Personalised treatments for kids with cancer
Challenge

Cancer is the most common disease-related cause of death in Australian children today.[1] This is despite an increase in cure rates from 10% in the 1950s to a current average of 80%.[2] In Australia, over 600 children are newly diagnosed with cancer annually, and in each year approximately 150 children will die of their disease.[3] Most cancer chemotherapeutics used are general cytotoxics, non-specific and often result in severe long-term side effects in those children surviving cancer treatment. To address the issues associated with chemotherapy, or “one-size-fits-all” treatments, Children’s Cancer Institute (CCI) started the Zero Childhood Cancer Personalised Medicine Program (Zero Childhood Cancer Program), jointly led by Sydney Children’s Hospitals Network, to develop “individualised” treatment regimens for all Australian children with high risk or relapsed cancer. A key challenge associated with the personalised medicine approach is the need to rapidly identify drugs or drug combinations that kill cancer cells isolated from individual patients.

How did the facility help?

The Drug Discovery Centre (DDC), located within Children's Cancer Institute, performs high-throughput and high content screening of small molecule libraries to identify novel hit compounds or re-position “known” drugs. This facility is directly responsible for developing one of three core technology platforms as part of the Zero Childhood Cancer Program. These platforms include genomic profiling, in vitro drug sensitivity testing (DST) and the establishment of mouse “avatars” using the tumour material from individual children with cancer. The focus for the DDC is the design, development and implementation of in vitro DST as a key component of the Zero Childhood Cancer national clinical trial which commenced in 2017. The trial involves all 8 paediatric oncology centres in Australia (www.zerochildhoodcancer.org.au). Around 400 children are expected to be enrolled on the clinical trial over the next three years.

The DDC continue to advance the development of the in vitro DST platform as follows during the current funding period: (a) further refined highly sensitive cell viability assays for four different childhood cancer types, (b) optimised novel multiplexed high content screening assays to measure markers of drug-induced cell death, (c) tested conditions for co-culture or 3D spheroids to more accurately reflect the in vivo tumour, (d) expanded the Approved Paediatric Oncology and Targeted Drug Library, (e) performed prospective in vitro DST on cancer cells from 12 of the 35 childhood cancer patients enrolled on the Zero Childhood Cancer pilot study, and (f) developed a first-generation drug combination testing method.

Outcome

The DDC has used the expertise of the staff in high-throughput and high content small molecule screening to advance the development of a unique in vitro DST platform and test different forms of the platform on childhood cancer patient tumour cells. The end result has been the establishment of all processes and procedures for patient referrals, tumour collection, sample processing, cell preparation, drug screening, data analysis and reporting. One outstanding hurdle for the platform is the low number of tumour cells obtained from patient biopsies. To address this challenge, the DDC is pursuing funding for the purchase of an acoustic (microfluidic) liquid handling workstation, which will permit the miniaturisation of the patient cell drug screening assays, lower the cost of testing and reduce the number of patient tumour cells required for each test.

Background

The Australian Cancer Research Foundation (ACRF) Drug Discovery Centre for Childhood Cancer (DDC) is a unique world-class facility, located within Children’s Cancer Institute at the Lowy Cancer Research Centre on the University of New South Wales campus in Sydney. The DDC has been operating for five years and, in that time, has completed numerous screening projects using childhood and adult cancer cell- and target-based assays. The Centre houses a sophisticated array of automation equipment and liquid handling robotics, as well as plate reader-based detection systems and two high content screening platforms. In addition, the DDC co-owns 160,000 small molecules, and other boutique compound libraries, and uses an advanced data management system to integrate biological assay data with chemical compound information.

Commonwealth funding has included funding through Therapeutic Innovation Australia and the Education Investment Fund/Super Science Initiative, with $650,000 to support acquisition of an integrated high content screening system and $240,000 (2014-17) in salary support. The DDC is a partner in the Cancer Therapeutics CRC (CTx), which was a recipient of $37.6M startup funding in 2007 and which recently received $34M of additional funding for the period 2014–2020.[4] In 2016, The Zero Childhood Cancer Personalised Medicine Program, of which the DDC is a major contributing facility, received $20M in funding from the Commonwealth towards the national roll-out of the Program.

 

[1] Australian Institute of Health and Welfare. A picture of Australia’s children 2009. AIHW Cat. No. PHE 112. Canberra: AIHW; 2009.

[2] Ries LAG, Melbert D, Krapcho M, et al. SEER Cancer Statistics Review, 1975–2004. Bethesda, MD: National Cancer Institute. Retrieved 12 March 2014, from http://seer.cancer.gov/csr/1975_2004

[3] Baade PD, Youlden DR, Valery PC, et al. Trends in incidence of childhood cancer in Australia,

1983–2006. Br J Cancer 2010;102:620–6.

[4] McFarlane I, Minister for Industry Media Release 21 February 2014: http://minister.innovation.gov.au/ministers/macfarlane/media-releases/driving-research-and-delivering-results-australia

Children's Cancer Institute Australia

Level 14, 330 Collins St

Melbourne 3000 VIC

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