Lentiviral-Induced Swine Model of Spinal Cord Glioma

PROJECT SUMMARY
High-grade Spinal Cord Glioma (SCG) is an orphan disease that results in significant
morbidity and mortality, with no effective treatment options available. Despite significant advances
in our knowledge of the disease process, there have unfortunately been limited changes to the
clinical outcomes. In part, this represents the malignant nature of a disease that is refractory to
the standard of care. On the other hand, this raises the question of the translational value of
existing preclinical animal models, especially from a surgical standpoint – where widely scalable
large animal models of SCG were previously unavailable. To this end, the Boulis and Canoll
laboratories partnered to begin addressing this gap in the field by developing a minipig SCG
model. Through lentiviral targeting of the well implicated RTK/RAS/PI3K and p53 pathways, our
preliminary data demonstrates the induction of high-grade astrocytoma with histopathologic,
radiologic, and transcriptomic characterization in 100% of minipigs. Consequently, we posit that
the next steps to advancement of this model system are to modulate tumor phenotype and to
demonstrate its utility in a directly translatable surgical application. In the enclosed proposal, we
will begin by evaluating the induction of SCG by targeting common genetic lesions implicated in
the human disease including PDGFB, P53, CDKN2A, EGFR, and PTEN (AIM 1). This represents
the opportunity to produce highly characterized SCG lesions for therapeutic testing in an
immunocompetent, more anatomically relevant, large animal model. In parallel, we will apply our
existing minipig SCG model (AIM 2) to perform the first intra-tumoral convection enhanced
delivery (CED) study for SCG in a large animal. Rodent studies of chemotherapeutic CED for
SCG have reported suppression of tumor growth and amelioration of neurologic deficits. However,
these data cannot be readily scaled for translation due to anatomic limitations of rodent systems.
Despite an ongoing Phase I human trial for CED in SCG, drug distribution and CED parameters
are poorly understood. Indeed, failures of CED in human trials for intracranial glioma can be
attributed to both ineffective drug distribution and single treatments. As such, our study will employ
implanted pumps for prolonged intratumoral CED. We will investigate parameters (flow rate,
volume of infusion) to evaluate optimal readouts (volume of distribution, reflux, safety, radiologic
vs chemotherapeutic distribution). These data will have immediate translational impact on present
and future trials.

Grant Number: 5R01CA251393-05
NIH Institute/Center: NIH
Principal Investigator: NICHOLAS BOULIS