Evaluation of Alternative Splicing Regulators as Targets for Selective Therapy of Triple-Negative (Basal) Breast Carcinoma
Abstract
The growth of most breast cancers is promoted by hormones (estrogen, progesterone) or by the epidermal growth factor. This addiction of the tumors to specific growth signals has allowed us to develop highly effective therapies that block hormone (tamoxifen, aromatase inhibitors) or epidermal growth factor (Herceptin) signaling in the tumor cell. However, approximately 20% of breast cancers do not rely on hormone or epidermal growth factors and as a result are resistant to these therapies. This type of cancer, commonly referred to as triple-negative breast cancer, has a higher probability of recurrence and lower rate of survival. The challenge in developing a therapy for triple-negative breast cancer has been to identify the factors that are required for its development and progression. Recently, large-scale genomics research carried out by The Cancer Genome Atlas (TCGA) project has provided an unprecedented insight into the genetic and molecular mechanisms that drive human cancer. By analyzing the data generated by TCGA, we have determined that a process termed alternative splicing may be hijacked in triple-negative breast cancer. Alternative splicing is one of a series of molecular processes that makes proteins following the instruction encoded in our genes. Alternative splicing allows multiple proteins with different functions to be produced from one gene. It generates enormous protein diversity (on average seven different proteins per gene) and is required for the normal function of every cell. We have found that triple-negative tumors produce three proteins, SRPK1, KHDRBS3, and SRSF12, which are not found in other types of breast cancer and normal breast tissue. The main function of these proteins is to control alternative splicing. We also found that the high levels of the SRPK1 protein are associated with high probability of breast cancer recurrence. This has led us to propose that triple-negative breast cancers hijack alternative splicing and rely on it for their growth. The objective of this application is to prove that SRPK1, KHDRBS3, and SRSF12 are required for the growth of triple-negative breast cancer. We also intend to prove that disabling these proteins will stop the progression of this type of cancer. By achieving these objectives, we will directly address the overarching challenge to identify what drives breast cancer growth and determine how to stop it. Importantly, our work will identify specific protein targets for the development of selective therapy for triple-negative cancers. The identification of these target proteins is a critical first step in the development of any therapy. Following the completion of this project, we will move to develop drugs that target the splicing factors on which triple-negative breast cancers rely for their growth. We have extensive experience in the development of compounds that target alternative splicing and have recently identified several such compounds that are potent HIV antivirals. We are confident that once a suitable target is identified, we will be able to develop suitable drug leads. We project that it will take us 3 years to complete the research proposed in this project. We will need another 2 to 3 years to develop the drug leads. Considering that an average drug trial takes approximately 8 to 12 years to complete, it is reasonable to expect that it will likely take 12 to 15 years before our work reaches the clinic. As outlined above, the proposed research will carry out the first basic step in the development of treatment for triple-negative breast cancer. By proving that hijacking of alternative splicing is an integral part of the progression of triple-negative breast cancer, our work will open an avenue for drug development that has not been explored to date. While the clinical application of our work is not immediate, during the course of our research we will identify diagnostic and prognostic markers that in the interim wi
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510349
Entities
People
- Peter Stoilov
Organizations
- United States Army
- West Virginia University