New preclinical study identifies promising drug combination for blood cancers
Institute of Oncology Research
A collaborative research team from the Institute of Oncology Research (affiliated to USI and member of Bios+), the Dana-Farber Cancer Institute (Harvard Medical School, Boston, USA), and iOnctura (a biotech company based in Amsterdam with subsidiaries in Geneva and Cambridge, MA, USA), has uncovered promising evidence that a novel drug candidate, roginolisib, may enhance the effectiveness of the approved therapy venetoclax in certain hematological malignancies.
The study, supported by Innosuisse, Switzerland’s innovation agency, and the U.S. National Institutes of Health, and now available in Haematologica, sheds light on a potential new combination strategy to treat blood cancers such as diffuse large B-cell lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia (CLL).
Roginolisib (IOA-244) is a next-generation selective PI3Kδ inhibitor with a unique non-ATP-competitive mechanism. Previous attempts to target this pathway have faced clinical setbacks due to toxicity. However, early-phase clinical data and this new preclinical work suggest that roginolisib may offer a more favorable safety profile.
In the study, researchers conducted large-scale pharmacological screenings and identified strong synergy between roginolisib and venetoclax, a BCL2 inhibitor already used for patients affected by several blood cancers. The combination induced potent cancer cell death in a wide panel of lymphoma cell lines and in patient-derived CLL samples, including those resistant to BTK inhibitors.
Mechanistically, roginolisib was shown to enhance venetoclax-induced apoptosis by reducing levels of the anti-apoptotic protein MCL1 and increasing levels of pro-apoptotic BIM—two key regulators of cell survival in lymphoid malignancies.
“These findings offer a rationale to clinically explore roginolisib as part of combination regimens, particularly in patients who have limited options after progression on other targeted therapies.” said co-senior author Prof. Francesco Bertoni, Group Leader of the Lymphoma Genomics Laboratory at the IOR.
Based on these results, a clinical trial evaluating roginolisib in combination with venetoclax and an anti-CD20 antibody has started in patients with relapsed CLL.
The study: https://haematologica.org/article/view/12114
