Targeting glioblastoma stem-like cells with custom-designed viral vectors

Abstract
GlioblastomaGBMis the most lethal form of adult brain cancers with a median survival of andltmonths
despite aggressive standard chemoradiationGBM are formed by GBM stem like cellsGSCsa major
contributor to tumor recurrence and a natural focus for therapeutic developmentThere are two main reasons
responsible for treatment failurehigh intraand inter tumor cellular and molecular heterogeneity with
multiple subclones possessing distinct genetic determinantsGSCs exhibit multiple redundant signaling
pathways requiring simultaneous targeting of overlapping pathwaysWe have invented and biologically
validated a novel tandem computational platformGeneRep nSCORE that integrates large scale gene
expression profiles with genomic changes to identify common founding alterations or master regulators of
GSCs that span a large numberif not allGSC subclones within and across GBM tumorsWe discovered such
a core set of four common master regulators in GCSs that are outstanding targets for clinical developmentExpression of these four factors was sufficient to reprogram normal astrocytes to GSCswhereas their
depletion profoundly abrogated GSCsand thus tumor development in vivoin all eight lines of patient derived
GSCs of varied genetic and molecular backgrounds examined to dateThe goal of this application is to develop a customized set of Adeno associated virusAAVbased genetic
tools to target the whole spectrum of GSCsPhase Ifor the purpose of delivering targeting constructs to
deplete the four common master regulators responsible for malignant transformation and proliferation in GSCsPhase IIThe specific objectives of this proposal areiusing directed evolution and available combinatorial
AAV capsid libraryand for the first timeintroducing a dynamic mode of administration of a library reagent
over the time course of tumor progressionto greatly increase the probability of identifying novel AAV variants
specifically targeting slowand fast cycling GSCs in patient derived xenograft modelsPDXPhase IiiTo
design and validate a panel of AAV vectors that express shRNAs targeting core master regulators of GSCs to
identify leads for preclinical testingiiiTo optimize modes of viral deliverypharmacokinetics and
pharmacodynamics parametersand safety and toxicity in normal and PDX treated with lead targeting AAV
cassettesandivBased on these resultstools and basic DMPK data createdto conduct preclinical efficacy
studies in PDX treated with lead targeting AAV cassettes either alone or in combination with standard
chemoradiotherapyPhase IIto prepare for an investigative new drug application for clinical testing in patients
with GBMand for commercial development of this novel technology Narrative
GlioblastomaGBMis the most lethal form of adult human brain cancersThe goal of this proposal is to
develop a customized set of viral vectors specifically targeting GBM stem like cellsThese novel viral vectors
will express targeting constructs to deplete common master regulators responsible for malignant
transformation and proliferation of these GBM stem cells such as tumor control and survival can be improved