RLIP76: A Novel Strategy for Preventing and Treating Breast Cancer
Abstract
Objective and Rationale: Treatment of localized breast cancer with surgery, radiotherapy, chemotherapy, and hormonal therapy is insufficient to eradicate breast cancer, as evident from development of metastatic breast cancer (MBC) in up to 40% of women presenting with localized disease. Our objective is to develop improved prevention strategies to alleviate the pain and suffering caused by MBC. We propose that chronic partial suppression of Rlip, a stress-defense protein, will prevent MBC by restoring the function of p53, a tumor suppressor gene that is deficient or dysfunctional in over one-third of breast cancers. The rationale for this proposal stems from our studies showing chronic Rlip depletion completely eliminates the uniform occurrence of malignancy that characterizes p53 gene-knockout (p53-/-) mice. This degree of cancer suppression in p53-/- mice is unprecedented, not achieved by any previous genetic or pharmacological intervention. Our discovery has fundamental implications in cancer prevention and the studies proposed herein are to define the role of key signaling networks and biochemical pathways that were identified in genetic studies in the experiment. The objective is to test whether Rlip depletion prevents (1) spontaneous and chemical carcinogenesis, (2) metastases, and (3) epigenomic, transcriptomic, proteomic, signaling, and biochemical abnormalities that predispose breast carcinogenesis. Ultimate Applicability: Which overarching challenge(s) does this research address? Prevention of MBC. What types of patients will it help, and how will it help them? The proposed method of treatment will help women in remission after treatment of localized or metastatic disease. What are the potential clinical applications, benefits, and risks? We anticipate application in an adjuvant setting for localized disease, and tertiary prevention in those with metastatic disease rendered in remission by treatment. Because Rlip is a drug and radiation resistance-mediating protein, the indications could include chemo-radio-sensitization to treat highly resistant malignancies. Because we have also shown effectiveness in lung, colon, pancreas, kidney, and prostate cancer, the implications are broad. Remarkably, depletion or loss of Rlip improves metabolic syndrome markers (obesity, hyperglycemia, insulin-resistance, hypercholesterolemia, hypertriglyceridemia, and inflammation). We predict that similar effects will be seen in humans. What is the projected time it may take to achieve a patient-related outcome? In this application, we are proposing to test whether Rlip depletion will prevent breast cancer in mice. In other studies, we have identified a natural compound, 2-hydroxyflavanone that suppresses Rlip. We are planning clinical trials of this GRAS (generally regarded as safe) compound for breast as well as kidney cancer, to begin within the next 1 year, as part of an independent project that is an offshoot of our studies showing the cancer preventative effect of Rlip depletion. Results of the presently proposed studies will answer the question of how Rlip depletion prevents breast cancer. What is the likely impact of this study on ending breast cancer? Complete protection from recurrence in both hormone receptors positive or negative, without or with BRCA or ERBB2 is predicted on the basis of gene expression analyses. Combined with early detection and effective local therapy, complete protection from recurrence will make death from MBC a thing of the past. The research proposed is quite basic and mechanistic. However, it is the scientific backbone of ongoing clinical translational efforts to develop metabolic-pathway-specific inhibitors targeting Rlip to end breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610641
Entities
People
- Sharad S Singhal
Organizations
- Beckman Research Institute of City of Hope
- United States Army