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Modification of the Asparaginase-based drugs for ALL

Acute pancreatitis is highly inflammatory pancreatic disease. It becomes a life threatening complication of childhood leukaemia treatment caused by the anti-leukemic drug Asparaginase. Once children develop acute pancreatitis, they cannot receive any more Asparaginase, because most likely the pancreatitis will happen again. Without Asparaginase treatments, the options for management of children with leukaemia are limited. Previously, attempts have been made to improve the Asparaginase treatment by changing the source of bacteria or other modifications of the protein. However, these changes have not given the expected results. One of the reasons was the absence, until now, of the fundamental study of the mechanism of Asparaginase-induced pancreatitis.

Project Details

  • Project Title

    Modification of the Asparaginase-based drugs for ALL

  • Lead Researcher

    Dr Oleg Gerasimenko

  • Research Centre

    Cardiff University

  • City & Institution Postcode

    Cardiff

  • Start Date

    1 June 2018

  • Duration

    36 months

  • Grant Amount

    £245,507

Overview

In their recent paper the team have reported in detail the mechanism of Asparaginase-induced acute pancreatitis, namely, activation through protease-activated receptor, abnormal calcium signalling, mitochondrial damage, loss of intracellular energy resources and cell death. More recently, the team has shown that supplementation the natural sugar galactose in vitro and in vivo helps to alleviate acute pancreatitis related pathologies.

These findings allowed the design of effective strategies to solve problematic side effects of Asparaginase-based drugs. A number of supplements or inhibitors could help here, i.e. energy supplements (galactose) or inhibitors of irregularities of calcium signalling could prove useful. However, none of them has been tested so far in humans for the treatment of acute pancreatitis.

Therefore, the team believe that the best and fastest way forward would be to introduce relatively minor changes into the current most effective anti-leukemic drugs based on Asparaginase. This will allow the creation of safe and effective treatments for children with leukaemia.

Potential impact

Modified Asparaginase will become a new anti-leukaemia drug prototype without side effects and have a potential to substantially improve future treatments of the childhood leukaemia.

About the research team

Dr Oleg Gerasimenko is one of the leading scientists in the UK working on acute pancreatitis. Together with Dr Julia Gerasimenko they made the important discovery (Cell, 1995) cited more than 313 times (Web of Science) about fundamental mechanisms of calcium signalling. They have an excellent track record in researching pathophysiology of AP and have made significant progress characterizing the pathological effects. The most important findings, published in PNAS (2009, 2011, 2013) and Current Biology 2012 clarified the molecular mechanisms responsible for AP initiation. Recent paper in Journal Clinical Investigation 2018 provided a real hope of developing effective treatment by using supplementation with the natural sugar galactose.

Dr Oleg Gerasimenko is a member of the Editorial board of Pflügers Archiv–Eur JPhysiol, and has had continuous Medical Research Council support from 2003. Dr Julia Gerasimenko has also been supported by the Medical Research Council since 2007. They are also both Faculty Members (F1000-Gastrointestinal-Physiology).

Dr Sujith Samarasinghe is Consultant Paediatric Haematologist at Great Ormond Street Hospital in London. He is a key member of the national leukaemia toxicity group and has worked on defining toxicities for UKALL 2011, with a view to developing strategies to reduce their incidence.

Recently, all applicants published together the first study exploring the molecular mechanism underlying AP induced as a side-effect of Asparaginase treatment of ALL (Peng 2016) and potential treatment (Peng 2018), therefore have the ability to make significant progress in the proposed grant period.

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