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Novel targeted chemotherapeutic agents against Diffuse Intrinsic Pontine Gliomas (DIPG) 

Principle: Dr Maria Tsoli – Children’s Cancer Institute Australia

Leaders: Dr Maria Tsoli, Dr David Ziegler – Children’s Cancer Institute Australia

 Maria Tsoli and David Ziegler

Research Idea

In an effort to develop new treatments for diffuse intrinsic pontine gliomas (DIPGs) we plan to test in vitro and in vivo the efficacy of novel combination therapies of anticancer drugs and clinically available agents identified by robotic screening approaches.

Problem

 Diffuse intrinsic pontine gliomas (DIPGs) are the leading cause of brain cancer-related death in children. These aggressive tumours represent the most deadly of all childhood cancers.  They can’t be effectively treated, and prognosis is poor. Radiotherapy is the only treatment that prolongs survival however it is primarily palliative and most children succumb to the disease within one year.

One of the principal reasons for this poor survival rate is our limited knowledge of the DIPG biology. DIPG tumours are located within the brainstem, which is the most critical area of the brain that controls basic bodily functions including breathing and heart function.  Because of this location, it is impossible to operate on these tumours and even performing a limited biopsy has been considered too dangerous.  As a result, DIPG tumours have rarely been studied at all in the laboratory and we have made no advances in our treatment strategies.

Solution

FWe have used a robotic technology to screen more than 3,500 biologically active, clinically approved, pharmaceutical compounds to test their ability to inhibit DIPG cell growth.

Amongst these we have identified 30 drugs with striking efficacy against DIPG tumour cells. Importantly, no toxicity was seen against normal healthy brain cells.

We subsequently performed a combination robotic screen with these 30 drugs and 50 anticancer drugs with reported ability to cross the blood brain barrier. This approach has resulted in 40 exciting novel drug combinations with remarkable synergies.

Here we seek to evaluate further the cytotoxic efficacy of these combinations in DIPG and understand their mechanism of action.

Why now?

Within the last 5 years it has been shown that viable DIPG cells can be grown in the laboratory from tumours harvested post mortem. Together with international collaborators we have grown the first DIPG cells every cultured, successfully established 8 DIPG cell lines in our laboratory and have these available as a unique tool to learn more about DIPG and help discover new and effective treatments.

Approach

Combination high throughput screening identified 40 novel combination therapies with remarkable synergies. We plan to examine further the cytotoxic efficacy of these combinations in a panel of DIPG and healthy cells.

Since irradiation is the main offered treatment therapy we will determine whether identified combination therapies work effectively with irradiation.

Furthermore we will evaluate for one of the best combination hits the mechanism of action in DIPG cells. Finally we intend to evaluate the efficacy of the most promising combination therapies alone, and together with radiotherapy in two independent, in vivo models of DIPG.  

Impact

Utilising compounds that are known to be clinically available will mean that positive results will be able to be rapidly translated to the clinic for testing in the early phase clinical trial setting.  Ultimately, this novel approach may lead to the rapid development of novel therapeutic combination strategies for a tumour that till now has proven devastating to patients and their families, with no known effective treatments.

Team & Partners

  • Dr Maria Tsoli (Senior Research Officer)
  • Ms Arjanna Chintranjan (Research Assistant)
  • Ms Danielle Lapin (Independent Learning Program, Medical Student)

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