BCI at ASCO 2014: Acelarin exceeds expectations

Zoe Leech Posted in Conferences, BCI on the Road, Grants & Awards 20 June 2014

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BCI's presence at the 50th ASCO Annual Meeting was certainly noteworthy, with significant attention and praise given to our researchers' work on an innovative modification of an existing anti-cancer drug that has shown exceptional results.

Congratulations go to Centre for Haemato-Oncology researcher Dr Essam Ghazaly, who won the Merit Award of Conquer Cancer Foundation for his poster, which includes a $1,000 prize, registration to the conference and a VIP pass.

"Merit Awards are given annually in recognition of outstanding abstracts submitted to the Scientific Program Committee for the upcoming Annual Meeting. The Merit Award program was established to encourage more fellows and residents to attend the Annual Meeting and to further promote clinical research in young scientists."

Dr Ghazaly worked with BCI's Professor John Gribben and Imperial College's Dr Sarah Blagden on the project presented at ASCO, centred around a drug called Acelarin (NUC-1031), which is a modified version of an existing chemotherapeutic called gemcitabine.

Essam Sarah Merit award pic

Sarah Blagden and Essam with the ASCO Merit Award by their poster showing clinical results from the ProGem1 trial.

The research presented is the result of a 15-year endeavour, begun by Professor Chris McGuigan from Cardiff University. The aim of their work is to modify chemotherapeutic agents to get around the mechanisms that cause cancer cells (and tumours as a whole) to become resistant to treatment.

What's special about the new drug?

NuCana BioMed has been awarded funding in excess of $50m to develop Acelarin and similar agents, which are simply but effectively modified to allow the drug to overcome three main problems that agents like gemcitabine typically encounter:

1) Cell Membrane Transporters. Many drugs require a protein on the cancer cell surface to move them across the cell membrane and into the cell. Acelarin's modification means it can travel through this barrier without the help of these transporter proteins.

2) Activation. Once gemcitabine gets inside the cancer cell, it still requires the help of a protein called a kinase to add a phosphate group to it and make it active. Acelarin has a phosphomimetic modification - that means it has an extra chemical group added that mimics the phosphorylated state, so it is permanently active.

3) Degradation. Gemcitabine can be degraded inside tumour cells by an enzyme called cytidine deaminase. Acelarin, with its phosphomimetic structure, is resistant to this enzyme and more stable inside cells.

AcelarinFig1From the poster: Acelarin (NUC-1031, top) is more efficient than Gemcitabine (below).
hENT1 - membrane transporter protein. dCK - deoxycytidine kinase. CDA - cytidine deaminise.

Once Acelarin is inside the cell, like activated gemcitabine, it blocks DNA replication and causes tumour cell death (apoptosis). Having presented pre-clinical work at AACR in 2013, this year the initial clinical study results have come in and they are extremely promising. Essam said:

"The plasma and intracellular pharmacokinetic data clearly show the overall superior properties of Acelarin compared with the conventional nucleoside analogues being prescribed."

The trial was conducted with patients with advanced cancers who were resistant to their treatment. The results showed a response rate over 80% and low toxicity, with the majority of adverse effects being reversible and tolerable. These qualities, of effectively killing formerly drug-resistant tumours and acting with minimal harm to the patient overall, are highly sought-after in drug development.

Special recognition

There was good interest in the poster from both medical researchers and pharmaceutical companies and the Merit Award meant that Essam's poster was presented in a Poster Highlights session on the first day in which the work is summarised and followed by a Q&A. These presentations select approximately 20 posters of the ~5000 displayed at the meeting in total and are attended by hundreds of leading academics.

The poster presentation was discussed by Professor Alex Adjei (Professor and Chair, Department of Medicine, Roswell Park Cancer Institute) in a short talk entitled "Innovative Targets in Drug Development". (A video of this talk will be available soon).

Essam's major role was in our Mass Spectrometry Suite here at BCI, testing samples from the trial to find out exactly how much Acelarin gets into the patients' cells from their blood plasma using a combination of ultra-high performance liquid chromatography (UHPLC) and mass spectrometry (MS). These techniques have been carefully set up and adjusted to make sure the results are accurate and reproducible and the company has found them indispensible.

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Essam showing visitors around the Mass Spec lab for a Cancer Research UK supporters' tour, Dec. 2013 (Photo by Natalie Mills)

MSc students here at BCI were also instrumental in the preclinical testing stage. Emily Rose Thompson is a co-author on the 2014 publication and will begin her PhD studies in Vancouver this September.

More from BCI at ASCO

During the conference, Essam also presented a poster about another drug success story here at BCI, that of ADI-PEG20. Led by Dr Peter Szlosarek in collaboration with the US-based Polaris Group, this project this project has developed a drug that effectively "starves" tumours by removing a food source – the amino acid L-arginine - they require from the patient's blood - while our normal cells can create it, tumour cells often have defective enzymes in the relevant pathway and cannot.

Dr Szlosarek presented the latest trial data (‘ADAM’) as an oral abstract at ASCO in the Lung Cancer Track session, showing that ADI-PEG20 and best supportive care reduced disease progression in patients with mesothelioma by 50% compared to best supportive care alone. Also, ADI-PEG20 was more effective with greater deficiency of the L-arginine pathway enzyme called argininosuccinate synthetase (or ASS1). Building on this work, Dr Szlosarek’s team have developed a new trial called ‘TRAP’ that will combine ADI-PEG20 with the chemotherapy standard of care in patients with mesothelioma and adenocarcinoma of the lung. The first patient will be recruited in July of this year.

The drug has been found to be effective in a range of other cancer types including prostate cancer, hepatocellular carcinoma, melanoma, and acute myeloid leukaemia (AML). Our Dr David Taussig has been involved in this last project, together with Essam, studying the effects of the drug on blood cancers. The UHPLC/MS techniques have been vital in this project to measure the changes to tumour metabolism after treatment, by looking at compounds present in the patients' blood plasma.

This work has been a "proof of concept" exercise - by understanding how treatments affects the patient's cancer, treatment options can be weighed more carefully. The group has identified potential biomarkers of treatment success, which can inform further successful treatments and, ultimately, cures - where previously no promising options have existed.

Note to Barts Clinical Researchers

If you require pharmacokinetic services for Phase I/IB clinical trials, please contact Dr Essam Ghazaly for more information about our facilities here at BCI.

Many thanks to Dr Ghazaly for his contributions to this story, including images and video.

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