Moffitt Cancer Center has received a USD 1.66 million National Cancer Institute R01 renewal to investigate a MYC-driven inflammatory pathway as a potential therapeutic target in myelofibrosis, a disease where approved JAK2 inhibitors leave a meaningful subset of patients without durable benefit.
The grant, awarded to principal investigator Seongseok Yun, centers on a MYC-S100A9 signaling axis that the Tampa, Florida-based cancer center's researchers identified as capable of driving myelofibrosis independently of the JAK2, CALR, and MPL mutations targeted by current standard-of-care agents — ruxolitinib, fedratinib, and pacritinib. Moffitt's preclinical work indicated that MYC copy number gain occurs frequently in myelofibrosis patient bone marrow cells and that MYC activation in hematopoietic stem cells is sufficient to provoke disease through upregulation of S100A9, a danger-associated molecular pattern protein implicated in innate immune activation and chronic inflammation. The research program will assess pharmacologic agents targeting this axis, characterize MYC-directed myofibroblast expansion in the bone marrow niche, and examine how the MYC-alarmin circuit interacts with JAK2 pathway mutations.
The translational rationale is clear: approximately 15% of myelofibrosis patients lack canonical JAK2-pathway mutations entirely, and even among those who carry them, JAK2 inhibitor therapy does not eliminate the underlying clone. Median overall survival in myelofibrosis remains under four years, and transformation to acute myeloid leukemia represents a persistent risk. Identifying a JAK-independent oncogenic driver with a pharmacologically tractable target could expand treatment options for patients who respond suboptimally to existing agents. NCI funding of this line of investigation reflects broader interest in alarmin and innate immune biology as therapeutic vulnerabilities across myeloid malignancies.
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