The median overall survival of patients with high-risk myelodysplastic syndromes refractory to hypomethylating agents is less than 6 months, and there is, to date, no  standard therapy for for the treatment of patients diagnosed with MDS.

A new study from researchers with Sylvester Comprehensive Cancer Center at the University of Miami Miller School of Medicine and collaborating organizations provides insight into the underlying mechanisms of gene mutations commonly seen in patients with myelodysplastic syndromes (MDS) and other myeloid neoplasms.

Their findings, presented at 65th American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, 2023,could lead to development of more effective drug combinations and targeted therapies for MDS patients carrying these mutations. [1][2]

Genetic alterations
About half of patients diagnosed with MDS carry genetic alterations, known as somatic mutations, in the spliceosome genes, with SF3B1 being the most common one. However, to date there are no successful therapies to target this pathway.

Previous findings from a phase 2 clinical trial of selinexor (also known as KPT-330; Xpovio®; Karyopharm), an Exportin-1 (XPO1) inhibitor for relapsed or refractory MDS, showed increased effectiveness in patients with SF3B1-mutated MDS.

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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.

As an XPO1 inhibitor, selinexor inhibits the export of tumor suppressor proteins and oncoprotein mRNAs, leading to cell-cycle arrest and apoptosis in cancer cells.

Researchers at Sylvester and their collaborators hypothesized that inhibiting XPO1 may preferentially affect SF3B1-mutant cells via altered splicing and that 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:

  • RNA sequencing to evaluate the underlying mechanism for the SF3B1 mutation’s sensitivity to XPO1 inhibitors.
  • Whole genome CRISPR screens in two myeloid leukemia cell lines with eltanexor, a next-generation XPO1 inhibitor with lower toxicity than the drug selinexor. The analyses identified several novel targets that were tested for synergy in combination with eltanexor for the specific SF3B1 mutation. Two drugs were identified for strong synergy with eltanexor: venetoclax and navitoclax.
  • In vitro studies to test combinations identified from the CRISPR screen using cell viability tests and western blots.
  • In vivo studies to further validate these combinations through use of transplant tests in laboratory mice.

XPO1 inhibition
“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,” noted Sana Chaudhry, BS , 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,” explained Justin Taylor, M.D., senior author and a member of the Translational and Clinical Oncology Program at Sylvester.

Taylor also noted that recent data from human studies has shown that venetoclax can overcome the poor prognosis often associated with acute myeloid leukemia patients with mutations.

“As a result, combining eltanexor with venetoclax could represent a potentially effective SF3B1-specific therapy,” he concluded.

Highlight of Prescribing Information
Selinexor (also known as KPT-330; Xpovio®; Karyopharm)[Prescritopn Information]

[1] Chaudhry S, Beckedorff F, Totiger TM, Affer M, Hariramani N, Montoya S, Cornista A, Bilbao D, Roberts ER, Afaghani J, Rodríguez JA, Wang E, Taylor J, (44) Altered RNA Export in SF3B1 Mutants Increases Sensitivity to Nuclear Export Inhibition. Presented during the the 65 annual meeting of the American Society of Hematology (ASH) [Abstract]
[2]  Taylor J, Mi X, Penson AV, Paffenholz SV, Alvarez K, Sigler A, Chung SS, Rampal RK, Park JH, Stein EM, Tallman MS, Sen F, Gönen M, Abdel-Wahab O, Klimek VM. Safety and activity of selinexor in patients with myelodysplastic syndromes or oligoblastic acute myeloid leukaemia refractory to hypomethylating agents: a single-centre, single-arm, phase 2 trial. Lancet Haematol. 2020 Aug;7(8):e566-e574. doi: 10.1016/S2352-3026(20)30209-X. PMID: 32735836; PMCID: PMC9209897.

Featured image: ASH 2022- Photo by © ASH/Nick Agro 2022 – 2023. Used with permission.

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