Since first establishing my independent laboratory in 1997, my research has been focused on characterization and targeting of leukemia stem cells (LSCs). In leukemia, like many forms of cancer, a small subset of so-called “cancer stem cells” are thought to be key drivers of pathogenesis and relapse. While therapies that reduce bulk tumor have been devised for many forms of cancer, effective eradication of cancer stem cells is more challenging, and represents an important goal towards improved therapies. In the most prevalent forms of adult acute leukemia, long-term survival rates are only ~20%, hence, better therapies are urgently needed.
My laboratory was the first to describe properties of human LSCs that are relevant to therapeutic targeting.(1,2) These observations have led to multiple clinical trials using antibodies, small molecules and cell-based immunotherapies designed to target the biological properties first reported from our studies. Our research was also the first to describe a drug regimen specifically designed to target LSCs in patients.(3)
Building on our initial basic science studies, in subsequent years we developed drug screening and identification methods to identify improved therapeutic agents to target LSCs. We were the first group to report a single agent (known as parthenolide) capable of selectively eradicating LSCs.(4) We subsequently collaborated with a leading medicinal chemistry group to develop a candidate clinical compound that was based on parthenolide.(5) That agent, known as DMAPT is currently being tested in a phase I clinical trial.
In parallel to our efforts to develop novel drugs, we have also generated new methods for drug characterization and new strategies to identify the most basic molecular properties of leukemia stem cells.(6,7) Intriguingly, in recent studies we have identified a distinct subpopulation of LSCs characterized by unique metabolic properties.(8) This discovery has led to a new therapeutic strategy for targeting LSCs based on pharmacological inhibition of Bcl-2, a concept that we will begin testing in clinical trials in the near future.
- Jordan, C. T., Upchurch, D., Szilvassy, S. J., Guzman, M. L., Howard, D. S., Pettigrew, A. L., Meyerrose, T., Rossi, R., Grimes, B., Rizzieri, D. A., Luger, S. M., and Phillips, G. L. (2000) The interleukin-3 receptor alpha chain is a unique marker for human acute myelogenous leukemia stem cells. Leukemia 14, 1777-1784.
- Guzman, M. L., Neering, S. J., Upchurch, D., Grimes, B., Howard, D. S., Rizzieri, D. A., Luger, S. M., and Jordan, C. T. (2001) Nuclear factor-kappaB is constitutively activated in primitive human acute myelogenous leukemia cells. Blood 98, 2301-2307.
- Guzman, M. L., Swiderski, C. F., Howard, D. S., Grimes, B. A., Rossi, R. M., Szilvassy, S. J., and Jordan, C. T. (2002) Preferential induction of apoptosis for primary human leukemic stem cells. Proceedings of the National Academy of Sciences of the United States of America 99, 16220-16225
- Guzman, M. L., Rossi, R. M., Karnischky, L., Li, X., Peterson, D. R., Howard, D. S., and Jordan, C. T. (2005) The sesquiterpene lactone parthenolide induces apoptosis of human acute myelogenous leukemia stem and progenitor cells. Blood
- Guzman, M. L., Rossi, R. M., Neelakantan, S., Li, X., Corbett, C. A., Hassane, D. C., Becker, M. W., Bennett, J. M., Sullivan, E., Lachowicz, J. L., Vaughan, A., Sweeney, C. J., Matthews, W., Carroll, M., Liesveld, J. L., Crooks, P. A., and Jordan, C. T. (2007) An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood 110, 4427-4435
- Hassane, D. C., Guzman, M. L., Corbett, C., Li, X., Abboud, R., Young, F., Liesveld, J. L., Carroll, M., and Jordan, C. T. (2008) Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data. Blood
- Ashton, J. M., Balys, M., Neering, S. J., Hassane, D. C., Cowley, G., Root, D. E., Miller, P. G., Ebert, B. L., McMurray, H. R., Land, H., and Jordan, C. T. (2012) Gene sets identified with oncogene cooperativity analysis regulate in vivo growth and survival of leukemia stem cells. Cell Stem Cell 11, 359-372
- Lagadinou, E. D., Sach, A., Callahan, K., Rossi, R. M., Neering, S. J., Minhajuddin, M., Ashton, J. M., Pei, S., Grose, V., O'Dwyer, K. M., Liesveld, J. L., Brookes, P. S., Becker, M. W., and Jordan, C. T. (2013) BCL-2 inhibition targets oxidative phosphorylation and selectively eradicates quiescent human leukemia stem cells. Cell Stem Cell 12, 329-341