Targeting Creatine Kinase, Brain Isoform (CKB) to Inhibit Metastatic Breast Cancer (MBC)
Abstract
Background: The overall survival rate of breast cancer patients diagnosed with metastatic breast cancer remains dismal. Breast cancer deaths are due to spread ("metastasis"), then growth, of tumor cells that have left the breast to seed distant organs. Therefore, to improve survival rates, cancer researchers must re-focus our efforts on finding safe, effective, and specific "targeted" drug therapies to block the pathways in the tumor that drive metastasis, even if preclinical studies reveal that primary tumor growth is not dramatically reduced by drug treatment. We must also strive to test promising therapies in the most appropriate preclinical animal models available, such as those that consistently metastasize, before initiating new clinical trials in patients. Rationale, Objectives, and Aims: In response to very low oxygen levels ("hypoxia"), cells try to restore balance through regulation of complex cellular energy pathways, production of more red blood cells, formation of new blood vessels, and executing decisions between survival or cell death. Most solid tumors have bypassed the normal controls that regulate these processes; therefore, oxygen- and nutrient-starved regions are a hallmark of most solid tumors, including breast cancers. The Hypoxia-Inducible Factors (HIFs) are proteins that control how cells respond to low oxygen. They function by regulating expression of hundreds of genes, in a pathway known as the "hypoxic" response. HIF-1 is a master regulator of the entire hypoxic response in cells. More importantly, hypoxic regions are known to be the source of the cells in tumors that are resistant to radiation and chemotherapy. Several studies have demonstrated that overexpression of HIF proteins in breast cancer correlates with poor prognosis and decreased relapse-free survival. In fact, HIF-1 expression significantly and independently correlates with a high risk of metastasis. Although it is tempting to try to block HIF activity using a "targeted" therapy, there are several roadblocks to developing HIF inhibitors for clinical use, including that most HIF inhibitors described to date are not specific to the HIF proteins and also have poor delivery in animals. Therefore, as experts in the role of the HIF proteins in breast cancer growth and spread, we decided to instead to identify genes that are increased in a HIF-dependent manner and to try to target these sets of genes, prioritizing those for which chemical inhibitors are available. We used a mouse model of highly metastatic breast cancer (MBC) known as polyoma middle T (PyMT) to profile for gene expression differences between cells with normal levels of HIF-1 (wild-type) or cells we engineered to delete HIF-1 expression (knockout). One gene we identified was creatine kinase, brain isoform (CKB). Although named brain isoform, CKB is expressed in several types of tumor cells at high levels. Unlike the HIFs, there are well-described, chemical inhibitors blocking CKB function, including cyclocreatine (cCr) and an improved version of cCr (a cCr derivative) known as LUM-001, which will be provided by Lumos Pharma to our lab. These drugs are generally well-tolerated in animals, with few side effects, they cross the blood-brain barrier, and they block tumor growth. The preliminary data included in this application will also show for the first time that CKB directly mediates breast cell invasion and metastasis to the lungs and that either deletion of the Ckb gene or cCr therapy blocks lung metastasis, or prevents the growth of small metastatic lesions into larger, lethal metastatic lesions. We have filed a patent based on these data. Project Aims/Goals: The proposed study design will define if hypoxia acts through the creatine kinase pathway, generally, and CKB specifically, to promote cell survival and conventional drug response, and will test the efficacy of the compound LUM-001 to reduce tumor growth and/or to block metastasis using state
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1610061
Entities
People
- Tiffany N Seagroves
Organizations
- United States Army
- University of Tennessee Health Science Center