Cotargeting the lncRNA-PIP3 Interaction and AKT/PI3K Signaling Axis: A Novel Paradigm for Treating Triple-Negative Breast Cancer
Abstract
Breast cancer, which is the second most common cancer worldwide after lung cancer, remains a serious healthcare problem despite improvements in early detection and treatment. The global burden of breast cancer exceeds that of all other cancers and incidence rates of breast cancer are only increasing. Breast cancer, especially the subtype that lacks expression of the estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2), and progesterone receptor (PR), commonly referred to as triple-negative breast cancer (TNBC), is more likely to be resistant to standard chemotherapy regimens and targeted therapies. Inhibitors that target the PI3K pathway have the potential to be effective anticancer agents and, as such, are being developed at a rapid pace. However, previous experience with targeted therapies of the PI3K pathway predicts that despite the initial favorable response, most cases experience relapse due to the acquisition of drug resistance. With the advent of contemporary global technologies, it has been made known that the majority of our genome is actually transcribed as long noncoding transcripts, also called long noncoding RNAs (lncRNAs). Notably, lncRNAs are often aberrantly expressed in a broad spectrum of cancers, including breast cancer, and play a key role in promoting and maintaining cancer cell characteristics; thus, these molecules are gaining attention as attractive therapeutic targets. In our examination of two TNBC tissues, we have identified a long noncoding RNA, called LINK-A, which is commonly overexpressed in TNBC; LINK-A regulates AKT/PI3K signaling through its physical interaction with PIP3. Our preliminary data also indicate that levels of LINK-A expression are correlated with breast cancer aggressiveness and potential to metastasize. In this proposal, we want to generate a lncRNA-based therapy by using a variety of biochemical, molecular, and cell-based assays as well as a breast cancer xenograft mice model. Additionally, we would like to determine the preclinical benefit of circumventing resistance to AKT/PI3K pathway inhibitors by simultaneous use of locked nucleic acid (LNA)-based antisense oligonucleotide (ASO) against LINK-A with classical AKT/PI3K pathway inhibitors. We believe that this study has clinical relevance, especially with regard to the treatment of breast cancer, and would, upon successful completion of our aims, foreseeably provide patients with metastatic TNBC access to the proposed treatment within the next 5 years and would be available to early stage patients, by clinical trial, within the next 7 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610289
Entities
People
- Liuqing Yang
Organizations
- United States Army
- University of Texas at Austin