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Cure Brain Cancer Neuro-oncology Group: Head of Biomarker and Translational Research

Research idea

The research idea is n=1. The one treatment fits all approach has not worked and a better understanding of the patient’s biology and a holistic understanding of druggable targets and druggable pathways will lead to improved survival times.

Problem

A significant unmet need is to discover new treatments to improve the standard-of-care therapy  (Radiation therapy plus temozolomide followed by 6 cycles of adjuvant temozolomide). 

The lab specializes in: (1) defining drug-diagnostic combinations where the presence of a molecular target or marker identifies who are most likely to respond to a specific therapy; (2) culturing and growing patient specimens in real-time to foster a “personalised medicine” approach utilizing patient derived xenografts (PDX) models. With time, we hope that we can report back to the clinicians with drugs and drug combinations that have reduced tumour size; (3) work with clinical trial groups and consortiums to identify “responders” to the treatment and better understand the underlying biology and (4) better understand the mechanisms of cancer resistance.

Why now?

We have been through a long development phase to establish a pipeline:

  1. Establishing patient derived cell lines and downstream PDX models; 
  2. Developing relationships with key oncologists to identify new compounds for testing; 
  3. Genomic characterization of the models: this enables the matching of the drug with the biomarker; 
  4. Accessing large cohorts to test hypotheses.

Our major advances are:

  • Collaborations with The Cancer Genome Atlas (TCGA)
  • Identification of a key aberration found in the promoter of a DNA repair gene. Not only does this aberration have an association with treatment response, we are now investigating whether this gene is an early driver of brain tumourigenesis
  • Launching the only epidemiology study in brain tumours in Australia (AGOG: II)
  • Running Australia’s largest biospecimen bank for brain tumours (AGOG I)
  • Identifying a target that can be treated as an adjunct to temozolomide
  • Working with the clinical trials group, COGNO, to identify responders of Avastin 
  • Investigating new compounds and compounds that work synergistically with radiotherapy

Approach

Our approach is to work in direct partnership with the clinician. The biobanking of patient specimens has been the strength of the laboratory. This overcomes a significant hurdle with drug development. Our models closely represent what is happening in the patient and the model retains all of the genetic features and the blood brain barrier. A consistent failure of drug development is inappropriate models. If a drug cannot permeate the blood brain barrier, it is quickly rendered useless. This model has now been extended to Prince of Wales Public and St George Hospitals. 

Another strong advantage to our team is the early establishment of a networked biospecimen repository, AGOG (Australian Genomics and Clinical Outcomes of Glioma). Tumours, blood and comprehensive clinical data have enabled us to examine new molecular targets that might be druggable as well as participate in international studies such as The Cancer Genome Atlas (TCGA). Large data profiling and “-omics” will lead to the discovery of new targets. As members of key clinical trials groups such as COGNO, we are also able to take a closer look at the trial outcomes and better understand response (and lack of response).

The natural progression of our work is to trial the biomarker-drug combinations in patients diagnosed with brain tumours. Phase I and II trials, but also trials where the patient is treated and then operated on to remove the tumour. This would give us a unique insight into whether the drug is working and if other pathways are being triggered to compensate for the drug.

The other important progression is to move the PDX models to a real time setting so that we can test different drugs and combinations in the PDX model for that specific patient and then report back to the clinicians in a trial setting. In addition, genotyping patient tumours to give them opportunity to be included in a “basket-type” trial, where it’s not just about “brain” but it’s about a “cancer” with a specific aberration. For example, numerous cancers harbour mutations in EGFR- it is more practical to group lots of rare cancers with similar biology together for one trial than it is to test on a rare cancer. And finally, moving forward with the clinical trials setting to enable phenotype to genotype and genotype to phenotype studies. What can we learn from clinical trials run in the past? There are always “exceptional” patients in every trial; we need access to the trial data and trial tissue to enable this to happen.

Team & partners

Members:

  • A/Prof Kerrie McDonald, Head
  • Dr Robert Rapkins, Postdoctoral Scientist
  • Dr Sheri Nixdorf, Postdoctoral Scientist
  • Ms Irene Daris, Research Assistant
  • Dr Pukar Thapa, Brain Cancer Translational Research Officer
  • Ms Wendy Ha, Research Assistant
  • Dr Hazem Abuhusain, PhD awarded in 2014
  • Dr Han Shen, PhD
  • Ms Dan Lu, PhD
  • Dr Eric Hae, PhD
  • Ms Sylvia Chung, PhD
  • Mr Matt Davies, Hons
  • Mr Daniel Madani, Hons
  • Ms Lianne Beunk, Visiting Scholar

We need the direct co-operation of clinical trials teams, in Australia and Australasia. We need to work much more closely with our neighbours China, South Korea and Japan, and get smarter about our trial designs. Combinations of treatments desperately need testing and “basket” trials and phenotype to genotype and vice versa designs need to be embraced.

Greater support for running early phase II trials needs to be prioritised. To move our findings from the lab to the clinic will always be on the back foot because of the money required conducting a thorough trial. We always have patients asking what's next when standard treatment fails. The truth is, we don't have many options.

Our lab is ready to push forward at least three new clinical treatments:

  1. Combination of ABT-888 (PARP inhibitor) with radiotherapy up front for patients diagnosed with unmethylated MGMT status GBM
  2. Combining DCA, PENAO and re-irradiation in recurrent GBM
  3. Treating patients with a combination of TMZ and PENAO; TMZ and Ibudilast  (MIF inhibitor)

Impact

New and more targeted treatments will lead to improved survival times.

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