Metabolomic Targeting of Heterogeneous Breast Cancer for Personalized Therapy Development
Abstract
Breast cancer is not just one disease -- there are many different subtypes of breast cancer with varying characteristics and responses to therapy. One major difference is in breast tumor histology, which is the minute structure and pattern formed by tumor cells visualized through a microscope. Subtypes of breast cancer can be categorized by differences in histology. Although we do not fully understand what causes these variations in shape, size, and structure of tumor cells, we know that genetic variations contribute to histological subtypes of breast cancer. Preliminary work in our laboratory shows that differences in tumor metabolism are associated with histological subtypes of breast cancer. Altered metabolism in breast cancer subtypes is an understudied area of research with great potential to make a significant impact in curing breast cancer through personalized therapy. In this proposal, we will address the following overarching challenge: identify what drives breast cancer growth; determine how to stop it. Our goal is to find weaknesses in metabolism of breast cancer subtypes and to target these weaknesses for personalized therapy. We will achieve this goal by characterizing metabolic differences and genetic mutations of breast cancer subtypes. To understand how these metabolic and genetic differences drive growth of breast cancer subtypes, we will use gene editing techniques. For example, if we find that a breast cancer subtype depends heavily on a specific metabolic pathway, we will delete each of the genes involved in this pathway and characterize the consequences of each deletion on cancer growth. We will also trace the effects on cancer metabolism following gene deletions. When we delete the same gene in two different breast cancer subtypes and one subtype stops growing while the second does not, we will know that the first subtype depends on this gene for its metabolism and growth. Thus, we will have identified a weakness for this breast cancer subtype. Finally, we will target the metabolic weaknesses of breast cancer subtypes using drugs that target metabolism. We will conduct these studies in mice that develop breast tumors, as well as mice that have been implanted with human breast tumors. Drugs that target metabolism are already being used to treat breast cancer; however, these drugs are used in general chemotherapy instead of subtype-specific treatment, leading to ineffective treatment with harsh side effects or overtreatment with more aggressive therapy than necessary. We will specifically target these drugs to breast tumor subtypes that are susceptible to them, leading to effective personalized therapy. Our proposed research will help patients with breast cancers by targeting therapy to their particular type of tumor. Based on histology and known genetic mutations, this work will better direct their cancer treatment. Individualized therapy will significantly reduce overtreatment with ineffective drugs or unnecessarily aggressive therapies that cause severe side effects. The projected time to achieve a patient-related outcome is expected to be about 10 years. After our 3-year study identifying and targeting metabolic weaknesses of breast cancer subtypes, clinical trials on patients will have to be conducted, which may take several years. We are planning on using Food and Drug Administration-approved drugs whenever possible, and this should decrease the projected time it may take to achieve a patient-related outcome. By focusing on metabolic weaknesses of breast cancer subtypes using the latest technology and tools available in research, this study has great potential to make a significant impact on ending breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510453
Entities
People
- Sophia Y Lunt
Organizations
- Michigan State University
- United States Army