Determining the Predictive Value, Functional Role, and Mechanisms of Action of NUSAP1 in Clear Cell Renal Cell Carcinoma
Abstract
In 2021, kidney cancer will be the sixth most common cancer in men and ninth in women in the United States. Kidney cancer rates are going up and there were 431,288 new kidney cancer cases worldwide in 2020. Renal cell carcinoma (RCC) makes up 95% of kidney malignancies, and among 15 subtypes of RCC with genetic variability and characteristics, a class of cancers referred to as clear cell RCC (ccRCC) is not only the most common form of RCC (80%), but also one of the most deadly. Clear cell RCC accounts for most cases of RCC that spreads elsewhere in the body (metastasis) and, therefore, is the leading cause of RCC deaths. The mortality rates of advanced and metastatic RCC (mRCC) are high, the five-year survival rate is only 10%, and all subtypes of RCC are innately resistant to traditional cancer treatments, such as chemotherapy and radiotherapy. One way to improve outcomes for RCC would be to identify which tumors are aggressive, with risk of metastasis, and treating them intensively as early as possible. For example, a biomarker of aggressiveness could be used to determine whether an incidentally discovered small cancer can be observed or needs immediate surgery. Likewise, cancers determined to be aggressive at the time of surgical removal might be selected for the immediate addition of other treatments, such as targeted therapy or immunotherapy. Finally, genes found to correlate with aggressive features in kidney cancer could lead to the development of new treatments, similar to Her2 in breast cancer, where an antibody-drug (Herceptin) improves survival. Ten years ago, our laboratory discovered that prostate cancers that have high levels of a gene called NUSAP1 behave more aggressively, and we have since shown that this gene can make cells spread more readily. After our discovery, NUSAP1 was found to be a marker of aggressiveness and driver of spread in several other cancers, including those of the brain, breast, liver, and intestines. We have recently found that NUSAP1 works by making cancer cells more primitive, such that they resemble developmental tissues called mesenchyme. In addition, NUSAP1 works with other proteins that are involved in repairing and protecting the cell s DNA. DNA can be vulnerable to damage (mutation) when it is paired up with a string of RNA, a normal phenomenon known as R-loops. We have recently discovered that NUSAP1 binds to two proteins that interact with R-loops in ways that might protect them from damage. If that were the case, high NUSAP1 in cancers might help cancer cells survive when we do not want them to, that is, when we are giving therapies that kill cancer cells by damaging the DNA. We have preliminary data showing that NUSAP1 identifies aggressive kidney cancers, and, therefore, could be a biomarker for aggressive kidney cancers. In this grant, we will further test whether NUSAP1 is a biomarker of aggressiveness in kidney cancer and could be clinically useful. In addition, we will see whether turning NUSAP1 expression up or down will influence whether kidney cancer cells spread using pieces of kidney cancers that have come directly from patients and are grown in mice, a unique system we have developed called patient-derived xenografts. Finally, we will try to understand how NUSAP1 interacts with R-loops in kidney cancers to make them more aggressive. Deepened understanding of the role of NUSAP1 in kidney cancer could improve the selection of patients for aggressive care, and this could be fulfilled by the end of my grant. If NUSAP1 is a driver of the spread of kidney cancer, it could lead to the development of new therapies to block NUSAP1, although that work would be a long-term goal, likely requiring more than 5-10 years, when I am in my faculty job. This proposal will serve as an important training vehicle for me to build on my knowledge of kidney cancer, both in research and clinical care. In addition, it will allow me to develop this new area of investi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210651
Entities
People
- Chun-Lung Chiu
Organizations
- Stanford University
- United States Army