Novel Small-Molecule Therapeutics Targeting Hypoxia-Regulated microRNAs Implicated in Breast Cancer
Abstract
Rationale for the Proposed Study: Breast cancer is the most common malignancy among women and results in over 500,000 deaths yearly worldwide. Depending on their status at initial diagnosis, patients are prescribed different treatment regimens including radiation, chemotherapy, and hormone therapy, but each is limited in overall effectiveness and produces unwanted side effects. For example, each year thousands of breast cancer patients who are prescribed chemotherapy suffer from a multitude of side effects including hair loss, mouth sores, vomiting, low blood cell counts, neuropathy, and heart damage. Indeed, for many patients the legacy of chemotherapy is chronic health problems and ongoing quality of life issues. Therefore, an urgent need exists to develop new cancer therapeutics with high selectivity and potency that do not leave behind a toxic footprint. A hallmark of tumorigenesis is the rapid, uncontrolled growth of cancer cells. This rapid growth is known to transiently create a low oxygen (hypoxic) micro-environment as blood supply cannot meet the oxygen demands of the emerging tumor. In fact, it is now believed that virtually all tumors experience a period of hypoxic stress and must adapt to this stress in order to survive. One way tumors adapt to low oxygen is to slow their growth and alter their cellular metabolism. Importantly, metabolic adaptation to low oxygen selects for tumor cells that are resistant to chemotherapeutic agents, and studies have shown that over 50% of locally advanced breast cancers have hypoxic regions that reduce the overall effectiveness of chemotherapy and radiation. Tumors also adapt by acquiring the ability to migrate away from the low oxygen environment via a process known as metastasis, which spreads the tumor to other parts of the body. Therefore, targeting cellular pathways responsive to hypoxia may prove effective in blocking tumor progression, reducing relapse rates following chemotherapy/radiation and preventing metastasis, which is the leading cause of cancer-related deaths. This application seeks to develop a novel therapeutic approach that eradicates tumors with high selectivity and low toxicity by targeting pathways that drive adaptation of tumor cells to low oxygen. To do so, we have developed a novel and highly innovative platform that identifies small molecules that via direct binding block the function of microRNAs induced in response to hypoxia to promote tumor cell survival. MicroRNAs are small non-coding RNAs that act as post-transcriptional regulators of gene expression and control a wide range of physiological processes. For example, our laboratory recently demonstrated that microRNA-544 (miR-544) is induced to high levels in tumor cells but not normal cells in response to hypoxia, targets critical regulators of cell growth and metabolism, and promotes metabolic adaptation of tumor cells to low oxygen by repressing these pathways. Therefore, miR-544 is a prime target for therapy. However, while miR-544 and many other microRNAs have been implicated in the development of cancer, few if any existing cancer therapeutics elicit effects by directly regulating miRNA function. The most common approach to targeting miRNAs is via the use of antisense oligonucleotides, but these synthetic RNAs have limited clinical utility due to the lack of effective in vivo delivery methods. To circumvent this problem, we devised a novel rationale design-based approach to identify small molecules that selectively block the biogenesis/maturation of miR-544 and have shown that one small molecule elicits biological responses with few off-target effects at a potency that far exceeds that of synthetic RNAs. Based on these advances, we propose the following objectives to further evaluate these small molecules as lead cancer therapeutics. Objectives: A major goal of our laboratory is to develop small molecules that modulate the function of tumor-promoting miRNAs via direct
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610029
Entities
People
- Donald G Phinney
Organizations
- Scripps Research
- United States Army