Targeting Chromosome Instability and the cGAS-STING Network in Pediatric Midline Gliomas-K27M Mutant
Abstract
Lay Abstract: This study will focus on the Department of Defense Peer Reviewed Cancer Research Program Focus Area “pediatric brain tumors,” and the militarily relevant risk factors associated with cancer (e.g., ionizing radiation, chemicals, infectious agents, and environmental carcinogens). The collection of diseases known as cancer is the result of cells in our bodies that have lost their ability to control their own proliferation. Instead of these cells remaining within the confines of their respective tissue and only dividing when it is necessary, cancer cells divide uncontrollably. They eventually acquire aggressive characteristics, physically crawling into other tissues in a process called “metastasis.” The underlying questions related to the biogenesis of cancer are: (i) How do cancers acquire changes making them cancerous in the first place, and (ii) how do they acquire subsequent changes that cause their aggressive behaviors? One potential cause for cancer development is mistakes during cell division (going from one cell to two cells) causing re-arrangements of chromosomes. This is called “chromosome instability.” We know that all cells arise from the division of a pre-existing parent cell. This process, called mitosis, involves the precise segregation of pairs of duplicated chromosomes in two cells – two sets of chromosomes are segregated exactly to the two daughter cells; each daughter cell must receive exactly one copy of each chromosome. If there is a mistake in cell division and a cell loses a chromosome, then it will lose the functions of all genes on that chromosome – there is no way for a cell to replace a lost chromosome. Some of those genes may be “tumor suppressors,” which function to prevent cancer. Lose one of these, and the chances of cancer go up. If a daughter cell gains a chromosome, it gains extra copies of those genes, which may promote tumor formation – these are called “oncognenes.” Gain an extra copy of one of these, and the chances cancer go up as well. Examination of pediatric brain tumors has revealed that by the time these have become cancerous, they have imbalanced chromosome numbers, meaning that they have lost or gained whole chromosomes. When a cell gains a chromosome, often that lonely chromosome does not get put in the nucleus, but rather forms its own “micronucleus.” These sit right next to the main nucleus. The problem is that these don t work properly. The membrane surrounding the micronucleus is “leaky,” and the DNA from the chromosomes leaks into the cytoplasm. DNA and cytoplasm do not mix – DNA in the cytoplasm “tells” the cell it has a viral infection (viruses have DNA but no nucleus). The cell responds by activating its immune system to fight of the infection, which is a very good thing. The good news is that when micronuclear DNA leaks into the cytoplasm, it triggers this same immune response, and the immune system attacks the abnormal cell. If this is a tumor cell, then the innate immune system will work to rid the body of this tumor naturally. The bad news is that, like just about everything in cancer, the tumor fights back. It tricks the immune system into thinking it is a normal cell, and we are back to square one. This is where we come in. In this proposal, we will test a drug that activates the innate immune system so it can boost the cell s response to micronuclear DNA, trigger the immune system, and do so in a short time so the tumor does not have time to fight back. We will couple this with another drug that causes a slight increase in chromosome missegregation, creating more micronuclei to boost the immune response as well. The experiments outlined in our proposal are designed to test whether these drugs – alone, in combination with each other, or in combination with radiation therapy – can turn mitotic mistakes into therapeutic vulnerabilities to fight pediatric brain cancers. Importantly, these vulnerabilities are also present in other forms of b
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110546
Entities
People
- Edward Hinchcliffe
Organizations
- United States Army
- University of Minnesota