Targeting Metastatic Breast Cancer with Copper Trap Assembled In Situ
Abstract
Breast cancer is one of the most frequently diagnosed cancers worldwide and remains the leading cause of cancer death among women. An estimated 90% of cancer-related deaths are due to metastasis, with the compelling fact that no cure is available once the metastatic disease occurs. The initiation and progression of breast cancer metastasis is strongly correlated with the tumor microenvironment. Increased influx of copper in the microenvironment is believed to trigger the upregulation of multiple pro-tumorigenesis factors. Striking evidence comes from a recent Phase II clinical trial. The report showed that the administration of a copper-depleting drug, tetrathiomolybdate, significantly prolonged the median survival of stage IV triple-negative breast cancer patients from a few months to over 8 years. This project thus aims at the design and construct of an effective copper-depleting molecular framework (CDMF). It will be activated by enzymes that are abundantly expressed in triple-negative breast cancer with high selectivity and specificity. Once activated, the CDMF framework will locally self-assemble into nano-sized structures, nest the copper, and effectively stop copper trafficking. The selective enzyme activation of CDMF within the tumor microenvironment maximizes the local impedance of copper trafficking without compromising the serum copper level. CDMF will be an effective and safe cure for breast cancer metastasis. Furthermore, we expect to gain new insights into the pro-metastasis mechanism of copper. This work will provide a solid foundation and important intervention points to cure breast cancer and prevent its recurrence. Equally important, a broad range of targeting ligands can be employed to broaden the spectrum of this new class of targeted therapeutics. This project aims to address the overarching challenge to eliminate the mortality associated with metastatic breast cancer. Upon successful completion of the project, we expect to provide a new therapy for metastatic breast cancer with high efficacy and minimum side effect. We envision a promising translation of this drug into clinical applications considering its biocompatibility, specificity, and high therapeutic potential toward metastatic breast cancer. We will continue the preclinical study of this drug after this award for a non-stop proceeding into clinical practice to the patients in need. This work will bring hope to the triple-negative subclass of patients with the poorest prognosis, to those with advanced-stage breast cancer facing high risk of distant metastasis, and to those even with no evidence of disease after standard clinical treatment procedure who still live with the fear that the aggressive cancer may bounce back. My long-term goal is to eliminate breast cancer-associated mortality. I have the strong motivation, top-notch training, and the leadership necessary to successfully achieve the aims of the proposed project. The implementation of this project will further improve my scientific skills. I will not only acquire more fundamental knowledge of breast cancer biology, but also gain clinical insight of translational medicine and treatment planning. I will receive the best mentorship throughout this project and my postdoctoral training from Dr. Jianghong Rao, the world’s foremost experts in developing enzyme activated sensors for applications in oncology, and Dr. Mark Pegram, one of the most renowned clinicians and scholars in breast cancer research. I will continue to develop my professional skills for a tenure-track faculty position with the abundant resources offered by Stanford University. This award will be a tremendous support for my future career as an independent researcher for breast cancer. In my future academic career, I will further expand my research of interest. I will devote my effort into the prevention of recurrence to strive for another breakthrough for breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810591
Entities
People
- Liyang Cui
Organizations
- Stanford University
- United States Army