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Irish research breakthrough on leukaemia

While leukaemia is considered one of the rarer cancers, research in this disease has been among the most productive of all cancer research. Virtually all of the major advances in cancer were first made in blood-related cancers, and subsequently transferred to other diseases, researchers in UCC point out. For example, the first chemotherapy was developed in leukaemia patients. The main reason that leukaemia has been so productive for scientific discovery is that the blood provides great flexibility for researchers, they say. Blood cells can easily be obtained from patients, and continue to be studied once outside the body. Cancerous blood cells can be drawn regularly from a patient receiving treatment with very little pain to the patient.

A molecule developed by scientists at UCC, derived from the berries of the Bloodhorn tree, has shown “a very significant reduction in tumour size”, particularly leukaemia cancer cells. The findings were published last month in the journal Investigational New Drugs.

After discovering the novel compound reduced leukaemia tumours by up to 70 per cent in mice, the next stage in the research will be to seek funding to see if the compound will kill leukaemia cells in human patients.

“The study outlines a very significant reduction in tumour size by a molecule developed in my group in the Department of Chemistry and the Analytical and Biological Chemistry Research Facility at UCC,” explained Dr Florence McCarthy, who leads a team of researchers in medicinal and pharmaceutical chemistry at UCC.

McCarthy’s research group is funded by the Irish Research Council, with the research also funded in part by the Programme for Research in Third Level Institutions (PRTLI), Cancer Research Ireland and Waters Ireland.

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Dr McCarthy’s team partnered with the National Cancer Institute in the US, where “the molecule showed promise against leukaemia cancer cells over other cancers,” before joining forces with Prof Tom Cotter, Chair of Biochemistry at UCC, to “identify if our molecule could in fact become a marketed drug and their work enabled us to see how the drug was killing cancer cells”.

The collaboration between the pair started “purely by chance”, Prof Cotter said, after meeting at a PR event in the Tyndall Institute and their joint venture developed from there.

With funding primarily from the Children’s Leukaemia Research Project and the Irish Cancer Society, they set up a study to see how effective the molecule might be in killing cancer cells.

“The fact that Tom ran across campus to deliver the results to me, rather than use the cursory email, indicated the significance of our findings. Our plan is now to see if other drugs can be accessorised in the same way and develop our drug to further improve the cancer-killing effect,” Dr McCarthy commented.

Prof Cotter added: “We targeted acute [myeloid] leukaemia [AML], which is a difficult-to-treat cancer, and to be honest I didn’t expect the experiments to work as well as they did. In fact, I was so surprised with the results I kept looking at them for ages; I couldn’t really believe what I was seeing.”

Dr McCarthy pointed out that the prognosis for AML patients is currently “not very good” (five-year survival is approximately 20 per cent, on average across all ages), and the research has “huge potential for future treatment”.

Cutting-edge

The molecule at the centre of the Cork research is derived from an ellipticine, which has been isolated from the berries of the Ochrosia Elliptica tree, commonly called the Bloodhorn tree due to the shape and colour of the berries, which grows on the north east coast of Australia and in the rainforests of Brazil, Dr McCarthy explained.

Ellipticine was first isolated from the leaf of Ochrosia elliptica Labill in 1959, and was found to display strong anti-cancer activity. However, ellipticine’s use is limited, as only a small fraction of the drug enters the blood. Making a small structural change to ellipticine rectifies this problem. The modified ellipticine is called isoellipticine.

The work in UCC has “taken the natural product and restyled it with unique features to improve the potency and solubility. What is truly exceptional is that these features are not common in drugs and so we aim to exploit this fully. There is also significant potential to apply this approach to other drugs in a similar fashion,” Dr McCarthy said.

Natural products are “an excellent source to look at when looking for a new target that could be used in medicine”,  he added.

Speaking to the Medical Independent, Dr McCarthy expressed excitement about how successful the mouse model trial results were. “But even more exciting beyond that was after 25 days treatment, the mouse showed no adverse effects or toxicity that you would expect from a standard anti-cancer therapeutic agent. We’ve just published the results now and are looking for funding for the next level, to bring testing to real-life patients.”

Dr McCarthy said there was no reason human sample testing could not be carried out in Cork. The research to date “showcases the facilities and expertise we have,” he commented.

Leukaemia: Clinical subtypes and definition

Leukaemia describes a number of diseases of differing aetiology and clinical course. The four main subtypes are chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), acute lymphocytic leukaemia (ALL) and acute myeloid leukaemia (AML).

The commonest of these (about 40 per cent of all cases) is CLL, according to the National Cancer Registry Ireland (NCRI).

All leukaemias combined form the 10th-most common cancer in Ireland, accounting for 2.4 per cent of all malignant neoplasms, excluding non-melanoma skin cancer, in women and 3.2 per cent in men.

There are over 400 cases diagnosed annually in men and it is more common in male patients.

 

Irish data on myeloproliferative neoplasms (MPN) and myelodysplastic syndromes 

Earlier this year, the NCRI published the latest cancer trends report on the incidence, treatment and survival for myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS) in Ireland. These are categories of haematological malignancy that largely comprise conditions that, before about the year 2000, were not considered full malignancies but are now recognised as such.

MPN are characterised by proliferation of one or more myeloid cell lineages, predominantly in the bone marrow. This results in increased numbers of normal granulocytes (granular white blood cells), erythrocytes (red blood cells) or platelets in peripheral blood.

MDS are characterised by cytopaenia, and dysplasia in one or more of the major myeloid cell lines). MDS are the most common precursors of leukaemia.

On average, 153 cases of MPN were diagnosed per year in Ireland during 1994-2012, or 124 cases if CML is excluded. The most common subtypes of MPN were chronic myeloproliferative disease of unspecified type, polycythaemia vera, essential thrombocythaemia and CML.

MDS cases (mainly unspecified subtype and refractory anaemias) averaged 112 per year over the same period. Among MDS, myelodysplastic syndrome, NOS (83 cases per year) was the most common diagnosis. The most frequent morphological subtypes in the MPN group were chronic myeloproliferative disease,

Trends in MPN are unclear (some increase but not significant overall), according to the report, while MDS showed a significant increase between 1994 and 2012.

However, the report suggests these trends may, in part, reflect underdiagnosis or under-registration in earlier years. Variation in diagnosis or registration of these conditions also complicates international comparisons of incidence of these conditions, and true geographic variation within Europe is not clear from published figures, the document adds.

Treatment

For patients with MPN, 48 per cent received tumour-directed treatment in the most recent diagnosis period (2006-2012), or 41 per cent of patients with MPN other than chronic myeloid leukaemia. Treatment mainly involved chemotherapy or immunotherapy.

Tumour-directed treatments for these diseases (excluding symptom-treating procedures) mainly involve chemotherapy or immunotherapy, but only a minority of patients had such treatment within the first year after diagnosis: 48 per cent of MPN cases, 41 per cent of MPN excluding CML cases, and only 16 per cent of MDS cases, during 2006-2012. For some patients, treatment may not begin until later disease progression (‘watchful waiting’). Five-year net survival was high for MPN (average 79 per cent for cases diagnosed 2006-2011) but was much poorer for MDS (55 per cent for 2006-2011).

Survival

On the positive side, survival for both groups has improved in recent years, the report notes.

For MPN, five-year net survival averaged 79 per cent in the most recent period, both overall and if CML is excluded. Survival for MPN as a whole, and haematological malignancies as a whole, improved significantly between all successive diagnosis periods (based on statistical models adjusted for age and length of follow-up, the report noted).

Survival for MPN excluding CML showed no significant change between 1994-1999 and 2000-2005, but improved significantly in 2006-2011. Survival from MPN was higher than the average for all haematological malignancies (five-year net survival 62 per cent, 2006-2011).

For MDS, five-year net survival averaged 55 per cent in the most recent period (2006-2011), lower than for haematological malignancies as a whole. There was no significant improvement in survival between 1994-1999 and 2000-2005, but survival of 2006-2011 cases was significantly improved, the report said.

For more information go to www.nrci.ie

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