PROJECT SUMMARY/ABSTRACT
Glioblastoma (GBM) is an aggressive and lethal form of primary brain tumor. Compared to other types
of cancers which have benefited from recent therapeutic advances, little progress has been made in GBM for
years. Therefore, novel therapeutic approaches are critically needed for GBM patients. The FDA recently
approved an oncolytic herpes simplex virus-1 (oHSV), Talimogene Laherparepvec (IMLYGIC®), for
unresectable metastatic melanoma patients. Likewise, the oHSV Delytact®, which is marketed by Daiichi
Sankyo, was recently granted conditional approval in Japan for therapeutic use against GBM. However,
despite this potent therapeutic modality, the therapeutic efficacy of oHSV is often diminished due to rapid viral
clearance, increased angiogenesis, pro-tumorigenic signaling, and immune evasion by tumor cells and cells
within the tumor microenvironment (TME), thereby becoming more resistant to therapies. Thus, it is critical to
understand the precise molecular mechanisms by which tumor cells develop resistance to oHSV-mediated
direct cell killing and evade oHSV-induced anti-tumor immunity for the development of more effective oHSV-
based therapies for GBM patients. Our preliminary unpublished data shows that oHSV therapy increases
expression and secretion of Insulin-like Growth Factor 2 (IGF2), resulting in the activation of the Insulin-like
Growth Factor-1 Receptor (IGF1R) pathway in infected tumor cells. Compromising the IGF2-IGF1R signaling
by the small molecule inhibitor for IGF1R, OSI-906, significantly increases oHSV-induced tumor cell killing in
vitro. However, combination treatment with oHSV and OSI-906 did not show efficacy for intracranial GBM-
bearing mice in vivo due to lack of brain penetration by OSI-906. Thus, we hypothesize that: (A) oHSV-
triggered activation of IGF1R signaling through IGF2 expression/secretion into the TME will critically limit the
therapeutic impact of oHSV, leading to enhanced tumor regrowth and immune suppression and (B)
compromised IGF1R signaling utilizing a decoy receptor for IGF2 will augment oHSV therapeutic efficacy. To
translate this observation into oHSV-based gene therapy, we generated a novel oHSV (oHSV-IGF2RD11Fc),
which expresses IGF2R domain 11 to function as an IGF2 decoy receptor. We will test our hypotheses with the
following aims: Aim 1) Identify the molecular mechanism behind oHSV-induced IGF2 expression and
secretion, and evaluate the consequences of IGF1R activation in the tumor and TME; Aim 2) Characterize the
mechanism of action of oHSV-IGF2RD11Fc in the tumor and TME of GBM and determine its therapeutic
efficacy in vitro and in vivo. To our knowledge, this is the first study to investigate the impact of activated IGF2-
IGF1R signaling on oHSV-treated tumor as well as the consequence of IGF1R blockade by oHSV-
IGF2RD11Fc for GBM therapy. Data obtained from the proposed study will provide a rationale for the
combination of oHSV with IGF1R blockade to accelerate the translation of oHSV therapy to an efficient and
improved treatment option for GBM patients in clinical settings.