Dissecting the Role of PPM1D in Leukemia Development and Treatment Resistance
Abstract
Over the past few decades, we have made great strides in our ability to prevent, diagnose, and treat a wide array of cancers. As a result, outcomes for individuals with cancer have significantly improved, resulting in fewer side-effects from treatment, longer survival, and more cures. In parallel, our scientific understanding of how cancers develop, grow, and spread have accelerated tremendously, in large part due to advances in the technologies we utilize to study these diseases. However, there are many cancers in which neither treatment options nor patient outcomes have meaningfully improved, and patient outcomes remain very poor. Blood cancers vary by the type of blood cell from which they arise, the types of treatments utilized, and the expected success of these therapies. Two types of blood cancers, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), remain highly lethal diseases. MDS and AML that occur in individuals who have been previously exposed to chemotherapy or radiation for the treatment of another cancer are referred to as therapy related. MDS or AML can also arise from environmental exposures such as ionizing radiation. Unfortunately, therapy-related MDS and AML are particularly resistant to treatment and carry an average life expectancy of less than one year. Thus, new prevention and treatment options are desperately needed. We have previously shown that a gene called PPM1D is often altered in the blood cells of people who have been exposed to chemotherapy and radiation. As a result, PPM1D is often altered in individuals with therapy-related MDS and AML. In our prior and preliminary work, we found that this alteration in PPM1D causes it to protect cancer cells from chemotherapy and radiation, thereby allowing cancer cells to become more resistant to subsequent treatments. The goal of this proposal is to better understand how PPM1D influences the ability of normal blood cells to become cancerous and how PPM1D causes these cancer cells to become resistant to therapy. We seek to utilize these biological insights to improve the outcomes of patients with therapy-related MDS and AML by identifying treatments that may be more effective and by discovering new approaches to prevent and treat these diseases. To achieve these goals, we have proposed three main experimental approaches. In Aim 1, we will utilize two new mouse models that we have developed, which allow us to control the levels of PPM1D in blood cells. Using these mice, we will determine how PPM1D impacts the ability of normal blood cells to become cancerous and study differences between cancer cells that have a normal version of PPM1D from those that have an altered version. In Aim 2, we will assess the ability of various classes of chemotherapies to kill leukemia cells, with the goal of finding the therapies rendered least effective by PPM1D. We will then test whether blocking PPM1D with an inhibitor drug reverses the protective effect of PPM1D and causes leukemia cells to become more sensitive to these chemotherapies. Finally, in Aim 3 we will use genetic tools to study exactly how PPM1D causes cells to be resistant to chemotherapies and investigate how a therapeutic strategy to inhibit PPM1D could be influenced by other genes in the leukemia cells. This work is highly aligned with the Topic Areas (blood cancers), health Focus Areas (environmental factors that cause cancer and mission readiness), and Overarching Challenges (prevention and therapeutics) of the Department of Defense’ Peer Reviewed Cancer Research Program (PRCRP). Our study of blood cancers seeks to understand how they develop (new prevention strategies) and become treatment resistant (new therapeutic approaches). Achieving both could improve mission readiness by limiting time in hospital and decreasing relapses. Moreover, active members of the Armed Forces and Veterans are at an increased risk of developing therapy-related AML and MDS for two r
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310646
Entities
People
- Peter Miller
Organizations
- Massachusetts General Hospital
- United States Army