Investigation of UBR5 and Its Signaling as a Novel Target for Breast Cancer Therapy
Abstract
Rationale, objective, and aims: Breast cancer is the most common cancer among women in the United States and the second most common cause of mortality among women ages 45 to 55 years. An estimated 249,260 new breast cancer cases were identified in the United States in 2016 and the predicted number of deaths is that year was 40,890. Despite the development of newer diagnostic methods, selective as well as targeted chemotherapies and their combinations, surgery, hormonal therapy, radiotherapy, breast cancer recurrence, metastasis and drug resistance are still the major problems for breast cancer. Clearly, more effective therapeutic modalities are needed for this deadly disease. We have recently discovered that a novel E3 ubiquitin ligase called UBR5 that profoundly impacts on breast cancer growth and metastasis, and it is a potentially excellent therapeutic target. In this project, we will take a multi-pronged and integrated approach to further delineate the fundamental ways UBR5 drives the aggression of breast cancer, and to begin to explore practical ways to target UBR5 immunologically and pharmacologically. The outcome of these pursuits will pave the way for developing innovative and transformative therapeutic strategies effectively and safely targeting UBR5 in breast cancer patients with this genetic lesion that often fail conventional therapies. Which overarching challenge(s) does this research address? The overarching challenge is to “Identify what drives breast cancer growth; determine how to stop it”. We not only want to understand comprehensively the novel biological activities of UBR5 in tumorigenesis but also to develop innovative therapeutic strategies to target UBR5 in combination with conventional therapy to treat aggressive and therapy-resistant breast cancer effectively and safely in the near future. What types of patients will it help and how will it help them? In a TCGA-based analysis involving 16 independent studies and more than 11,000 cancer samples, we found that human UBR5 gene alterations (predominantly amplifications) occur in ~20% of breast cancer (variable depending on the studies conducted). Overexpression of UBR5 occurs in ~40% of breast cancer and is responsible in a major way for the highly aggressive behavior of the cancer, for chemotherapy resistance, and for poor prognosis of the patients with drastically reduced median disease-free months. Our experimental work demonstrates that UBR5 functions like an oncogene and represents an excellent therapeutic target for breast cancer, particularly triple-negative breast cancer, because of its fundamental and indispensable role in cancer growth and metastasis. What are the potential clinical applications, benefits, and risks? This project will lay the groundwork for three clinical applications that will directly benefit breast cancer patients. It will lead to identification of new routes that can be pursued to stimulate patients’ immune system to fight the cancer proactively and to prevent cancer recurrence via immunosurveillance. It will result in prototypical strategies to block breast cancer metastasis. The unknown “risks” at this point is the fact that we cannot yet fully predict the toxicity of targeting UBR5 in breast cancer therapy in human patients, although the great differential in the expression of UBR5 between normal and cancer cells is expected to lessen that fear. What is the projected time it may take to achieve a patient-related outcome? In 3 years, we will be able to fully understand UBR5’s immunoregulatory functions driving tumor growth as well its cell intrinsic activities promoting metastasis to establish the basis going forward for pharmacological discovery of UBR5 blockers followed by clinical trials in breast cancer combination therapy and immunotherapy. In parallel, we are conducting a concerted pharmacological campaign to identify such UBR5 blockers, thanks to a grant from the Daedalus Fund for Innovation at
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110261
Entities
People
- Xiaojing Ma
Organizations
- United States Army
- Weill Cornell Medicine