Targeting Internal Ribosome Entry Site Transacting Factors

Institution: Stanford University
Investigator(s): Mark Pegram, M.D. -
Award Cycle: 2017 (Cycle 23) Grant #: 23IB-0010 Award: $236,225
Award Type: IDEA
Research Priorities
Biology of the Breast Cell>Pathogenesis: understanding the disease

Initial Award Abstract (2017)

Non-technical overview of the research topic and relevance to breast cancer: In order for cells to function and to survive, they have to make proteins. After all, proteins are the “executioners” of all the instructions contained in the genetic code. Indeed, new protein synthesis is THE most energy-consuming function of the cell, particularly in cancer cells, because of their relatively rapid rate of growth compared to normal cells. Breast cancer cells live in a rather hostile environment, called the “tumor microenvironment”. Common characteristics of the breast cancer microenvironment include: acid pH, inflammation, nutrient deprivation, and low oxygen, not to mention exposure to genotoxic stress from chemotherapy and radiation exposure, as well as hormone deprivation – all resulting from common treatment approaches used in the clinic. Moreover, metastatic breast cancer cells must survive in completely different tissue environments outside the breast that are foreign to them. Accordingly, conditions in the breast cancer microenvironment lead to enormous cell stress. Under such stress conditions, the normal mechanism of protein production (called “cap-dependent” protein synthesis) is shut down. So how do breast cancer cells survive -- indeed somehow even manage to thrive with this insult? They shift to an alternate mechanism of protein production called “alternative protein translation” (translation simply means manufacture or building of proteins). This alternative pathway uses structures, called “IRESs”, instead of the “cap” to initiate building of new proteins. Many viruses use this exact same process in order to make new virus proteins during active viral infections. In fact, a number of large drug companies are attempting to identify IRESs as drug targets for new anti-viral drugs. In cancer, a family of newly discovered proteins called “ITAFs” (short for IRES-TransActing Factors) help to orchestrate the whole process of alternative protein translation. And numerous cancer driving proteins (called onco-proteins) have recently been discovered to harbor IRES motifs.

Central hypotheses of the research: The overall goal of this proposal is to examine whether ITAFs, which control the expression of cancer-driving proteins, can be effective drug targets. This proposal specifically examines two ITAFs, one called Interleukin Enhancer Binding Factor 2 (ILF2), the other Splicing Factor Proline/Glutamine Rich (SFPQ).

General methodology: Our laboratory has recently determined that the levels of ILF2 and SFPQ are increased in BC, and that higher levels of these two ITAFs predict poorer overall survival in BC patients. We also plan to elucidate whether or not HER2 has an IRES (particularly for a truncated version of HER2 called p110HER2 that appears to be a bad actor in driving cancer growth, causing drug resistance to drugs like trastuzumab (Herceptin?). Achieving the aims of this proposal will provide critical information by determining the conditions that regulate ITAFs, elucidating their mechanism of action in BC cells, characterizing the effect of targeting ITAFs on BC cells, and for the first time, measuring ITAF levels in clinical BC tumor samples.

Innovative elements and potential impact: Our observation that ITAFs are turned on in BC is an entirely novel line of investigation into breast cancer biology. Our proposed research questions are important to the BC patient and survivor communities because new drug targets that could be exploited can potentially improve long-term clinical outcomes. Understanding of ITAFs’ mechanism(s) of action, and their effect on BC cells, may provide a way to eliminate cancer-driving proteins, potentially leading to a new class of drugs for treating BC. One of the ITAFs (ILF2) to be explored in this research proposal is associated with basal BC, which is usually triple negative, and for which there are very few, if any, effective targeted drug treatments. Basal BC disproportionately afflicts underserved populations, including African Americans and younger women. Following successful completion of this project, a totally new line of investigation in BC will test the possibility that targeting ITAFs could be an important therapeutic advance.