Investigating CD97 blockade as a therapeutic strategy in glioblastoma

University Of California, San Francisco, San Francisco CA

Investigators

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Abstract

PROJECT SUMMARY Glioblastoma (GBM) is the most lethal primary brain tumor with a median survival of less than 2 years. The standard of care remains unchanged for the past decade ? maximal safe resection followed by adjuvant chemotherapy and radiation. The poor prognosis is driven by tumor invasion, which limits the surgical resection of microscopic disease and makes tumor recurrence inevitable. Targeting tumor invasion has long been proposed as a strategy for treating GBM, but effective targets are lacking, stressing the need to identify novel mediators of GBM invasion. CD97 is a leukocyte adhesion marker with roles in cell adhesion and migration. My previous work identified CD97 expression in GBM cell lines, primary GBM cultures, and brain tumor initiating cells. Using data from The Cancer Genome Atlas, I showed that upregulation of CD97 was associated with worse survival and more commonly occurred among the classical and mesenchymal subtypes, consistent with their worse prognosis. Subsequent experiments showed that knockdown of CD97 resulted in decreased tumor cell migration and invasion. This proposal builds upon my previous work and will investigate CD97 blockade as a therapeutic strategy in GBM. Decay accelerating factor (DAF) is one of three CD97 ligands. We have collaborated with an industry partner to explore the use of DAF-Fc, a fusion protein that combines DAF with the human IgG1 Fc region. This compound has the potential to induce anti-tumor effects through inhibition of invasion via CD97 blockade and antibody-dependent cellular toxicity via Fc promotion of NK cell activation. We present pilot data showing that DAF-Fc binds CD97 with a high affinity and is capable of reducing tumor cell migration and invasion in vitro. Here we propose to investigate the central hypothesis that DAF-Fc will inhibit GBM cell migration in cultured primary GBM cells and in preclinical GBM models in vivo. This hypothesis will be investigated through three specific aims: Aim 1 - Confirm the effects of CD97 blockade in cultured primary GBM cells; Aim 2- Characterize the spatial expression of CD97 and its ligands in patient GBM samples; and Aim 3 - Determine the effect of CD97/CD55 blockade in patient-derived xenograft models of GBM in mice. Importantly, besides preclinically verifying the efficacy of DAF-Fc, these experiments will also identify the drug's therapeutic window. To characterize the regional expression of CD97 and its ligands in GBM, we will use intraoperatively acquired site- directed biopsies from GBM patients for which we have correlative MRI scans. Banked cells from these patients will be treated with DAF-Fc to assess for changes in cell morphology and invadopodia formation. Lastly, intracranial patient-derived xenografts will be treated with DAF-Fc administered intracranially via osmotic pumps. Besides our industry collaborator, we are also collaborating with a neuropathologist to assess for changes in tumor cell invasion and morphology after treatment. If successful, this project has the potential to translate into a human clinical trial of CD97 blockade as a therapeutic strategy in GBM.