Supervisor View Full Details 2nd

• genetics, genomics and molecular biology
• cancer/oncology

• Medicine
• Surgery
• Paediatrics

• Oncology

The broad focus of my research group is the induction of apoptotic death in glioblastoma and medulloblastoma. We develop ex-vivo and in-vivo models of these complex diseases, to examine the clinical efficacy of novel biologics, as potential treatment options for both adult and paediatric patients. I have successfully secured independent funding (~€1.2 Million) from the Health Research Board, the H2020 Research and Innovation Framework Programme and the National Children’s Research Centre to establish RCSI’s first brain tumour research group. I have mentored two post-doctoral researchers and graduated two PhD students. I am currently supervising three PhD students and a research assistant.

1. Frank Lincoln, et al., Brona M. Murphy and Markus Rehm (2018). Sensitization of glioblastoma cells to TRAIL-induced apoptosis by IAP- and Bcl-2 antagonism. Cell Death & Disease Nov 1;9(11):1112. doi: 10.1038/s41419-018-1160-2. [Epub ahead of print]. PMID: 30385739
2. Andreas Lindner, et al., Brona M. Murphy, William Gallagher, Arnold Hill, Leonie Young, Jochen Prehn (2018). Low cleaved caspase-7 levels indicate unfavourable outcome across all breast cancers. Journal of Molecular Medicine Aug 1. doi: 10.1007/s00109-018-1675-0. [Epub ahead of print]. PMID: 30069746
3. Janis Noonan, Jennifer Zarrer, & Brona M. Murphy (2016). Targeting Autophagy in Glioblastoma. Critical Reviews in Oncogenesis 21(3-4):241-252. PMID: 27915974
4. Birgit Weyhenmeyer, Janis Noonan, et al., Markus Rehm, Brona M. Murphy (2016). Predicting the cell death responsiveness and sensitization of glioma cells to TRAIL and temozolomide. Oncotarget Sep 20;7(38):61295-61311. PMID: 27494880
5. Á. Murphy, B. Weyhenmeyer, J. Noonan, et al., B. M. Murphy (2014). Modulation of Mcl-1 sensitizes glioblastoma to TRAIL-induced apoptosis. Apoptosis Apr;19(4):629-42. PMID: 24213561
6. Murphy ÁC, Weyhenmeyer B, Schmid J, Kilbride SM, Rehm M, et al., Murphy BM (2013). Activation of executioner caspases is a predictor of progression-free survival in glioblastoma patients: a systems medicine approach. Cell Death and Disease May 16;4:e629. PMID: 23681224

Glioblastoma (GBM) is the most aggressive and common primary brain tumour in adults. The disease is stubbornly resistant to the treatment strategies of radiation and TMZ chemotherapy that typically engage apoptosis to relay their death signals. Evading apoptosis is a hallmark of cancer. This underscores the need to find novel therapies that sensitise resistant cells to apoptotic stimuli as well as therapies that target inhibition of pro-survival signalling mechanisms that contribute to apoptosis resistance. For these reasons, autophagy, which can be either survival-promoting or death-inducing depending on the cellular context, has received increasing scientific attention.

Studies have shown that modulation of autophagy sensitises brain tumour cells to chemotherapy- and radiotherapy- induced death. Our group has highlighted how basal autophagy differ across a panel of GBM cell lines. Interestingly GBM cells with higher autophagic flux were more resistant to treatment with the death receptor ligand, TRAIL (Tumour necrosis factor-related apoptosis-inducing ligand) when compared to cells that were sensitive to TRAIL. Using TRAIL as an anti-cancer has numerous advantages: firstly, TRAIL can trigger apoptosis independently of p53, which is commonly mutated in GBM, and secondly, TRAIL can kill cancer cells without conferring significant toxicity to normal cells. However, numerous studies have demonstrated that GBM is resistant to TRAIL monotherapy. Instead, combination strategies seem to be required for TRAIL to elicit maximum impact. In this project, we hypothesise that manipulation of autophagy in GBM improves responsiveness to TRAIL treatment.

Objective 1: Evaluate basal autophagic flux in GBM
Objective 2: Assess how autophagic flux is altered upon TRAIL and TMZ treatment.
Objective 3: Characterise the cell death – apoptosis, necrosis, autophagy, lysosomal - elicited in GBM upon treatment with autophagy modulators and anti-cancer therapies.
Objective 4: Examine the expression of key targets in tumour resections and evaluate associations between their levels of expression and survival.