Targeting the Lin28/let-7 Axis in Acute Myeloid Leukemia
Abstract
Acute myeloid leukemia (AML) is an aggressive, fast-growing blood cancer in which genes in blood-producing stem cells are damaged and, therefore, become abnormally functioning leukemic stem cells (LSCs). These LSCs produce a vast amount of immature white blood cells, so-called myeloblasts. Myeloblasts build up in the bone marrow and blood, thereby leaving less room for healthy blood cells. Despite treatment with aggressive chemotherapy and newer targeted therapies, more than 70% of patients die from AML within 5 years of diagnosis. LSCs are likely the root cause of therapy resistance and treatment failure. Therefore, there is an urgent need to determine strategies by which we can kill LSCs with new, more effective therapies. We have identified a new class of compounds, which inhibit the Lin28 RNA binding protein, which is frequently over-expressed in many cancers, including AML, as a result of genetic damage to blood producing stem cells. The goal of our studies is to (i) determine how Lin28 regulates AML growth and therapy resistance in vivo and (ii) to test new Lin28 inhibitors with improved target specificity and potency. By understanding how Lin28 regulates chemotherapy resistance of LSCs and the identification of novel Lin28 inhibitors with improved specificity and potency, we will obtain important data to accelerate the development of a new targeted therapy for AML and other blood cancers, ultimately leading to increased numbers of cures in patients. Dr. Martina Roos is a translational scientist with a background in cancer, stem cell biology, and drug development. She seeks to be an investigator with an enduring career at the forefront of blood cancer research and to make important contributions to the development of new targeted therapies in AML. This career development award will allow her to establish an innovative blood cancer research program focused on the development of new, more efficient, less toxic therapies for AML. Importantly, this program has high relevance for many other cancers that show similar genetic damages. Dr. Roos will use innovative AML mouse models and patient cells to better understand the mechanisms by which LSCs regulate chemotherapy resistance and to develop a new class of compounds that inhibit these mechanisms. She has outlined a detailed plan to achieve these goals by (1) obtaining expertise and training in translational blood cancer research and its communication, (2) additional coursework to successfully acquire research funding and become an independent investigator, and (3) advance skills needed to present scientific findings and establish a network in the field of translational blood cancer research. Dr. Roos has assembled an interdisciplinary team of clinicians, physician-scientists, and basic researchers to pursue her ultimate goal of developing a new targeted therapy for LSCs. In addition, she will receive guidance from Co-Career Guides Drs. John Chute and Hanna Mikkola. Both are experts in translational research, run successful laboratories devoted to the identification of new therapies for blood cancers, and will provide scientific and career development mentorship. Dr. Roos will leverage her excellent interdisciplinary training, strong preliminary data, a well-conceived career development plan, and fruitful interactions with both her collaborators and Career Guides, to achieve her ultimate goal of pushing boundaries at the forefront of translational blood cancer research. The proposed studies will help to improve blood cancer patients’ lives on multiple levels. First, the proposed research will establish Lin28 as a novel target for AML blood cancer to overcome chemotherapy resistance of LSCs. Second, our innovative studies will yield important knowledge about how a new class of compounds inhibits human AML growth in vivo. Third, we will develop a novel targeted therapy for AML with improved potency, specificity, and safety. The successful completion of the experiments pr
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110924
Entities
People
- Martina Roos
Organizations
- United States Army