Targeting the Synthetic Essential Kinases of Breast Cancers
Abstract
The rationale and objectives for the proposed project: Many breast cancer tumors grow quickly and expand beyond the capacity of the local blood supply, leading to regions within the tumor that have poor access to oxygen. This limited oxygen supply, termed "hypoxia," forces cancer cells to burn sugar without oxygen to generate energy leading to an increase the production and accumulation of lactic acid. This condition is known as "lactic acidosis" and creates an environment similar to the accumulation of lactic acid in the muscle tissues during intense exercise. Most breast tumors contain regions of varying levels of hypoxia and lactic acidosis, which can make tumors more resistant to treatment, which can result in treatment failure and relapse. In addition, cancer cells experiencing hypoxia and lactic acidosis tend to migrate and metastasize distantly. The failure of anti-angiogenesis agents for breast cancers may be also caused by the treatment-induced hypoxia since these anti-angiogenesis treatments work by inhibiting the development of new blood vessels. Even though the negative consequences of hypoxia and lactic acidosis in tumors have long been recognized, there are very few available options to address these conditions as they exist deep in tumors. Some scientists are currently addressing these conditions by improving tumor oxygenation, reducing oxygen consumption, hypoxia-activated toxins, and systematic pH neutralization; however, these efforts have been met with limited clinical success. To fill this gap, we pay particular attention to a specific category of enzymes, called kinases, which alter the activity of other proteins through molecular modification. These kinases are good treatment targets because they are critical for tumor development and can be inhibited by small compounds (drugs). We have used large-scale screening procedures and found 10-20 kinases that are required for cancer cells to survival hypoxia or lactic acidosis. The advantage of identifying these kinases is that inhibiting them with drugs will likely not be toxic to normal tissues, and thus potential treatments may be less toxic to patients. We think if we block these kinases using both genes and small compounds (drugs), breast cancer cells won t be able to survive under hypoxia or acidosis any more. Therefore, we will carefully study these kinases and develop chemical compounds that block these kinases to selectively kill breast cancer cells under stress. The ultimate applicability of the research: Since 40% of breast cancers have regions of hypoxia and lactic acidosis, we expect that inhibition of the kinases essential for survival under these conditions may benefit many patients with breast tumors. Especially exciting is the potential to provide help to those patients whose cancers have been resistant to previous therapies. Technology already exists to identify patients with tumors exhibiting prominent hypoxia and lactic acidosis. These are the patients who will likely benefit the most from treatments targeting these conditions. Some of the kinases and drugs identified in this study are drugs already in use or under development for other diseases or tumor types. Therefore, depending on the particular kinase or kinase inhibitors we find in this project, they can be either re-tooled or further refined for treating breast tumors. Importantly, this study promotes the simultaneous development of more efficient, novel therapeutics as well as identifies already developed drugs that can be applied in a new clinical setting, thus decreasing the amount of time between the lab bench and bedside use. Overall, the benefits of this study are improving treatment efficacy, reducing treatment failure, and preventing future relapse. These treatments may also reduce the distant metastasis of breast cancer cells caused by hypoxia and lactic acidosis. The likely contribution to advancing the field of research: Our research will sp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510027
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army