An active ingredient in eye drops that were being developed for the treatment of a form of eye disease has shown promise for treating an aggressive form of blood cancer. Scientists have found that this compound, which targets an essential cancer gene, could kill leukaemia cells without harming non-leukemic blood cells. The results, published in Nature Communications reveal a potential new treatment approach for an aggressive blood cancer with a poor prognosis.
Acute myeloid leukaemia (AML) is a form of blood cancer that affects people of all ages, often requiring months of intensive chemotherapy and prolonged hospital admissions. It develops in cells in the bone marrow crowding out the healthy cells, in turn leading to life-threatening infections and bleeding.
Mainstream AML treatments have remained unchanged for over thirty years, with the current treatment being chemotherapy, and the majority of people's cancer cannot be cured. A subtype of AML, driven by rearrangements in the MLL gene has a particularly bad prognosis.
In a previous study, researchers developed an approach, based on CRISPR gene editing technology, which helped them identify more than 400 genes as possible therapeutic targets for different subtypes of AML. One of the genes, SRPK1, was found to be essential for the growth of MLL-rearranged AML. SRPK1 is involved in a process called RNA splicing, which prepares RNA for translation into proteins, the molecules that conduct the majority of normal cellular processes, including growth and proliferation.
In a new study, researchers set out to work out how inhibition of SRPK1 can kill AML cells and whether it has therapeutic potential in this disease. They first showed that genetic disruption of SRPK1 stopped the growth of MLL-rearranged AML cells and then went on to study the compound SPHINX31, an inhibitor of SRPK1, which was being used to develop an eye drop treatment for retinal neovascular disease - the growth of new blood vessels on the retinal surface that bleed spontaneously and cause vision loss.
The team found that the compound strongly inhibited the growth of several MLL-rearranged AML cell lines, but did not inhibit the growth of normal blood stem cells. They then transplanted patient-derived human AML cells into immunocompromised mice and treated them with the compound. Strikingly, the growth of AML cells was strongly inhibited and the mice did not show any noticeable side effects.
SRPK1 controls the splicing* of RNA in the production of new proteins. An example of a gene that is affected when SRPK1 is blocked is BRD4, a well-known gene that maintains AML. Inhibiting SRPK1 causes the main form of BRD4 to switch short form to long form, a change that is detrimental to AML growth. This was associated with BRD4 eviction from genomic loci involved in leukemogenesis including BCL2 and MYC. The authors go on to show that this switch mediates at least part of the anti-leukemic effects of SRPK1 inhibition.