DLK1 Promotes Tumorigenesis and is a Biomarker for MPNST

About This Grant

PROJECT SUMMARY / ABSTRACT Neurofibromatosis type 1 (NF1) is one of the most common cancer predisposition syndromes, affecting approximately 1 in 2500 individuals worldwide. It is caused by pathogenic variants or deletions of the NF1 tumor suppressor gene resulting in Ras pathway hyperactivation. A hallmark feature of NF1 is the development of histologically benign peripheral nerve sheath tumors (PNST) called plexiform neurofibromas (PNF). While benign, the lifetime risk of these pre-existing neurofibroma undergoing malignant transformation to a highly aggressive sarcoma called a malignant peripheral nerve sheath tumor (MPNST) is 8-16%. The progression of PNF to MPNST typically occurs with little to no warning and clinical features concerning for malignancy often manifest after transformation has already occurred. The development of MPNST from pre-existing neurofibroma often proceeds through intermediate lesions known as atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP). However, not all neurofibroma will progress to MPNST and there are currently no clinically validated biomarkers capable of accurately identifying lesions at a high risk of undergoing malignant transformation. Risk assessment and therapeutic stratification of NF1-PNST is associated with several challenges as these tumors can exhibit significant intratumoral heterogeneity and diverse trajectories. During biopsy, sampling bias and the location of tumors in anatomically complex regions can hinder capture of the full spectrum of histopathological features. Current imaging methodologies also have limitations. On both MRI and FDG-PET scan, it challenging to definitively distinguish between benign and malignant tumors, particularly in cases of intermediary lesions or those actively transforming. These challenges underscore the need for diagnostic tools. We have identified DLK1 as a biomarker that holds potential promise in the setting of NF1-PNST. In collaboration with the Indiana Biosciences Research Institute (IBRI) and the Indiana Institute for Biomedical Imaging Sciences (IIBIS), we propose to build upon this work by undertaking a series of experiments to comprehensively elucidate the role of DLK1 in MPNST tumorigenesis and therapeutic sensitivity. We will extend these studies by developing and validating a novel DLK1-targeted diagnostic tools comprised of tissue- and molecular imaging-based approaches. Our overarching goal for the studies proposed in this application is to increase mechanistic DLK1 facilitated tumor progression and the development of clinical-grade DLK1- targeted diagnostic tools that can proceed immediately to clinical trial for further evaluation.