Insulin-like Growth Factor Receptor 1 in GIST
GIST Support International contacted Andrew Godwin, PhD about his lab's recent research into insulin-related growth factor family signals in GIST. At the time of this writing, Dr. Godwin was director of the Clinical Molecular Genetics Laboratory at the Fox Chase Cancer Center (FCCC) in Philadelphia, PA. As of fall 2010 Dr. Godwin joined the University of Kansas Cancer Center where he will serve as associate director of translational research. These new studies are on the cutting edge regarding treatment of GIST patients.
The studies in the Godwin laboratory are directed at improving the understanding of the etiology of several types of cancer (primarily gastrointestinal stromal tumors (GIST), ovarian, and breast cancers) and assessing molecular-targeted therapies for the treatment of these diseases. Dr. Godwin became interested in GIST in the early 2000’s when he began collaborating with Burton Eisenberg, MD (then Chief of Surgery at FCCC, now Deputy Director, Norris Cotton Cancer Center at Dartmouth) and Margaret von Mehren, MD (Medical Oncologist and Director of the Sarcoma Program at FCCC). Godwin’s first studies identified genetic markers that could predict the response of patients with metastatic/recurrent GIST to imatinib treatment. His current studies focus on genomic and proteomic changes associated with the development of GISTs and their response to molecular targeted therapies. More recently, Dr. Godwin and colleagues have identified an important gene expression signature that appears to predict likely tumor shrinkage while on imatinib (Rink et al., submitted, 2008; and Belinsky, et al., submitted, 2008). The current excitement surrounding their studies emanates from a discovery that the insulin-like growth factor receptor-1 (IGF1R) may be an interesting therapeutic target to consider in GIST patients, especially in tumors that lack mutations in c-KIT or PDGFRA, as well as in pediatric cases in which treatment options are extremely limited. These so called “wild-type” tumors are clinically more resistant to imatinib-based therapies. Their studies have been supported by Tania Stutman and the GIST Cancer Research Fund and grants from the NIH (CA106588, P30 CA006927, CA009035, and U10 CA21661).
In this Q&A piece, Dr. Godwin responds to questions about his group's investigation of insulin-related growth factor family signals in GIST. They have reported that wild-type GISTs greatly overexpress IGF1R and drugs that target IGF1R can inhibit the ability of GIST cells to grow (Tarn et al., Proc. Nat. Acad. Science, 2008 and ASCO, 2008 abstract 10507). For abstracts of Dr. Godwin's other papers on GIST and free access to three papers, see this PubMed link.
1. What have you found about the strength of expression of insulin-like growth factor receptor 1 (IGF1R) in wild-type versus KIT- mutant gastrointestinal stromal tumors?
We recently reported at the American Society of Clinical Oncology (ASCO) meeting and in a manuscript (Tarn et al., PNAS, 2008) that the insulin-like growth factor receptor (IGF1R), although expressed in most GISTs is highly expressed in many wild-type GISTs, i.e., those that lack mutations in the c-KIT and PDGFR alpha (PDFGRA) genes, as compared to their mutant counterparts. IGF1R also appears to be highly expressed in pediatric GISTs. Since the majority of pediatric GISTs arise in females and lack mutations in c-KIT and PDGFRA, it is not surprising that they may have some of the defects found in adult wild-type GISTs.
2. Did you find gene amplification of IGF1R?
We did find amplification of IGF1R in GISTs, which had not been reported before. In normal cells there are two copies of each gene. When a gene is amplified this means that the number of copies of a given gene is more than 2. The number of copies of genes, such as c-MYC and EGFR can range from a few extra copies to hundreds in certain types of cancers and can lead to abnormal expression of these genes. Importantly, we found a higher frequency of gene copy changes in wild-type GISTs as compared to mutant GISTs. While we observed low-level amplification (3 to 8 copies) of IGF1R in GISTs, we believe that these changes in copy number are not the entire reason for why IGFR1R is overexpressed in GISTs.
3. What are your findings regarding the expression of the growth factors IGF-1 and IGF-2 in wild-type versus mutant GIST?
These studies are still under development and we hope to complete our final analyses soon. The insulin-like growth factors (referred to as IGFs) are small proteins that are closely related to insulin. IGFs are part of a complex system that cells use to communicate with their physiologic environment. This complex system (often referred to as the IGF "axis") consists of two cellsurface receptors (IGF1R and IGF2R), two ligands (IGF-1 and IGF-2), and a family of six IGF binding proteins (IGFBP 1-6). So IGF signaling is very complex, but extremely important in normal physiology. IGF-1 is mainly secreted by the liver as a result of stimulation by another small protein referred to as growth hormone. Levels of circulating IGFs can be influenced by many factors including an individuals genetic make-up, their age, sex, race, stress levels, nutrition level and body mass index, estrogen status, etc. IGF-1 is required for achieving maximal growth, while IGF-2 is important for the development and function of organs such as the brain, kidney and liver. How these proteins and the pathway as a whole are altered in cancer, not only GISTs, is an area of active study.
4. You tested the drug NVP-AEW541 on two KIT-mutant GIST cell lines. What type of inhibitor is this, and what did you learn about its effectiveness?
NVP-AEW541 is a small molecule kinase inhibitor of IGF1R. It was developed by Novartis, Inc. but has not been tested in human clinical trials. Many drugs that appear promising from their development to preclinical studies do not make it into patients. However, they still serve as valuable tools to help unravel signaling pathways that have gone awry. We demonstrated that this compound could inhibit cell signaling and growth in the GIST cell lines, independent of altering KIT signaling, suggesting that this pathway could be an important therapeutic target for GIST.
5. In your ASCO presentation you mentioned some ongoing new research efforts. Please tell us a little about your wild-type cell lines and the new monoclonal antibody inhibitor you plan to test using them.
We have many studies underway and several new discoveries that have been submitted for publication. We are using state-of-the-art molecular tools to further dissect GISTs and study changes at the DNA and protein levels. We have also been working to establish model systems to mimic how GISTs behave in patients. We are collaborating with several pharmaceutical groups to explore some new anti-cancer agents, several that are in clinical trials, and are also working with our long-term collaborator, Dr. Meg von Mehren (Medical Oncologist and Director of the Sarcoma Program) to initiate new clinical trials for patients that might benefit from novel agents and new combinations of drugs.
6. How can patients assist your research by making tissue donations? What types of tissue do you need?
We very much appreciate the effort of GIST patients and family members who contact us and express interest in contributing their tissue samples to our studies. All GIST tissues are extremely important for our research to continue to identify the genomic and proteomic changes that contribute to tumor development. Our studies use fresh tissue and fresh-frozen tissues which typically come from patients undergoing surgery at our institute (Fox Chase Cancer Center), but tissue collection can be arranged with other hospitals prior to surgery. We also have been able to obtain tissue samples embedded in paraffin blocks from many outside hospitals. Patients can request (fresh and fresh-frozen) tissue to be sent to us at the time of their surgery. Any questions regarding tissue donations can be addressed to Dr. Lori Rink (Lori.Rink@fccc.edu).
7. Is your lab offering clinical testing of IGF1R yet?
Our Clinical Molecular Genetics Laboratory (CMGL) at Fox Chase is CLIA/CAP approved for many tests including mutation analysis for c-KIT and PDGFRA. Dr. Betsy Bove (Betsy.Bove@fccc.edu) is the supervisor of the laboratory and can be contacted if patients would like to submit samples for clinical testing. We are currently establishing tests for IGF1R and related members of the pathway and will update our clinical website when those tests are available.
[For a related summary on our website, link to IGF Signals in GIST.]