BACKGROUND
Medulloblastoma is the most common malignant pediatric brain tumor consisting of at least four distinct molecular sub-groups: Wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4. These subgroups are characterized by divergent genetic aberrations, cytogenic features, and distinct phenotypes including patient demographics and clinical outcome.
Tumors with WNT pathway activation have the most favourable prognosis whereas Group 3 medulloblastomas have the worst outcome. Group 3 tumors are restricted to pediatrics patients, characterized by the amplification of MYC (a regulator gene encoding a transcription factor), and are frequently metastatic at the time of diagnosis.
These tumors are particularly resistant to conventional therapies with radiation and chemotherapy, even at maximally tolerated doses, highlighting the need for novel and more effective therapeutic options.
DESCRIPTION OF INVENTION
Dr. James Rutka’s team has identified small molecule inhibitors which effective in prolonging survival in medulloblastoma preclinical models. Using a Connectivity Map (C-MAP) algorithm, asterpaullone (ALP), a potent inhibitor of CDK1/cyclin B, CDK2 and CDK5, was identified as a compound with the ability to reverse the gene expression signature of Group 3 medulloblastoma and, thus, exhibited a specific antitumor effect. This compound can be further optimized and developed into a novel treatment for medulloblastoma.
ALP may be administered via one or more routes depending upon desired results. Dosages range 1-100 mg/kg body weight. It may also be administered in conjunction with one or more additional therapeutics useful to treat medulloblastoma.
ALP was efficacious both in vitro and in vivo models for Group 3 medulloblastoma. ALP effectively decreased cell proliferation and induced apoptosis through AKT pathway blockade. In mouse xenografts of Group 3 medulloblastoma, treatment with ALP significantly inhibited tumor growth and improved survival (Fig. 1&2). Multiple CDK genes (that were upregulated in untreated control medulloblastoma cells) were significantly inhibited in cells treated with ALP.
ADVANTAGES & APPLICATIONS
- This technology allows for high content drug screen to target Rho-GTPase pathway in medulloblastoma.
- ALP demonstrated monotherapy efficacy in a Group 3 Medulloblastoma xenograft model.
- ALP, a pan-CDK inhibitor, is differentiated from current FDA approved CDK inhibitors which are challenged by treatment resistance.
DEVELOPMENT STAGE
Pre-clinical: in vivo POC
PATENTS
Issued Patent US 10,413,552 B2
PUBLICATION
Faria C. C, et al. Oncotarget, 2015. https://doi.org/10.18632/oncotarget.4304
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Figure 1. Kaplan-Meyer survival curve demonstrating improved survival of nude mice with D425 cerebellar xenografts treated with asterpaullone (ALP)
Figure 2. H&E staining demonstrates reductions in medulloblastoma growth after treatment with ALP when compared to control group. Scale bar: 500 μm.
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