| Project title | Overcoming Resistance to Antibody-Drug Conjugates in Glioblastoma Patients |
|---|---|
Grant Amount | $199,233 |
Institution | La Trobe University |
Investigator Team | Principal investigators Prof. Andrew Scott, A/Prof. Hui Gan and A/Prof. Alexander Dobrovic |
Grant Type | 2014 Innovation Grant |
Years | 2014 – 2016 |
Utilising unique Australian resources, this study will undertake vital research into the mechanisms of resistance to antibody-drug conjugates, a group of drugs which have shown highly encouraging efficacy in patients with GBM.
The team have shown that ABT-414, an antibody-drug conjugate, can cause impressive and prolonged tumour shrinkage in some GBM patients, whilst other patients with similar clinical characteristics appear to derive little benefit.
Understanding the causes of resistance in the latter group will allow treatment to be directed only to patients who are likely to benefit and/or allow them to delay or overcome such resistance altogether, thereby allowing a greater group of patients to benefit from treatment.
“Given the impressive early response data for ABT-414 in recurrent GBM patients, this research may significantly impact on the development of this exciting new treatment for GBM patients.”
Prof. Andrew Scott
Progress
The funding from Cure Brain Cancer Foundation has been pivotal in supporting our research into developing new treatments for brain cancer, which is a central theme of our laboratory program.
Our project explores the mechanisms by which resistance occurs to ADCs in GBM patients (both de novo and in response to treatment) using the ADC ABT-414. We hypothesise that there are factors that regulate ABT-414 sensitivity that are altered in GBM, or can mutate during treatment.
During the grant period we have evaluated ABT-414 effects in vitro and in vivo in a range of GBM cell lines and PDX models. Through protein, transcriptomic and genomic analysis, we have shown that EGFR expression is an important factor in development of resistance to ABT-414, however other factors including cell cycle and tubulin biology, and the immune system, may also contribute to patient response and resistance to therapy. This information is being used to develop new trials and strategies for the use of ABT-414 in GBM patients.