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Overcoming resistance to antibody-drug conjugates in glioblastoma patients  

Lead PI: Prof Andrew Scott, Ludwig Institute for Cancer Research, Austin Health, VIC

Prof Andrew Scott 

Research idea

Utilising unique Australian resources, this study will undertake vital research into the mechanisms of resistance to antibody-drug conjugates (ADCs), a group of drugs which have shown highly encouraging efficacy in patients with GBM; this research is particularly important since the ADC ABT-414 is undergoing accelerated testing for GBM patients and the knowledge derived from this research will help determine patient selection strategies and combinatorial treatment approaches.

Problem

The team have shown that the antibody drug conjugate (ADC) ABT-414 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.

Solution

The team are in a unique position to undertake this research due to our GBM, antibody and ADC expertise. PI Scott led the development of the mAb806 antibody that forms the antibody component of ABT-414. PI Gan currently leads the global ABT-414 Phase 1 GBM study (NCT01800695), allowing them to generate the only human xenograft models of ABT-414 resistance in the world. They have a strong ongoing collaboration with AbbVie and are able to align this work with Abbvie’s own translational work in a complementary, non-overlapping way such that our results will be directly relevant to future planned studies with ABT-414.

"The antibody that is being used to target this toxin to the GBM tissue was actually developed here in Australia... so we have a very deep understanding of how the antibody works and we're translating that knowledge into the clinical trials which are currently occurring." 

- Prof Andrew Scott 

Why now?

The field of ADC treatment of GBM is only now emerging as a potential therapeutic option for GBM patients. The Phase 1 study of AMG595 began in November 2011, whilst the Phase 1 GBM study of ABT-414 began in April 2013. The patient derived xenograft models of ABT-414 resistance were generated in early 2014. The relevance of such research has also increased rapidly with the accelerated testing of ADCs in phase 2/3 studies in GBM patients planned for the near future.

Approach

This proposal forms a highly competitive body of preliminary data to guide further academic research (as funded by conventional funding bodies such as NHMRC) and enable on-going industry collaboration with groups involved in ADC development such as AbbVie and Seattle Genetics. Basic science and translational research will result in development of better ADC constructs for GBM and other tumours in the medium term. Rationally guided combination therapy trials (e.g. with novel payloads, non-cross reacting tubulin poisons or other targeted agents against cell surface/signalling pathways) will immediately inform clinical trials for GBM patients.

Impact

ADCs are an exciting new approach to GBM treatment. Challenges include lack of response in some patients despite target expression in their tumour, and the development of resistance following initial response. Understanding why this occurs and developing methods to abrogate resistance, will result in marked improvement in therapeutic responses in patients receiving ABT-414. Given the impressive early response data for ABT-414 in recurrent GBM patients (ASCO 2014), this research may significantly impact on the development of this exciting new treatment for GBM patients.

Team & Partners

PI's Scott and Gan will oversee the proposed work in the Tumour Targeting Laboratory (Ludwig Institute for Cancer Research). There is considerable expertise in the group in research assessing protein expression (including RPPA arrays), cell proliferation and viability, apoptosis, and phosphoprotein expression. They also have longstanding expertise in animal models, in vivo therapy and imaging experiments. AI Dobrovic has extensive experience in molecular pathology of tumours including transcriptomic arrays (Illumina-based RNA-seq).

  • PI: A/Prof Hui Gan, Ludwig Institute for Cancer Research, Melbourne
  • Co-Investigator: A/Prof Alexander Dobrovic, Ludwig Institute for Cancer Research, Melbourne   

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