Unearthing Clues to Stop Acute Myeloid Leukemia in MDS
"Notes from the Lab" spotlights innovative work addressing problems in cancer research and care from Columbia investigators, post-docs, fellows, and students.
The Kousteni Lab
We examine the role of the bone marrow microenvironment (or niche) in hematopoietic stem cells, specifically during the development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Our work identifies cell subpopulations in the bone microenvironment and the mechanisms through which they interact with cancer cells to drive the initiation and progression of MDS and AML.
“SAAMIZUMAB: A monoclonal antibody therapy to target the niche and prevent relapse in hematological myeloid malignancies,” recipient of a recent Columbia Life Science Accelerator Pilot award.
The cancer problem we are solving
In the last 50 years, the main approaches for treating myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) have not changed. Patients are mainly treated with standard-of-care chemotherapy. New targeted therapies have been developed from a better understanding of the genetic landscape of MDS and AML that target specific mutations, but they are unfortunately still not effective. Both the standard-of-care chemotherapy and the newer targeted-therapies are not curative and the vast majority of patient’s relapse. Even when achieving complete remission, resistant leukemic clones persist after treatment. Resistant clones lead to disease relapse, which remains the main challenge and highlights the imminent and urgent need for new therapies for MDS and AML. We’ve been working on investigating resistance to therapy, what we call “resistant clones,” cancer cells in MDS and AML that survive standard-of-care treatments.
What we’ve uncovered so far
We have defined the mechanism and means of therapeutic targeting of a novel crosstalk between MDS or AML cells and bone cells. We are deciphering targetable signals that are crucial for MDS and AML pathogenesis, which control how the disease starts as well as its progression and growth. We’re particularly interested in identifying not intrinsic signals (that come from the MDS or AML cells) but from their precursors or initiating cells. In prior work, we’ve discovered signals that originate from sites in the bone marrow microenvironment where MDS and AML cells proliferate. We’ve now identified a novel MDS- and AML-niche crosstalk within the bone as a potential therapeutic target. We found that MDS and AML cells instruct bone-forming cells (osteoblasts) to secrete a protein that maintain and promotes MDS and AML growth. Levels of this protein increase in MDS and AML patients and mark disease progression and transformation of MDS to AML.
Why is this discovery important
We believe that the signal coming from a cell that is not cancerous but promotes cancer growth, is a more stable target. By blocking it, we target the MDS and AML cells, regardless of whether they change, and their precursors, and also the leukemic drug-resistant clones, regardless of their specific mutations before they expand. This approach should be broadly applicable and may be a new effective way to overcome resistance.
We are targeting a cell outside the MDS and AML cell lineage--an osteoblast in the stromal lineage--that provides a growth promoting signal. We investigated an antibody therapy using a mouse model of AML; results from these preliminary studies showed that while the antibody had low efficacy in blocking its target, we still see a significant improvement in survival as well as decreased leukemic cell proliferation and tumor burden in the lab studies.
We are currently in the process of developing an antibody optimized for its specificity and blocking activity to target this specific signaling pathway in MDS and AML in the bone microenvironment.
We’ll be testing several clones of this antibody in our established assays to determine which one has the highest efficacy and strength. We will then test this antibody for its ability to block disease in all our systems--mouse models implanted with patient-derived human samples and cultures of cells from all different types of MDS from our vast MDS patient tissue repository.
Our goal with this research
At least 30% of MDS patients evolve into AML. In the field right now we’re in the dark on why this happens and we’re trying to uncover which MDS patients advance to AML. Our aim is to understand and identify the progression of MDS disease into AML as well as to identify new drug targets to treat patients more successfully, with the goal of being able to prevent the disease itself and its transformation. By targeting signals outside the cancer cells we aim to create a cancer cell independent approach for preventing MDS or AML progression and decreasing relapse.