Identifying and characterizing actionable kinase fusions in Inflammatory Myofibroblastic Tumors

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Christine Lovly, MD, PhD,  Vanderbilt University Medical Center
Recipient of the: $50,000 Dr. Richard and Valerie Aronsohn Memorial Research Award

Inflammatory myofibroblastic tumor (IMT) is a tumor of visceral soft tissue which harbors anaplastic lymphoma kinase (ALK) gene fusions in approximately 50% of cases. ALK tyrosine kinase inhibitors (TKIs) have been validated as an effective therapy for patients with ALK positive IMT, however, the efficacy of these inhibitors is limited by the development of acquired resistance.  Furthermore, molecular targets for the ALK negative IMT cohort remain undefined.  The objectives of this proposal are to define and characterize novel therapeutic targets in ALK negative IMT and to study mechanisms of sensitivity/resistance to ALK TKIs in ALK positive IMT. In our initial studies, we used a targeted capture-based next-generation sequencing platform to evaluate 30 IMT samples. In addition to ALK fusions, we also identified several other potentially actionable kinase fusions in the ALK negative cohort, including 2 distinct ROS1 fusions (YWHAE-ROS1, TFG-ROS1) and 1 PDGFRß fusion (NAB2-PDGFRß). To extend on these preliminary data, we propose the following specific aims:  (1) Identify novel oncogenic ‘driver mutations’ in ALK negative IMT.  From our initial studies, kinases fusions were found in 6/10 ALK negative cases. We hypothesize that the additional 4 ALK negative cases also harbor kinase fusions which were not captured in this platform. We will broaden our approach by using a genomically based systematic kinase fusion screen that can detect potential fusions involving all 90 tyrosine kinases in the human genome plus AKT-1/-2/-3 and BRAF. (2)  Characterize novel ROS1 and PDGFRß kinase fusions identified in ALK negative IMT. We hypothesize that tumor harboring ROS1 and PDGFRß fusions comprise distinct molecular subsets of IMT that may be targeted therapeutically. Using a variety of molecular and biochemical techniques, we will examine the sensitivity of these fusions to existing targeted therapies and evaluate the effects of these inhibitors on downstream signaling. (3) Elucidate potential modifiers of sensitivity/resistance to ALK TKIs through deep sequencing of an ALK positive IMT sample pre- and post- neoadjuvant crizotinib. We have procured samples from a patient with ALK positive IMT who had a partial response to the ALK TKI, crizotinib, in the neoadjuvant setting prior to surgical resection of the tumor. We hypothesize that an improved understanding of the genomic landscape of the tumor before and after ALK TKI therapy will provide insights into mechanisms of sensitivity/resistance to ALK inhibition. We will perform whole genome sequencing of DNA from frozen tumor and matched normal tissue. Overall, an improved understanding of the biology of known fusions as well as discovery/characterization of novel kinase fusions will provide new therapeutic targets and innovative strategies to improve the care of patients with IMT and other kinase fusion driven malignancies.