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Full NameDr Brona M Murphy
Department:Physiology and Medical Physics
Organisation:Royal College of Surgeons in Ireland
- genetics, genomics and molecular biology
Postgrad Medical Specialties
The broad focus of my group’s research is the induction of cell death, and in particular apoptosis, in glioblastoma (GBM), the most common and aggressive form of brain cancer. These tumours are highly resistant to this particular form of cell death, which actively contributes to their progression. We study apoptosis within GBM, utilising various methods.
Through systematic analyses of the interplay between apoptotic proteins, we have highlighted that ‘one-size-fits-all’ approach to treating this disease is not valid. Instead, a more personalized approach is necessary to select the most appropriate drugs for a given patient. See [1, 2] for further details.
We are also interested in increasing the susceptibility of GBM to apoptosis-inducing stimuli. Recent efforts to sensitize GBM to apoptosis have focused on ligands to death receptors, such as TRAIL, to activate apoptosis. GBM are completely resistant to monotherapy with TRAIL however, due in part to their overexpression of anti-apoptotic proteins, such as Mcl-1. We have published that R-roscovitine, a first generation cyclin-dependent kinase inhibitor down-regulates Mcl-1 in GBM, via its selective targeting by CDK9. We have subsequently demonstrated that combining R-roscovitine with TRAIL re-establishes apoptotic sensitivity in both GBM cells grown as monolayers and in a stem-cell 3D tumour model .
This project will combine basic cell death mechanisms and systems-based analyses of apoptotic signatures, in the assessment of the therapeutic efficacy of a second-generation CDK inhibitor, CYC065 in GBM. CYC065 is mechanistically similar to R-roscovitine but with significantly improved potency (40-fold) and metabolic stability, giving it the propensity to be an even better therapeutic candidate. For example, CYC065 causes proportionally greater CDK9 inhibition than R-roscovitine, leading to more prolonged down-regulation of the anti-apoptotic protein, Mcl-1, in turn making tumour cells more vulnerable to apoptosis. CYC065 is also more selective for CDK5 which is particularly significant given that CDK5 promotes the migration and invasion of glioma cells. Finally, CYC065 is orally available and lipophilic in nature, which means if its therapeutic potential is realised it should have the propensity to cross the BBB, providing efficient and quick relief for the patient.
Initially, a thorough analysis of the preclinical efficacy of this drug, both on its own and as part of combinatorial approaches, which may be required for CYC065’s killing potential to be realised will be conducted. Furthermore, the project will develop an innovative data integration and statistical model, as a translationally relevant approach to deliver CYC065 in a personalised and tailored manner to GBM patients.
1. Murphy, A.C., et al., Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach. Cell Death Dis, 2013. 4: p. e629.
2. Weyhenmeyer, B.C., et al., Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide. Oncotarget, 2016. 7(38): p. 61295-61311.
3. Murphy, A.C., et al., Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. Apoptosis, 2014. 19(4): p. 629-42.