The miR15a/16 Axis and Precision Gene Intervention to Provide a Novel Therapy for Lung Cancer
Abstract
Cancers of the lung are the second most common among men and women, but are the most lethal among both, accounting for roughly 25% of all cancer deaths. While great strides in prevention and treatment have been made (largely due to smoking cessation efforts), the prognosis for those diagnosed with lung cancer remains poor, with a combined 5-year survival rate of only 19%. As such, new and innovative treatments to fight lung cancer are sorely needed. Within every cell in the body is a series of regulatory networks, controlled by a specific set of genes, that govern cell function. Underlying the development of cancer is the disruption of these networks and their related genes, leading to the out-of-control growth characteristic of malignant tumors. A root cause of the changes to these networks, and thus the switch from healthy to cancerous cell, is the loss of tumor suppressing genes. If these cancer suppressing signals are unable to do their job, the cell loses the ability to regulate itself and begins the process of out-of-control growth that is a hallmark of deadly cancers. Much progress has been made in uncovering these networks, revealing the specific genes and signals that act to slow cancer growth. One important group of candidates are small strands of messenger RNA, called microRNA or miRs, that disrupt the expression of numerous genes in the cell. There are literally hundreds of species of these miRs being manufactured in living cells. Two important miRs associated with the progression of cancer are MiR15a and miR16, which together are responsible for shutting down several cancer-promoting pathways. Further, these regulators have been demonstrated to be absent in lung cancer. These facts make the miR15a/16 axis an attractive target for new methods to help combat death and suffering from lung cancer. While many efforts have been made to target the cellular networks that promote cancer growth, advances in the field of genetic editing have brought the field of science close to an exciting potential: direct editing of the cancer cell genome to restore the function of tumor suppressing genes, thus flipping the switch from cancerous back to healthy and abolishing the cancerous state. In particular, the CRISPR/Cas9 platform makes targeted and specific editing of DNA possible, allowing the insertion of specific genes into the genetic code through a process called homology-directed repair. This proposal aims to use CRISPR/Cas9 to insert a functional miR15a/16 gene into the DNA of lung cancer cells, with the goal of restoring the function of this important tumor suppressor and shutting down the growth of aggressive cancer cells. A separate set of experiments will explore the role of miR15a/16 in the initiation and progression of cancer in the hopes of identifying a novel biomarker that will have utility in guiding diagnosis and treatment decisions. In Specific Aim 1, cancer cells will be specifically targeted with a therapeutic treatment capable of editing the cancer cell genome to restore miR15a/16 expression, with the hypothesis that this vector will cause cell-specific reductions in lung cancer cell growth. One of the greatest complexities in cancer treatment is fighting cancer cells without damaging healthy ones. To ensure that only cancer cells are targeted, we will attach to the therapeutic an antibody to a protein that is found on the surface of cancerous, but not on healthy, cells. This will ensure that the therapeutic can only enter malignant cells and will be barred from attacking healthy ones, creating a highly specific vehicle for delivering gene therapy. While the current proposal is targeted toward lung cancer, this platform will be scalable to any cancer expressing unique surface proteins or to deliver any alternate package. In Specific Aim 2, the role of miR15a/16 in cancer initiation in progression in both SCLC and NSCLC will be investigated, with the hypothesis that the loss of m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210988
Entities
People
- James Fluckey
Organizations
- Texas A&M University
- United States Army