2013 in the United States as a third-line therapy in GIST, and is currently under review for approval in Europe and across the world (Approved in Japan). Some patients benefit from Stivarga for significant periods of time, but the typical duration of benefit (median time before progression) was about five months in the Phase III clinical trial. Guided by recent lab insights, the Boston group is studying approaches that combine Stivarga with other drugs to maximize clinical benefit. One possibility that is being intensively pursued is to sequentially administer Stivarga with a second effective drug in GIST. This plan would require a clinical trial to test the dose and schedule, and to monitor for new or unexpected toxicities that might develop from giving the two drugs together in sequence. This is an innovative way to try to improve outcomes for patients using all the tools proven effective against this disease.
Dr. Chris Corless, reporting for the Heinrich/Corless labs, reported new data about methylation status of the SDH proteins in pediatric-like GIST (SDH deficient GIST). Mutations in one of the SDH subunits (either SDHA, SDHB, SDHC or SDHD) have been reported in about half of pediatric-like GIST cases. However, all pediatric-like GIST patients seem to have a defective SDH protein. Pediatric-like GIST patients stain negative (indicating the protein is missing or defective) for the SDHB protein and all other GIST patients stain positive for this protein. A change in methylation has been suggested as a possible aberration in pediatric-like GIST by Dr. Katherine Janeway.
Methylation is an important regulator of which genes are used in a cell. Alterations in DNA methylation are common in a variety of tumors. Alterations include hypermethylation (too much) and hypomethylation (too little). One consequence of hypermethylation can include silencing of tumor suppressor genes. Several drugs are available that target hypermethylation in cancer. At this time, it is unknown if these drugs would be appropriate for SDH-deficient tumors (or a subset of them).
Dr. Corless noted a change in methylation for a small group of pediatric-like GIST. Additional research is needed on more cases. In order to do this, wildtype samples from the LRG tissue bank will be studied; but more cases are needed. Wildtype patients that are not currently participating in the tissue bank are welcome to participate in this research. See the Life Raft Group website for details about how to participate in the LRG tissue bank and LRG GIST Patient Registry.
In other SDH-related news, LRG Research Team member Dr. Brian Rubin has managed to locate a SDH deficient paraganglioma cell line. He is currently working on access to that cell line. A recent study in a yeast model of cells with SDH deficient suggested several drugs that might be effective in cells with these deficiencies. The paraganglioma cell line, if available, should allow for further drug testing in a cell line that more closely resembles the GISTs and paragangliomas that occur in patients.
As reported at the meeting, technology to detect very small bits of DNA that are circulating in plasma is getting better. In theory, this technology could be used to identify GIST patients at risk of relapse due to resistance or after surgery or adjuvant therapy from a simple blood draw. Plans were made to start looking at the logistical requirements for incorporating plasma collection into the LRG tissue bank.
In summary, LRG research team members are continuing to examine all possible avenues in their search for a cure for GIST. The research mentioned here, which represents a small part of the data reported in the meeting, directly affects particular subsets of patients with GIST, such as those who would benefit from combination therapies and those with specific mutation types. It also benefits the GIST community as a whole, however, as lessons learned may be transferrable to other subtypes, and every approach eliminated helps us narrow our focus and ultimately find the correct one.