| Project title | The Therapeutic Targeting of Cell Cycle Regulators and Mechanisms of Resistance to Cell Cycle Therapy in Medulloblastoma |
|---|---|
Grant Amount | $345,000 |
Institution | The University of Queensland |
Investigator Team | Early Career Fellow Dr. Laura Genovesi and supervisor Prof. Brandon Wainwright, with associate investigators Prof. Michael Taylor and Prof. James Olson |
Grant Type | 2017 Early Career Fellowship |
Years | 2017 – 2021 |
Medulloblastoma is a leading cause of cancer-related mortality and morbidity in children. Few effective therapies are available for patients with high-risk disease or tumours that recur following standard-of-care therapy and thus, these patients have a poor prognosis.
This project focuses on identifying targeted therapies for medulloblastoma.
Using a functional genomics and bioinformatics approach, the gene networks and abnormalities in all medulloblastoma subtypes have been mapped, and a druggable genome analysis carried out. This mapping has identified potential new therapeutics, showing inhibition of CDK4/6 – an enzyme that is often overactive in cancer cells – as a promising strategy for multiple medulloblastoma subtypes. Dr. Laura Genovesi and her team will now transition this knowledge to the development and testing of new targeted therapies.
“This project focuses on identifying targeted therapies for medulloblastoma.”
Dr. Laura Genovesi
Progress: First annual progress report (September 2019)
My research focuses on using network-based methods to identify and validate novel targeted biological therapies for medulloblastoma. On the basis of my postdoctoral work, I published a manuscript illustrating the potential of CDK4/6 inhibitors’ highly effective strategy for the treatment of medulloblastoma. Five clinical trials are now underway investigating the efficacy of CDK4/6 inhibitors in medulloblastoma and overall data generated in this project will progress pilot data and heavily influence the next future clinical trials for CDK4/6 inhibitors for patients with brain tumours.
This study aims to identify genetic factors or “biomarkers” which define how a cell will respond to CDK4/6 inhibitors and will greatly assist with accurate patient selection for clinical trial.
Given cytotoxic chemotherapy is the cornerstone of childhood anti-cancer treatment, we will also use this information of how a tumour responds to CDK4/6 inhibitors to help construct a “biologically driven” dosing scheme for combining CDK4/6 inhibitors with cytotoxic chemotherapy. This is essential to maximising cytotoxic effects of both of these agents and ensuring that patients will achieve an overall response greater than that that could be obtained by single agents alone.
In addition to CDK4/6 inhibitors, more recent data obtained in this project have highlighted the potential of another class of novel therapeutics for patients diagnosed with brain tumours. The pipeline of analysis described above will be repeated for this class of drugs aiming to identify biomarkers which will predict tumour response to these agents and how best to combine these agents with existing treatment strategies.
The computational systems biology approaches developed to identify biologically driven novel therapies for medulloblastoma are currently being prepared for publication. Once published, this provides a resource of “druggable nodes” for brain tumour researchers to ignite the appropriate preclinical studies required to translate this novel biology into clinical practice. With similar genomic and transcriptomic datasets, these sophisticated analyses could also be repeated for other brain tumour types, particularly those where conventional therapy is currently ineffective.