Improved targeting of leukemia stem cells using advanced genomic strategies.
Acute myeloid leukemia (AML)Abbreviated "AML", this leukemia is an abnormal accumulation of immature myeloid cells, which comprises all white blood cells that are not lymphocytes. The accumulation of abnormal cells prevents the formation of healthy blood cells. Thus, symptoms can include fatigue and abnormal bruising and bleeding.
The standard therapeutic regimen involves treatment with chemotherapeutics that target actively cycling cells by interfering with DNA metabolism, specifically cytarabine (Ara-C) and anthracyclines. While these drugs can eliminate most of the AML cells in a patient, AML is maintained by a rare subpopulation of leukemia stem cells (LSCs)Leukemia stem cells are cancer stem cells in leukemia. As with other cancer stem cells, these cells are capable of regrowing the entire tumor and have been shown to resist chemotherapy.. Standard therapy fails to target leukemia stem cells (LSCs) because these cells remain in a quiescent non-dividing state with reduced DNA synthesis. By surviving chemotherapy, months later the LSCs can regrow the AML, resulting in a relapseThe re-emergence of cancer following treatment. With acute myeloid leukemia, relapse often occurs within 8 months!. This hypothesis is supported by clinical evidence showing that patients who have a higher percentage of LSCs demonstrate worse outcome.
There is a clear need for the development of new therapies to overcome this deadly disease by eliminating LSCs. We therefore use genomic strategies including gene expression profilingGene expression profiling involves measuring the level of all genes expressed in a population of cells. These data are then useful for looking at what genes are turned on and off in a particular disease or in response to a drug perturbation. and genome sequencing to understand LSCs and how they respond when challenged with various drugs. Using these data, we are developing essential blueprints for defining the genes and pathways crucial for ablating LSCs so that we can tailor better drugs and drug combinations. Moreover, we hope to define subsets of patients who are more likely to respond to a particular therapy. As not all complex patterns in genome-scale datasets with thousands or millions of variables are likely to be appreciable to humans, we have successfully used and continue to "train" machine learningThe use of artificial intelligence to learn from examples of data, discover hidden and complex patterns in that data, and search for these patterns in new data. algorithms to recognize important patterns that may lead to a new drug for targeting LSCs. Ultimately, we envision these trained artificial intelligences scouring through public and private datasets, improving hit-to-lead times in drug discovery so that patients can benefit from biomedical research more quickly.
Detailed molecular profiling of leukemia.
We are currently working in collaboration with other investigators in the Leukemia Program at Weill Cornell Medical College to develop a more detailed molecular understanding of LSCs. The ultimate goal is to develop therapeutic targets and state-of-the-art tests that are likely to positively impact patient care in the near term. First, we aim to understand what drives the molecular evolution of AML, eventually leading to relapse and therapy refractory disease. Second, we are developing a molecular map of the pathways that are dysregulated in AML stem, progenitor, and bulk cells toward defining therapeutic targets with greater precision. Third, we are employing next generation sequencing to map the mutations and gene expression changes that give rise to drug resistance and leukemia relapse.
Understanding the emergence of secondary malignancies.
Sometimes, patients who receive treatment for cancers such as breast cancer and multiple myeloma develop secondary malignanciesA cancer or "pre-cancer" such as leukemia or myelodysplastic syndrome arising as a result of the treatment another type of cancer. such as acute myeloid leukemiaAbbreviated "AML", this leukemia is an abnormal accumulation of immature myeloid cells, which comprises all white blood cells that are not lymphocytes. The accumulation of abnormal cells prevents the formation of healthy blood cells. Thus, symptoms can include fatigue and abnormal bruising and bleeding.
Relapse of this leukemia is frequent and survival is poor. Most patients will relapse and die of their disease. However, the specific prognosis for any one patient depends on the particular characteristics of their disease, including cytogenetic features and subtype. The capacity for AML to relapse is thought to be driven by leukemia stem cells.
or myelodysplastic syndrome (MDS)MDS is group of hematopoietic stem cell disorders in which the the formation of mature myeloid cells is impaired. It is considered a form of pre-leukemia as approximately 30% of patients progress to AML. The mechanisms driving the development and progression of secondary malignanciesA cancer or "pre-cancer" such as leukemia or myelodysplastic syndrome arising as a result of the treatment another type of cancer. are poorly understood. Recent advances in genomics allow unprecendented insight into the cellular changes occuring as these processes unfold. We are currently using advanced genomic strategies to develop novel approaches for preventing the emergence of secondary malignanciesA cancer or "pre-cancer" such as leukemia or myelodysplastic syndrome arising as a result of the treatment another type of cancer. and understanding the mechanisms driving this progression.
These publications and commentaries on our work highlight some of our efforts:
[ Highlighted in Inside Blood commentary by Dr. Kimberly Stegmaier ]
[ Highlighted in Inside Blood commentary by Dr. Mickie Bhatia ]
[ Highlighted in Inside Blood commentary by Drs. Tessa Holyoake and Mhairi Copland ]