Investigation into the Mechanisms of Acute Myeloid Leukemia (AML) Tumorigenesis and Chemoresistance via Systems Analysis of Mitochondrial Form and Function
Abstract
The present application aligns with the FY18 PRCRP Military Relevance Focus Area: Blood Cancer. While the proposed work specifically focuses on blood cancer, experimental findings from this work will likely have broad relevance to most all types of cancer. Unlike solid tumors, which can at times be removed through surgical intervention, cancer of the blood is primarily treated using various small-molecule drugs referred to as chemotherapeutics. The main drawback of these drugs is that, in addition to killing cancer cells, they often also promote the death of non-cancerous cells, including red blood cells and cells of the immune system. In addition to these "off-target" toxic effects, cancer cells often develop resistance to the commonly used therapeutics, preventing the surviving cancer cells from being treated with the currently available chemotherapeutics. The present application aims to lay the foundation for the eventual development of new chemotherapeutics that are better able to kill only cancer cells. This requires scientific experiments that can pinpoint unique characteristics of cancer cells. Previous studies have shown that the metabolism of the cancer cell is fundamentally different from non-cancerous cells. That said, the scientific community has not yet discovered what causes these metabolic differences. The present proposal hypothesizes that metabolic differences between cancer and noncancer originate within the energy-producing organelle of the cell referred to as the mitochondrion. Therefore, this proposal plans to investigate differences in these energy-producing organelles in both cancer and noncancer to diagnose the unique features of cancer mitochondria. Once these distinguishing characteristics of cancer cell mitochondria are identified, it becomes possible to design new drugs that target only these features. The benefit of this approach is that these new mitochondrial-targeted drugs will lead to the death of only cancer cells and therefore eliminate much of the secondary toxicity typically observed with chemotherapy. Although the development of new drugs for the clinic does take considerable time, identifying cancer-specific drug targets is the necessary first step. The short-term goal of this application is to identify these cancer-specific drug targets such that in the long-term, patients diagnosed with blood cancer can be afforded better, more targeted therapies that have considerably fewer harmful side effects. The work described herein has considerable relevance to both current and former military service members are as these individuals are at an increased risk for developing blood cancer due to increased exposure to various carcinogens during active service.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jul 16, 2019
- Source ID
- W81XWH1910213
Entities
People
- Kelsey H Fisher-Wellman
Organizations
- East Carolina University
- United States Army