MDS & AML Research Projects
MOON SHOTS PROGRAM
MDS and AML Flagship Projects
By focusing our largest efforts on the approaches that have near-term measurable success, our research projects address the crucial issues facing patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These research efforts are aimed at overcoming resistance to hypomethylating agents (HMAs), developing new cellular therapies to treat AML and enhancing the safety and effectiveness of stem cell transplants and preventing disease relapse.
Uncovering the biological underpinnings of resistance to HMAs and developing more effective therapies
Improving the safety and effectiveness of stem cell transplants and enhancing the immune system to better fight AML
Developing innovative therapies to eliminate minimal residual disease and ensure lasting cures
A central goal of the MDS and AML Moon Shot™ is to prevent and overcome resistance to hypomethylating agents (HMAs). We’re using in-depth molecular analyses to gain a better understanding of the molecular features of MDS and how this disease progresses to AML. With this information in hand, our experts can identify new or alternative drug candidates that can be developed to better treat MDS and AML. Our studies have uncovered three main causes of the drug resistance that develops in response to HMA treatment: molecular rewiring of critical cellular pathways, disordered methylation of genetic sequences and incomplete clearance of primitive MDS hematopoietic stem cells (HSCs).
The Moon Shot™ team has identified several major pathways that contribute to HMA resistance and are examining which of these pathways are the most therapeutically targetable. This investigative strategy, and our powerful cellular models, have enabled the discovery of several signaling pathways that contribute to HMA resistance, including a set of genes involved in cellular metabolism. This finding suggests that targeting cellular metabolism may offer a potential mechanism to overcome resistance. Through a collaboration with the Institute for Applied Cancer Science and Center for Co-Clinical Trials Moon Shot platforms, we’re capitalizing on this new target in a Phase I clinical trial examining whether a drug designed to starve blood cancer cells improves clinical outcomes for AML patients.
Recent evidence suggests that disease relapse and HMA resistance may result from the inability to completely eliminate primitive MDS hematopoietic stem cells (HSCs). These cells likely promote disease maintenance, even upon clinical remission. Our Moon Shot experts are investigating HSC dynamics during HMA treatment in an effort to identify the MDS HSC responsible for resistance and relapse. This information will provide prognostic value and may potentially uncover new therapeutic targets.
In addition to discovering pathways important for resistance to HMAs, we’ve uncovered that HMA therapy doesn’t decrease DNA methylation uniformly throughout the genome. Instead, HMA treatment leads to preferential methylation alterations in specific regions. We’re investigating the mechanism behind this disordered DNA methylation in an effort to identify alternative therapeutic strategies that may overcome this and prevent HMA resistance.
Our Moon Shot researchers are also focused on understanding and preventing therapy-related MDS. We’ve uncovered a cellular pattern of resistance, at the stem cell level, that can be detected prior to a patient’s exposure to chemotherapy or radiation. Through genomic characterization, we’re defining the signatures that can identify the patients who are at risk for developing therapy-related MDS or AML. Additionally, this information will guide the development of therapeutic prevention strategies for such patients.
Allogeneic stem cell transplants (SCTs) can result in complete remission for some MDS and AML patients, but many will suffer from disease relapse. The curative effect of allogeneic SCTs experienced by some patients is largely due to the anti-leukemic activity of specific immune cells, called NK cells and T cells, of the donor. NK cells, in particular, further benefit treatment outcomes by reducing the risk of graft-vs-host disease. We’re capitalizing on the cancer-killing activities of these cells to improve MDS and AML treatment outcomes by co-administering large numbers of pre-activated NK cells during allogeneic SCTs. This strategy has already shown promise in Phase I clinical trials and will continue into Phase II trials soon.
NK cells have natural anti-leukemic activities, but our Moon Shot experts are enhancing these powerful immune cells even further. To enable NK cells to more efficiently target leukemia, we’re engineering these cells to recognize a molecule present on the surface of MDS and AML cells. This strategy has shown promising results in preclinical models, and we hope to soon translate this effort into a Phase I/II clinical trial.
Anti-viral immunity is diminished following allogeneic stem cell transplants, which leads to an increased risk of life threatening infections for patients that receive this treatment. The current anti-viral drug portfolio used to treat these infections is sometimes ineffective and cellular therapy strategies are emerging as a promising alternative. We’re developing pre-activated T cells engineered to specifically detect cytomegalovirus (CMV) and BK virus (BKV) to prevent infections by these two common viruses. With current clinical trials already underway, we’re aiming to expand upon the number of viral infections that can be treated through this treatment strategy.
While bone marrow biopsies may indicate remission, it’s well established that the vast majority of AML patients will relapse. The prognosis for these patients is dismal and hasn’t significantly improved over the last 40 years. Recent evidence suggests that disease relapse may result from the inability to completely eliminate primitive MDS cells, which lead to minimal residual disease. To address this, our Moon Shot team aims to better target minimal residual disease through the development of novel therapies.
The goal of this project is to use molecular analyses and single-cell proteomics to identify the cellular characteristics that can be exploited to eliminate the presence of minimal residual disease, ultimately preventing relapse. Through genetic sequencing techniques, 100 high-risk AML samples will be collected throughout disease progression and analyzed for molecular signatures that are associated with the initiation of relapse. These signatures will be validated by extensive preclinical testing, with the final goal of developing curative therapeutics for AML patients.
STORIES OF HOPE
AML survivor gives back
Ten years cancer-free, Kenneth Woo looks back on his treatment for both Hodgkin's disease and AML at MD Anderson.