The University of Texas MD Anderson Cancer Center
Project Term: July 1, 2018 - June 30, 2023
In previous studies of recurrently amplified 1q21 genes in myeloma, we identified ILF2 as a modulator of the DNA repair pathway, which promotes adaptive responses to genotoxic stress. Thus, ILF2 may have clinical utility as a biomarker of aggressive myeloma and blocking the ILF2-mediated repair signaling may enhance the effectiveness of current DNA-damaging agent-based therapies. We are seeking to determine the feasibility of therapeutically targeting ILF2 with antisense nucleotides and identify DNA repair effectors whose loss of function induces synthetic lethality in ILF2-depleted myeloma.
Multiple myeloma (MM) is a cancer of a type of immune cells called plasma cells, which are mature B cells that constitute the second most commonly diagnosed blood-related tumor. New drugs introduced in recent years have doubled survival in standard-risk patients; however, high-risk patients survive only 2-3 years. While 20% of newly diagnosed patients are high-risk, this number increases dramatically as patients relapse. The vast majority of patients relapse, and average survival is a dismal 9 months. Genes are contained within large structures of proteins and DNA called chromosomes. Chromosomes often undergo changes that are associated with cancer. One change is the amplification of chromosomal regions, which increases the levels of certain oncogenic proteins, thereby contributing to the formation and maintenance of the cancer. A region of one chromosome called 1q21 is amplified in some MM patients, and it defines one of the most high-risk MM subtypes associated with resistance to therapy and a poor prognosis. Using a genetic screen, I have identified 5 genes within 1q21 that are likely the most essential genes for MM pathophysiology. One gene, called interleukin enhancer binding factor 2 (ILF2), makes MM cells less responsive to chemotherapy when it is present in extra copies, which may explain why 1q21 MM patients benefit less from chemotherapy than non–1q21 MM patients. I am currently extending these studies to the other 4 candidate genes by reducing their expression in MM cells to see if that reduces MM survival, and I will further see if any effect can be enhanced by the simultaneous application of MM drugs. I will also overexpress these genes in mouse models to determine their role in tumor formation and to see if they collaborate with other oncogenes to form MM. Lastly, I am partnering with IONIS Pharmaceuticals to develop a novel therapeutic approach using molecules called antisense oligonucleotides. These molecules are expected to reduce the level of ILF2, and I will functionally validate their effectiveness, both alone and in combination with chemotherapy, in inhibiting the growth of MM cells in preclinical mouse models of high-risk MM. This research will expand our understanding of the contribution of 1q21 genes to MM development and will inform the development of new approaches to improve the outcomes of MM patients who have high-risk disease that is not responsive to current therapeutic agents.