Project: Musashi1 is a novel target in medulloblastoma.


Medulloblastoma is the commonest malignant brain tumor in children. Treatment with surgery, irradiation, and chemotherapy has improved survival in recent years, but patients are frequently left with devastating neurocognitive and other sequelae. Therefore, there is a dire need for less aggressive treatments with minimum or no side effects.

There is substantial evidence that tumors contain a unique population of cells with stem cell characteristics which are often named “tumor initiating cells” or “cancer stem cells”. This population is unique in respect to its central role in tumor initiation, relapse, chemo- and radio-resistance. It is often suggested that effective treatments against cancer including medulloblastoma should target regulators that are required for the viability of these cells. Our lab identified the RNA binding protein Musashi1 (Msi1) as such a regulator and as a main driver of medulloblastoma and glioblastoma development.

Why Musashi1 as a target in medulloblastoma treatment?

Our rationale is based on the following findings of our lab:

  1. Msi1 is widely over-expressed in high-grade gliomas and high risk medulloblastoma;
  2. in medulloblastoma, there is a strong correlation between high Msi1 expression and poor clinical outcome,
  3. Msi1 is enriched in tumor-initiating cells that successfully engraft when injected into SCID mouse brain;
  4. Msi1 is essential for clonogenic growth of primary human GBM and medulloblastoma cells and affects the expression of key stem cell markers; (v) Msi1 is implicated in chemo- and radio-resistance;
  5. Msi1 knockdown influenced a range of cancer related functions including proliferation, apoptosis, adhesion, migration, cell cycle control and invasion;
  6. genomic analyses determined that Msi1 controls the expression of various oncogenic factors associated with numerous cancer-relevant pathways.

We hypothesize that aberrant Msi1 expression is essential for tumor-initiation and growth and that blockage of its function will significantly delay, or prevent, tumor progression and relapse.

We propose a four phase drug discovery pipeline, going from screening to in vivo analysis.

Phase 1– Using biochemical fluorescence polarization, we identified a collection of compounds that interact with MSI1 RNA binding domain. We plan to validate this interaction with NMR and test if selected compounds interfere with MSI1 regulatory function.

Phase 2– The leading compounds identified in the screening phase will have their structure altered using medicinal chemistry, aiming to increase, solubility, absorption, permeability, interaction with MSI1 and capacity to cross the brain blood barrier.

Phase 3– Newly designed compounds will be tested and then evaluated in a collection of in vitro assays to determine if they can disrupt medulloblastoma cells proliferation and survival via their impact on MSI1.

Phase 4 – The compound with best overall results will be tested in vivo in the context of intracranial xenografts to determine if it can block medulloblastoma growth.

We hope to finish with at least one inhibitor to be tested in clinical trial.

We are requesting donations to carry out this study.

Project Period: 2 Years.

Aproximate Total Cost: $250,000

Resourse needed/used Cost
Molecular biology reagents: $30,000
Sequencing experiments: $15,000
Tissue Culture: $25,000
Animals: $20,000
Cost of design, synthesis and evaluation of compounds: $30,000
Post-doctoral fellow salary: $130,000

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