An industrial standard cancer drug development platform using human induced pluripotent stem cell technology

Lead Research Organisation: Newcastle University
Department Name: Northern Institute for Cancer Research


My career intent is to become an independent research leader working on real patient problems at the interface with industry, reducing and replacing animal use through non-animal technologies and solutions. Home Office figures tell us that more than 183,000 animal procedures take place every year in cancer research in the UK. In addition, when we study figures from the Home Office and major cancer research funding charities more than 9000 mice are being used every year to study leukaemia. Mice are being used by researchers to grow patient-leukaemia cells, to study their biology and to develop better medicines. Such animal procedures can reach moderate severity; these mice often show signs of distress such as weight loss, hunched back and dishevelled fur-coat.

Cancer research and cancer drug development have been identified by the NC3Rs as a strategically important area to bring about animal replacement. Currently, children's cancer treatment comprises a 2-3 years regimen with severe side effects such as death due to infections, kidney damage, heart problems and bone destruction. Hence better medicines are urgently needed and justifiably there is a lot of research being carried out in this area. Research into childhood cancer is urgent and important and this field will continue to expand in the immediate and distant future.

Improved medicines can be developed only by researching the biology of cancer cells taken directly from patients. Such patient-derived cells faithfully replicate leukaemia biology and are indispensable in scrutinising leukaemia cell-characteristics. This in turn is essential in developing better medicines. Although leukaemia is a very aggressive disease such patient-derived cancer cells rapidly die outside the body. Hence currently these cells can be grown and studied only in mice-models. My aim is to develop a technology that will allow researchers and the pharmaceutical industry to study leukaemia cells and develop better medicines without having to use mice.

I have developed a platform whereby patient-leukemia cells can now be grown in a petri-dish with the help of leukemia-supporting human bone-marrow cells. Given these bone-marrow cells do not survive long in the petri-dish they have to be constantly sourced from different individuals. Thus they behave differently across different laboratories resulting in high variability and inconsistent drug development data. To address this problem, I have developed a novel solution by which we can now use stem cells to generate such human bone marrow cells with uniform biology. These bone-marrow stem cells will provide an environment whereby patient-leukaemia cells can be grown and their biology can be studied without having to use mice. This means that dependence on animals in children's cancer research will reduce as fewer mice will be needed to develop better cancer medicines. In addition my non-animal solution is applicable in several other types of cancer affecting children and adults. I will establish an industrial standard biological test which will have a defined workflow pipeline and quality control programmes. I have established links with Cancer Research Technologies and working with a multidisciplinary team I will ensure that my test demonstrates high consistency at all times across different laboratories nationally and globally.

In summary I will engineer a technology that will help scientists and pharmaceutical companies to test and formulate new medicines for cancer without having to heavily depend on animal-models. The defining characteristic of my platform will be setting it up at a standardised industrial level with validated protocols and authenticated quality control measures. The deliverables of this fellowship will replace and reduce animal procedures in cancer research and will also reduce drug failure rates which is currently a big problem in the pharmaceutical economy.

Technical Summary

Although leukaemia is a very aggressive disease patient-derived cells do not survive outside the body. Hence more than 9000 mice are used annually in leukaemia research. Animals are used to expand leukaemia cells and for drug development purposes. Cell lines are used for pre-in vivo target validation of cancer therapies. Given cell lines do not represent the complexity of disease presentation this pipeline results in high in vivo drug attrition rates.

I have developed a clinically relevant ex vivo platform which expands primary leukaemia cells using human bone marrow mesenchymal stem cells (BM-MSC). However, BM-MSC can be maintained for only short periods and need to be constantly sourced from different individuals compromising reproducibility across different laboratories. The aim of this fellowship is to develop a uniform source of BM-MSC through induced pluripotent stem cell (iPSC) technology. iPSC are characterised by indefinite in vitro proliferation and ability to differentiate into a wide repertoire of cell types. Human BM-iPSC will be engineered through a virus free, integration free RNA vector using re-programming factors OCT4-SOX2-KLF4-GLIS1. Flowing deep phenotyping BM-iPSC lines will be differentiated into an array of BM-feeder cell types. The overall aim is to establish an industry standard non-animal technology with defined standard operating procedures and quality assurance programmes. Existing partnership with a multidisciplinary team in industry and academia will further ensure that rigorous standards are reached. Following this, further commercial collaborations will be sought though NC3Rs CRACKIT and Innovate UK.

Widespread endorsement will reduce in vitro to in vivo drug attrition rates in the drug development pipeline. My platform will replace and reduce animal procedures by expanding primary leukaemia cells ex vivo and by acting as a pre-in vivo screen to filter off failed candidates from going forwards with in vivo validations.


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