Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma

We respond here to a Funding Opportunity Announcement (FOA) for multi-institutional teams to form a
Glioblastoma Therapeutics Network (GTN). Basic scientists and clinical/translational investigators from three
institutions in the Dana-Farber/Harvard Cancer Center (DF/HCC) have joined forces with their counterparts in
the Stanford Cancer Center (SCC) to create the “Harvard/Stanford GTN”. UT Southwestern is also
represented in one key collaboration. Distinctive features of this bi-coastal GTN include (i) broad and deep
expertise in brain-penetrant, small molecule therapeutics and (ii) a strong presence in the emerging field of
Cancer Neuroscience – a field that addresses the central role of the nervous system in glioblastoma
pathogenesis. Our objective is to improve the treatment of adult glioblastomas (GBMs) and Astrocytoma, IDH-
mutant, grade 4 by taking novel, effective, brain-penetrant small molecule drugs through lead optimization, to
preclinical development and into early phase clinical trials. Our study plan features three projects:
Project 1 targets metabolic reprogramming in Astrocytoma, IDH mutant, grade 4. Project 2 targets the
constitutive, ligand-independent EGFR signaling observed in more than 50% of adult IDH wild-type GBM.
Project 3 targets a recently appreciated forward-feeding gliomagenic loop between tumor cells and electrically
active neurons in IDH wild-type adult glioblastomas. All three projects feature surgical window clinical trials of
brain-penetrant drugs that are hitherto untested in GBM. In addition, Project 2 will develop novel allosteric
inhibitors that promise to address a shortcoming of all current EGFR antagonists as GBM therapeutics – to wit,
lack of a therapeutic window. Insights from clinical trials will be enhanced by a Pharmacological and
Genomic Imaging Core (PGIC). This core will allow our trialists to monitor drug impact on glioblastoma cell
populations using specialized single cell RNAseq protocols. Drug penetrance within tumors and drug-induced
changes in key metabolites will be visualized using matrix assisted laser desorption ionization mass
spectrometry imaging and non-invasive magnetic resonance spectroscopy methodologies.
In addition to these clinical/translational research projects and the PGIC, the Harvard/Stanford GTN
offers to host a Network Coordinating Center (NCC) for the broader GTN initiative (as described and
specified by the FOA). Our proposed NCC offers essential skill sets in neuropathology, cancer genetics,
clinical trials, biostatistics, and clinical trial design that will enable multiple GTN centers to work together in
ways that exceed the sum of their component parts. An Administrative Core will serve as the primary contact
and communication resource for the Projects, the PGIC, an Internal Advisory Board, the NCC, the GTN
Steering Committee, and NCI program officials. The Harvard/Stanford GTN Principal Investigator is Tracy
Batchelor, M.D. an experienced clinical trialist with much practical experience in leading large, multi-
investigator/multi-institutional initiatives.

Grant Number: 5U19CA264504-05
NIH Institute/Center: NIH
Principal Investigator: Tracy Batchelor