Inhibition of osteoblast activity to treat acute myeloid leukemia (AML) and myelodysplasia (MD)

This technology is the identification of an oncometabolic axis involving the immune activation of osteoblasts and the proliferation of AML cells via kynurenine and serum amyloid A (SAA).

Unmet Need: Therapeutic treatment for AML and MD microenvironment

Available acute myeloid leukemia treatments focus on targeting the tumor, which can lead to side effects in elderly patients and the emergence of therapy-resistant leukemic clones. Oncometabolism, the production of self-augmentative metabolites by cancer cells, employs the tumor microenvironment to sustain themselves. Therefore, patients need a treatment specifically targeting the tumor microenvironment that blunts leukemia progression.

The Technology: Targeting osteoblast-leukemia crosstalk to treat AML and MD

This technology elucidates kynurenine and SAA as two main components in this molecular network of leukemia proliferation. Kynurenine is produced by AML cells which induce osteoblasts into a pro-inflammatory state, resulting in the production of SAA to increase production of kynurenine in a feed-forward mechanism. Overproduction of kynurenine amplifies this effect and enhances AML proliferation. Inhibition of this axis decreases leukemia burden on the microenvironment and overall progression of the disease.

This technology has been validated in mouse models of AML.

Applications:

• Treatment for acute myeloid leukemia or combination therapy with chemo/immunotherapies
• Research tool for studying myeloid differentiation, bone marrow, and osteoblast-leukemia crosstalk
• Treatment candidate for SAA-mediated amyloidosis
• Biomarker to track disease development and progression in patients

Advantages:

• Targets the tumor microenvironment
• Directly targets proliferative capacity of tumor cells
• Can be combined with existing therapies
• Allows for development of many therapeutic types to target this pathway

Lead Inventor:

Stavroula Kousteni, Ph.D.

Patent Information:

Patent Pending

Related Publications:

• Galán-Díez M, Borot F, Ali AM, Zhao J, Gil-Iturbe E, Shan X, Luo N, Liu Y, Huang XP, Bisikirska B, Labella R, Kurland I, Roth BL, Quick M, Mukherjee S, Rabadán R, Carroll M, Raza A, Kousteni S. “Subversion of serotonin receptor signaling in osteoblasts by kynurenine drives acute myeloid leukemia” Cancer Discov. 2022 Apr 1; 12(4): 1106-1127.

• Luo N, Mosialou I, Capulli M, Bisikirska B, Lin CS, Huang YY, Shyu PT, Guo XE, Economides A, Mann JJ, Kousteni S. “A neuronal action of sirtuin 1 suppresses bone mass in young and aging mice” J Clin Invest. 2022 Oct 4; e152868.

Tech Ventures Reference:

• IR 21282, 21283

• Licensing Contact: Jerry Kokoshka