Therapeutic targeting of AML stem cells 2018
Craig Jordan
PhDUniversity of Colorado Denver, Anschutz Medical Campus
Project Term: October 1, 2018 - September 30, 2023
Our SCOR team seeks to fundamentally reinvent the ways in which physicians diagnose and treat acute myeloid leukemia (AML). For over 40 years, AML has been treated with a combination of chemotherapy drugs that have major side effects and usually only provide short-term benefit to patients. Indeed, survival rates for most AML patients are dismal, and quality of life for these patients is poor. Consequently, improved strategies for AML are a huge priority for the field. We believe that the lack of progress against AML is due to a single, fundamental failure of existing therapies: While current therapies attack leukemia cells, they fail to act against the real root of the problem, namely leukemia stem cells. It’s like mowing over weeds in a lawn. If the roots are not removed, the weed (disease) will grow back. And like eradicating the roots of weeds, AML stem cells have proved difficult to treat. This is primarily due to the fact that AML stem cells within a given patient can exist in multiple forms, each of which has a differing response to therapy. In other words, while various drugs can often kill some AML stem cells in a patient, completely eradicating all the AML stem cells can be very difficult.
In this SCOR program, we seek to create therapies that broadly attack what we show to be a common Achilles’ heel of AML stem cells. In order to address these challenges, we have assembled a multidisciplinary team of scientists and physicians. These investigators each have important expertise that will contribute to our goal of killing AML at the root, i.e. the leukemia stem cell population. The main components of the program are:
1) Targeting AML stem cell metabolism: Work by Dr. Craig Jordan has shown that leukemia stem cells depend on a unique method of energy production. This is their Achilles’ heel. The focus of Dr. Jordan’s SCOR project is to develop drugs that kill AML stem cells by blocking their ability to produce energy.
2) Using the immune system to attack AML stem cells: Dr. Terry Fry leads this project, which leverages the newly emerging field of immunotherapy by designing new strategies to teach T cells from an AML patient to specifically target AML stem cells
3) Seed vs. Soil, using the tissue “ecosystem” to suppress AML stem cells: For this highly innovative effort, Drs. James DeGregori and Michael Becker will assess how surrounding tissues (i.e. the “soil”) influence the growth and survival of AML stem cells (i.e. the “seed”). Our investigators will seek to identify new methods that do not damage the tissue “soil” in which AML and healthy stem cells reside. We believe that by making the soil inhospitable for AML stem cells and hospitable for healthy stem cells, we can help to create a tissue ecosystem in which healthy stem cells are able to out-compete their AML rivals.
4) A “Land, Sea, and Air” attack on AML stem cells: This final project will integrate the concepts in projects #1-3 to conduct new clinical trials. We believe that simultaneous use of multiple, different strategies is an important tactic, what we call a “land, sea, and air” attack. These trials will be directed by Drs. Clayton Smith and Daniel Pollyea, leading experts in clinical research for AML. Together, the three projects outlined above, along with personalized combinations of these projects (project 4), represent a completely unique approach to the treatment of AML.
Individually, each component of the SCOR has already demonstrated value towards the care of AML patients, and we believe the outcome of combining these efforts will represent a new paradigm in the treatment for AML.