Targeting a niche-initiated proinflammatory driver to prevent and treat MDS and AML

The proposed studies will address two major issues in treating two hematological cancers: myelodysplasia (MDS) and acute myeloid leukemia (AML): Lack of new effective treatments for the last 30 years; Identification of stable pathways that can be targeted for personalized treatment.

We have identified a new pathway of communication between stromal cells of the bone marrow and MDS or AML cells. This pathway involves secretion of the inflammatory protein Serum amyloid A1 (SAA1) from bone cells, induces growth of malignant cells with affecting healthy ones, it is detrimental to disease development and progression, and is active in MDS and AML patients, independent of their mutational profile and cytogenetics . This shows that SAA1 is a unifying oncogenic signal that defines a large category of MDS and AML patients across all disease subtypes.

We have developed a robust and simple screening test for identifying the patients who have the pathway active using cells from their bone marrow. Blocking SAA1 in mice treats MDS and AML and prevents lethality without toxicity. We have generated antibodies that block SAA1 activity and can be used in treating MDS and AML patients.

Our purpose is to test efficacy of the most active antibodies in all subtypes of MDS and AML. Our studies will benefit patients by screening and identifying the ones with pathway activity. These patients will be treated with the antibody. This precision medicine approach will increase the success and efficacy of treatment. Targeting an oncogenic signal originating from a non-malignant cell can be a more stable target than targeting MDS and AML cells that gain new mutations and become resistant to conventional treatments.