University of Colorado Denver, Anschutz Medical Campus
Project Term: July 1, 2019 - June 30, 2024
My focus is to develop a program in which novel therapies targeting leukemia stem cells (LSCs) are tested in clinical trials. This is achieved via partnership with laboratory-based colleagues who identify vulnerabilities in LSCs. Once recognized, we find or develop drugs to exploit these weaknesses through clinical trials for acute myeloid leukemia patients. The goal is to bring forward new therapies that result in deep and durable responses, which also have the potential to cure this disease.
This study explores a novel potential use of the drug venetoclax, which was recently FDA-approved for some leukemias, to treat a broad spectrum of acute myeloid leukemia (AML) patients. AML is the most common adult acute leukemia and among the most aggressive of all cancers. Historically, outcomes for AML patients have been very poor. In the last ten years, enormous advances toward understanding the complex biology of this disease have translated into the FDA approval of several new therapies, providing hope for a promising future in which we effectively treat this disease. Stem cells are a small population of cells that are the root cause of the disease. Relapses occur from this reservoir of stem cells because they are typically resistant to traditional chemotherapy. Recent breakthroughs have identified weaknesses in stem cells, suggesting that exploiting these vulnerabilities may lead to a cure. My clinical research program interfaces with leukemia stem cell biology experts, leading to the creation of the first clinical/translational research program wholly focused on eradication of leukemia stem cells in the clinical setting. We have shown that the use of a novel therapy, venetoclax, in AML patients selectively eradicates leukemia stem cells. The way by which venetoclax targets stem cells is exciting; it exploits a weakness in the way they metabolize energy. No therapy has ever been shown to work in this way, and it has nearly limitless implications. My specific goals are to improve and broaden the use of venetoclax and other stem cell-targeting therapies in the clinic. Primarily, we hypothesize that larger doses of venetoclax and careful monitoring of residual disease can lead to even better outcomes for older newly diagnosed AML patients. We also hypothesize that this strategy can be effective for younger patients at the time of diagnosis as well, and if this pilot clinical trial is successful, it could help to usher in the end of traditional intensive, toxic chemotherapy. Finally, venetoclax works comparatively poorly in patients with relapsed AML; we hypothesize that there are unique metabolic weaknesses of relapsed stem cell populations and that the impressive clinical outcomes seen with venetoclax in newly diagnosed patients can also be seen, with a different strategy, in patients with relapsed AML. This research will directly lead to a clinical trial to test our findings and hopefully provide new ways to target AML leukemia stem cells in the clinic.