Targeting Ferroptosis and Mitochondrial Pathways in Acute Myeloid Leukemia
Abstract
This project aims at establishing a new therapeutic concept for acute myeloid leukemia (AML), which is categorized in one of the Peer Reviewed Cancer Research Program (PRCRP) Topic Areas: Blood Cancers. AML is a rapidly progressive blood cancer. While subsets of AML are curable, the average 5-year overall survival is only 30%. Particularly in elderly patients or those who relapse, the clinical outcome is dismal, with only 10%-15% 1-year survival, underlining the urgent unmet need in therapeutics for therapy-resistant AML. A shared goal of all cancer researchers is to cure cancer. As therapeutic strategies for eliminating cancers, surgery is to physically remove cancer cells, chemotherapy or radiation damages and kills them (but may also damage normal cells), and immunotherapy is to activate immune cells to selectively kill cancer cells. This project will employ another concept: Let cancer cells die by turning on a particular molecular switch. Scientists term it regulated cell death (RCD). The best-established mode of RCD is apoptosis, and its molecular switch is controlled by BCL2 family proteins. As perhaps the best example, venetoclax is a selective inhibitor of BCL2 protein function, induces cancer-selective apoptosis, and has recently been developed into a breakthrough therapy for AML patients with a very high rate of remissions. However, relapse frequently occurs, and resistance to venetoclax has become a major clinical challenge. A different type of cell death may result in cures of more patients; we therefore propose to therapeutically induce another mode of RCD, ferroptosis, to improve the clinical outcomes of therapy-resistant (apoptosis-resistant) AML patients. The disease target of this project includes two of the most challenging groups of AML patients: (1) AML carrying TP53 gene mutations. The TP53 protein, when it is normal without mutations, functions as a major tumor suppressor gene. However, when mutated, it prevents apoptosis of AML cells induced by anti-leukemia drugs. (2) AML cells that acquired resistance to venetoclax. In contrast to venetoclax-induced or TP53-mediated apoptosis, ferroptosis operates completely different mechanisms, which are known to be iron dependent and related to pores and increased permeability of the cell membranes. Our preliminary data suggest that inducing ferroptosis, by targeting one of the key regulator proteins GPX4, could overcome this therapy-resistance in AML, resulting in longer remissions and perhaps more cures of patients with AML in general, and specifically in those with TP53 mutations and/or resistance to Venetoclax. Of note, not much is known about ferroptosis in AML, and this project therefore breaks new ground. In our Specific Aim 1, we will first establish the clinical and therapeutic relevance of ferroptosis pathways in AML. We will determine the prognostic impact and clinical relevance of mRNA/protein expression of our target, GPX4, and of other ferroptosis-regulating molecules. We will further test if GPX4-mediated ferroptosis is indeed a therapeutic vulnerability of therapy-resistant AML cells and so-called AML stem cells. Leukemia stem cells (LSC) are immature cells that have leukemia-initiating potential and are known to be resistant to standard chemotherapies. Therefore, LSC-targeting ferroptosis induction is one of our goals. As a novel discovery, we found that ferroptosis in AML is largely regulated by the intracellular organelle mitochondria, which is also the place where apoptosis occurs, although through entirely different mechanisms. Mitochondria provide energy to cancer cells, and any major disruption of their function will result in the death of cells harboring damaged mitochondria. Moreover, we discovered that GPX4-mediated ferroptosis induction can induce synergistic leukemia cell kill in combination with venetoclax, even in apoptosis-resistant AMLs. Therefore, we propose to develop the novel concept of th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310736
Entities
People
- Jo Ishizawa
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army