Exploiting the Remodeling of Ca2+ Signaling in Breast Cancer Cell Microenvironments to Control Metastasis and to Specifically Target Brain Metastases
Abstract
This proposed study targets the overarching challenge of eliminating morbidity associated with metastatic breast cancer. Breast cancer metastasis to the brain is a major challenge because the mortality rate is 100%, and average survival is only 4-18 months from diagnosis, which is generally when the tumors start to produce very challenging neurological symptoms such as cognitive decline and seizures. In 2016, over 30,000 breast cancer patients in the United States alone will develop this deadly complication, and a disproportionately large number of these are young women. Alarmingly, the incidence of breast cancer spread to the brain is increasing. New therapies have been proposed and others are being evaluated in clinical trials, but it is clear from the limited progress so far that we will need to be more innovative in our approach to treating these brain tumors because they are very resistant to treatment and invariably persist despite multiple lines of therapy. This recalcitrant behavior is partly enabled by close interaction with components of the brain tissue in which the tumor cells reside. One new idea that is gaining strong support in medical research is to simultaneously target tumor cells and features of the surrounding normal tissue on which tumor growth depends (the so-called "tumor microenvironment"). Research has focused heavily on developing tumor-targeting drugs, but far less is known about which aspects of the microenvironment could be safely targeted at the same time. The authors of this proposal have discovered alterations in specific "calcium channels" in both breast cancers and brain metastases, consistent with the idea that changes in the dynamic flux of calcium ions into and within the tumor cells are involved in breast cancer spread, particularly to the brain where the calcium conditions are unique. A detailed understanding of these altered calcium processes is anticipated to lead to new, innovative treatment strategies that could be used to reduce the chance of disease spread from the breast and/or arrest the growth of tumors once they are detected in the brain. Clinical evaluation of findings from this research would likely be fast-tracked because drugs targeting particular calcium channels are already in clinical use for cardiovascular disease and chronic pain or are undergoing current clinical trials or are part of drug development programs. Hence, these agents are known to be safe and tolerable and such agents could thus be trialed very quickly. Other targets this project may identify could prompt drug development programs similar to those that the investigators are currently involved in and are based on their related research at the University of Queensland. This 3-year study has been designed to provide preclinical data required to initiate a clinical trial or drug development programs after 2019, if the data support it. The overarching impact of this study will be in combating the very high morbidity and mortality of metastatic breast cancer, particularly for the poorest outcome patients who develop disease in the brain. Looking even further ahead, this approach could also be adapted for treatment of lethal brain metastases originating from other cancer types, such as lung cancer and melanoma. In summary, this project s potential breakthrough dates back to the seed and soil hypothesis for cancer metastasis. It has been established for many years that changes in the microenvironment surrounding cancer cells is key in facilitating growth and/or the induction of a more metastatic phenotype. It is also increasingly clear that cancer cells adapt to survive at metastatic sites. However, we still lack therapies that target these changes in poor prognosis breast cancers. Results from this work should see the identification of a new set of drug targets with unprecedented potential for pharmacological modulation and tolerable side effects to target metastasis particularly in th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710065
Entities
People
- Sunil R. Lakhani
Organizations
- United States Army
- University of Queensland