A new study from researchers with Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and collaborating organisations provides insight into the underlying mechanisms of gene mutations commonly seen in patients with myelodysplastic syndromes (MDS) and other myeloid neoplasms.
Their findings, to be presented at ASH 2023, the American Society of Hematology’s annual meeting in Santa Diego, Dec. 9-12, could lead to development of more effective drug combinations and targeted therapies for MDS patients carrying these mutations.
About half of MDS patients carry genetic alterations, also known as somatic mutations, in the spliceosome genes, with SF3B1 being the most common one.
However, no successful therapy exists to target this pathway.
Previous findings from a phase 2 clinical trial of selinexor, an Exportin-1 (XPO1) inhibitor for relapsed or refractory MDS, showed increased effectiveness in patients with SF3B1-mutated MDS. Exportin-1 is the nuclear export receptor responsible for exporting more than 200 proteins, but also plays a role in transporting multiple small nuclear RNAs and select messenger RNAs.
Sylvester researchers and collaborators hypothesised that 1) inhibiting XPO1 may preferentially affect SF3B1-mutant cells via altered splicing and 2) high-risk MDS patients with this mutation would have a better response to dose-controlled, targeted drug combinations with next- generation XPO1 inhibitors.
For this study, the researchers deployed a combination of scientific techniques in their analysis, including:
Expert Commentary
“This is the first study to examine the effects of XPO1 inhibition on RNA export to better understand the underlying mechanisms involved with the most common mutation seen in MDS patients,” explained Sana Chaudhry, Sylvester researcher and lead presenter at the ASH conference.
“Our study’s findings may contribute to development of synergistic therapeutic combinations to better treat SF3B1-mutant MDS,” said Justin Taylor, M.D., senior author and a member of the Translational and Clinical Oncology Program at Sylvester.
Additionally, Taylor noted, recent data from human studies has shown that venetoclax can overcome the poor prognosis often associated with acute myeloid leukaemia patients with mutations. “As a result, combining eltanexor with venetoclax could represent a potentially effective SF3B1-specific therapy,” he concluded.
Source: ASH
We are an independent charity and are not backed by a large company or society. We raise every penny ourselves to improve the standards of cancer care through education. You can help us continue our work to address inequalities in cancer care by making a donation.
Any donation, however small, contributes directly towards the costs of creating and sharing free oncology education.
Together we can get better outcomes for patients by tackling global inequalities in access to the results of cancer research.
Thank you for your support.