Genetically-Engineered Mouse Models of Cancer

A critical first step towards identifying new treatments for people affected with brain tumors, nerve sheath tumors (neurofibromas and sarcomas) or cognitive delays is the development of robust informative preclinical mouse models of human disease.

Over the past 20 years, our laboratory has generated numerous genetically-engineered mouse models of NF1-associated brain tumors, NF1-associated attention and learning deficits and sporadic pediatric low-grade brain tumors. We have extensively credentialed these models with respect to their ability to accurately represent the human counterparts, and employed them to discover and validate new promising treatments for NF1-associated learning deficits and optic glioma. Several of these drugs are now in clinical trials for children with NF1. In addition, these models provide highly instructive platforms to critically dissect the pathogenesis of human disease.

Current projects in the Gutmann research laboratory are focused on developing additional mouse models of Nf1 optic gliomas, brainstem gliomas and neurofibromas, as well as sporadic non-NF1-associated low-grade pediatric brain tumors.

GEMMs

GEMMs2

We have developed several genetically-engineered mouse models of brain tumors, including four models of neurofibromatosis-1 (NF1)-associated optic glioma. These mice develop glial cell tumors (gliomas) with nuclear atypia and clusters of abnormal cells (MIDDLE PANEL, left; arrows). These gliomas form along the prechiasmatic optic nerve and chiasm, which can be visualized by small-animal magnetic resonance imaging (MRI; RIGHT PANEL, arrow), similar to patients with NF1. The corresponding optic nerves and chiasm are shown below the magnetic resonance images (LEFT PANEL; bottom). The first set of images are from a normal mouse while the second set are from a mouse with an optic glioma. Examination of the tumors in these mice demonstrates GFAP+ glioma cells (MIDDLE PANEL, right) and neovascularization (BOTTOM PANEL; left). Nf1 optic glioma mice have been used for preclinical drug studies. Following treatment with rapamycin to inhibit mTOR signaling, the number of proliferating (Ki67+) tumor cells is reduced compared to vehicle-treated mice in vivo (BOTTOM PANEL; right).

We have developed several genetically-engineered mouse models of brain tumors, including four models of neurofibromatosis-1 (NF1)-associated optic glioma. These mice develop glial cell tumors (gliomas) with nuclear atypia and clusters of abnormal cells (MIDDLE PANEL, left; arrows). These gliomas form along the prechiasmatic optic nerve and chiasm, which can be visualized by small-animal magnetic resonance imaging (MRI; RIGHT PANEL, arrow), similar to patients with NF1. The corresponding optic nerves and chiasm are shown below the magnetic resonance images (LEFT PANEL; bottom). The first set of images are from a normal mouse while the second set are from a mouse with an optic glioma. Examination of the tumors in these mice demonstrates GFAP+ glioma cells (MIDDLE PANEL, right) and neovascularization (BOTTOM PANEL; left). Nf1 optic glioma mice have been used for preclinical drug studies. Following treatment with rapamycin to inhibit mTOR signaling, the number of proliferating (Ki67+) tumor cells is reduced compared to vehicle-treated mice in vivo (BOTTOM PANEL; right).