# Small molecule inhibitors of Slit2/Robo signaling as novel therapeutics for glioblastoma

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $547,687

## Abstract

PROJECT SUMMARY/ABSTRACT:
 Glioblastoma (GBM), the most prevalent malignant primary brain tumor, is an extremely aggressive form of
diffuse glioma originating from astrocytic lineage. Despite recent advancements in multimodal GBM therapy,
which incorporates surgery, radiotherapy, chemotherapy, and supportive care, the overall prognosis remains
dismal, and long-term survival is rare. Immunotherapy holds promise in leveraging the immune system to
target and eliminate brain tumor cells. However, the highly immunosuppressive environment within GBM
represents a critical impediment to successful immunotherapy. SLIT2/ROBO signaling is a novel immune
evasion mechanism in the tumor microenvironment of GBM. High SLIT2 expression in GBM patients results in
the accumulation of immunosuppressive tumor-associated macrophages (TAMs) as well as vascular
dysmorphia. This is further supported by the prevention of TAM tumor-supportive polarization and angiogenic
gene expression upon systemic SLIT2 inhibition, resulting in improved tumor vessel function and enhanced
efficacy of chemotherapy and immunotherapy in GBM mouse models. Therapeutic targeting of SLIT2/ROBO
interaction is currently restricted to biologics, and there are no active clinical trials for GBM evaluating
SLIT2/ROBO inhibition as a therapeutic strategy. In comparison to biologics, small molecules will minimize the
immunogenicity risk, enable better management of adverse events (AEs) based on their amenability for
pharmacokinetic optimization, and hold promise for central nervous system (CNS) penetration. In response to
PAR-23-264, our three-year proposal aims to establish a novel macrophage-based immunotherapy approach
for GBM based on targeting SLIT2/ROBO interaction with small molecules, which may synergize with current
FDA-approved therapies for GBM. Our expertise in assay development, high-throughput screening (HTS),
discovery of small molecule immunomodulators, hit-to-lead optimization, and immunopharmacology uniquely
positions us to achieve this goal. Aim 1 will complete the screening of a CNS-focused chemical library of small
molecules for SLIT2 binding, followed by an evaluation of the ability of the hits to inhibit SLIT2/ROBO
interaction using fluorescence-based assays. Aim 2A will validate the top hit compounds as SLIT2/ROBO
inhibitors using a panel of cell-free and cell-based assays, including an in vitro spheroid invasion assay using
patient-derived cells from GBM tissue. Aim 2B will perform exploratory medicinal chemistry and preliminary
structural optimization of the top validated hits in order to guide future extensive optimization. The proximal
expected outcome of this work is introducing first-in-class small molecule SLIT2/ROBO inhibitors as candidates
for preclinical evaluation, particularly within innovative combination therapies for GBM.

## Key facts

- **NIH application ID:** 10942698
- **Project number:** 1R01CA293456-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Moustafa Gabr
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $547,687
- **Award type:** 1
- **Project period:** 2024-07-08 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10942698

## Citation

> US National Institutes of Health, RePORTER application 10942698, Small molecule inhibitors of Slit2/Robo signaling as novel therapeutics for glioblastoma (1R01CA293456-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10942698. Licensed CC0.

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