Innovative Treatments Offer New Hope for Hard-to-Treat Blood Cancers

Researchers from King's College London have unveiled a groundbreaking approach to tackling certain difficult blood cancers by repurposing existing drugs. This novel strategy involves targeting a previously overlooked component of our DNA, known as transposable elements (TEs) or 'junk DNA,' which are now recognized as potential therapeutic targets in cancer treatment.

The study, published in the journal Blood, focused on myelodysplastic syndrome (MDS) and chronic lymphocytic leukemia (CLL). These cancers frequently harbor mutations in two critical genes, ASXL1 and EZH2, which normally regulate gene activity by switching genes on or off. When these genes are damaged, there is a breakdown in the control of cell proliferation, leading to abnormal cell growth.

Most current cancer therapies aim to inhibit harmful proteins produced by faulty genes. However, in cases where these genes are completely inactivated, such as with these mutations, the absence of the target proteins renders many drugs ineffective, leaving patients with limited options.

Interestingly, the researchers discovered that in cancers with mutated ASXL1 and EZH2, TEs become overly active. This overactivity exerts stress on cancer cells and damages their DNA, creating vulnerabilities that can be exploited for treatment.

One promising approach involves PARP inhibitors, drugs already used in treating some other cancers. While their traditional role involves preventing cancer cells from repairing DNA damage, the researchers found an alternative mechanism in these cases. When TEs move within the genome, they cause DNA breaks that are usually repaired by PARP proteins. Blocking PARP proteins with inhibitors prevents this repair, leading to accumulation of DNA damage and ultimately causing cancer cell death.

Further experiments demonstrated that blocking TEs using reverse transcriptase inhibitors neutralized the effects of PARP inhibitors, confirming that the therapeutic mechanism is linked to TE activity rather than the drugs' conventional pathways. This discovery suggests a new way to use existing drugs against blood cancers with specific genetic mutations.

Professor Chi Wai Eric So from King's College London emphasized the significance of this finding, stating, "This discovery offers new hope for patients with these challenging cancers by repurposing existing drugs and turning previously considered 'junk DNA' into a powerful target for therapy." Although the research primarily focused on MDS and CLL, the insights gained could extend to other cancers with similar genetic alterations, potentially broadening the scope of PARP inhibitor use in oncology.

This research underscores the potential of leveraging the activity of transposable elements to develop innovative treatments for cancers that are currently difficult to manage, providing a promising avenue for future therapeutics.