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Pharmacological inhibition of MCL-1 and BCL-xL to treat human medulloblastoma 

Lead PI: Prof Andreas Strasser, The Walter and Eliza Hall Institute of Medical Research, VIC  

 Prof Andreas Strasser

Research idea

The team aim to develop novel strategies to efficiently kill brain cancer cells without causing intolerable damage to healthy tissues, by utilising recently developed BH3-mimetic drugs that directly activate the cell death pathway. Notably two of these drugs are currently undergoing phase 2 clinical trials for the treatment of haematological cancers whereas another has only recently been developed and is still undergoing pre-clinical testing.

Problem

There are only a limited number of drugs available for the treatment of brain cancers. The standard treatments involve surgery, radiation and chemotherapy; these treatments are either invasive or can through other processes, cause substantial damage to healthy tissues, lead to impaired motor, sensory and cognitive function. This is particularly problematic in young children with a developing nervous system. The team plan to investigate the potential of using BH3 mimetic drugs (currently only being trialled for haematological malignancies) to efficiently kill brain cancer cells without causing detrimental damage to healthy tissues

Solution

Currently, only little is known about the role of the apoptotic cell death machinery in the development of brain cancer and whether targeting it has therapeutic value. MCL-1 and BCL-XL are important for the survival of neuronal cells during embryonic development and appear essential for the sustained survival and growth of human cancer cells. Inhibition of BCL-2 and/or BCL-XL using the BH3-mimetics ABT-199 or ABT-263, respectively, has shown tremendous promise in phase 1 and 2 clinical trials in CLL and other malignancies. These BH3 mimetics were developed in collaboration between major pharmaceutical companies and Walter and Eliza Hall Institute (WEHI) research divisions. 

"We aim to develop emerging drugs that block the machinery for cellular survival (developed in a collaboration between our laboratory and major pharma companies) for the treatment of brain cancers with poor prognosis."

- Prof Andreas Strasser

Why now?

BH3 mimetics that inhibit pro-survival BCL-2 and/or BCL-XL belong to a new class of drugs that are showing great promise in clinical trials of human CLL and other malignancies. The team have recently established a collaboration with a major pharmaceutical company to develop a BH3 mimetic that selectively targets MCL-1; this is the first of its kind and clinical trials are planned for mid-2015. The access to this unique MCL-1 inhibitor combined with the knowledge and resources from Strasser, Voss and Wainwright place them in a unique position to make discoveries that will lead to substantial advances in the treatment of brain cancer.

Approach

The team predict that the BH3 mimetics that target BCL-XL and MCL-1 will be highly efficient in killing mouse and human medulloblastoma cells in their pre-clinical xenograft and other mouse models. Their division together with WEHI clinician/scientists have collaborated with Genentech Inc and AbbVie in the development of BH3 mimetics for cancer therapy and are now collaborating with a major European pharmaceutical company to develop an MCL-1 inhibitor for clinical cancer trials. They are therefore in a unique position to advance the development of BH3 mimetics for clinical trials in brain cancers.

Impact

Medulloblastoma mostly affects young children and current therapies are highly invasive with substantial side effects; this necessitates long periods of hospitalisation and recovery. The team hope to develop novel strategies to treat patients with brain cancer in a more effective and less invasive way to ideally achieve complete regression of the tumour and prolonged survival without the commonly observed detrimental side effects by minimising the damage to healthy tissues. They aim to provide patients with better quality of life by developing improved treatment strategies, thus allowing them to spend more time outside the hospital with their families

Team & Partners

Their team consists of Profs Strasser Voss and Wainwright who are leading experts in the field of cancer and developmental biology. Dr Grabow has been working highly successfully in the field of cell death and cancer for several years, demonstrated by several publications in leading journals (notably some on the testing of BH3 mimetic drugs). They have established collaborations with additional research teams including clinician/scientists, structural biologists and chemists across Australia and overseas. Importantly, they have long-standing, highly productive collaborations with major pharmaceutical companies (e.g. Genentech and AbbVie).

PI:

  • A/Prof Anne Voss, The Walter and Eliza Hall Institute of Medical Research, VIC

Co-Investigators

  • Prof Brandon Wainwright, The University of Queensland, Institute for Molecular Bioscience
  • Dr Stephanie Grabow The Walter and Eliza Hall Institute of Medical Research 

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