Gordon B. Mills, MD, PhD

2009-2010 BCRF Project:
With the support of BCRF in the past 12 months, Dr. Mills and colleagues have established the roles of a potent and abundant lipid molecule in our body, lysophosphatidic acid, in development and progression of breast cancer in laboratory models. Next, they will determine whether this lipid molecule and other related proteins are suitable for drug development. Based on their preliminary and published data, novel compounds that inhibit production and actions of lysophosphatidic acid may represent a new class of drug with the potential to improve outcomes for breast cancer patients.

Mid-Year Progress Report:
Lysophosphatidic acid (LPA) is a potent lipid mediator that acts on LPA receptors present on many cancer cells. LPA exerts diverse biological actions that are suitable for the development and progression of cancer. Indeed, some patients with breast cancer exhibited marked increases in production and actions of LPA due to elevated levels of autotaxin (ATX, an enzyme that produces LPA) and LPA receptors—LPA1, LPA2 and LPA3.

In the first year of this BCRF support, Dr. Mills and colleagues demonstrated that expression of either ATX or each of the LPA receptors at high levels in the mammary glands of laboratory models was sufficient to cause breast tumors that retained several important biomarkers found in the tumors of breast cancer patients. Therefore, these ‘transgenic’ models should serve as clinically relevant tools for validating ATX and LPA receptors as novel therapeutic targets for breast cancer. To obtain the tumors in our transgenic models, multiple pregnancies (at least five times) are required since the researchers have modified their genomes, in which pregnancy hormones directly induce expression levels of ATX and the LPA receptors. They expect that some of these models will develop breast tumors in the next few months according to the onset (ranging from 8 to 24 years old) and rates (30 to 50%) observed previously.

In addition, the researchers have genetically modified human breast cancer cells to express high levels of LPA1, LPA2 or LPA3 receptors. Elevated levels of the LPA receptors have been confirmed in these cells. Next, they will create 'xenograft' models of breast cancer, in which the modified human breast cancer cells will be injected into mammary fat pads of immunodeficient laboratory models. Tumor formation will be monitored. Lastly, they have assessed the effectiveness of the proposed compounds that selectively inhibit LPA production and/or actions. Indeed, the initial data suggested that these compounds effectively suppressed cell viability in culture and tumor invasion. These compounds are now ready for evaluation in both transgenic and xenograft models of breast cancer.

Bio:
Dr. Mills earned his MD and his PhD in biochemistry from the University of Alberta. From 1985 to 1994, Dr. Mills was a member of the faculty of the University of Toronto, rising to the rank of Associate Professor in the departments of Obstetrics and Gynecology, Immunology, and Clinical Biochemistry. He was an active staff member and director of Oncology Research at the Toronto Hospital during this time.

In 1994, Dr. Mills was recruited to The University of Texas MD Anderson Cancer Center, where he holds the rank of professor with joint appointments in Systems Biology, Breast Medical Oncology and Immunology; serves as chairman of the Department of Systems Biology; head of the section of Molecular Therapeutics and holds the Ann Rife Cox Chair in Gynecology. Dr. Mills is co-Director of the Kleberg Center for Molecular Markers and director for the Gita and Ali Saberioon Molecular Markers building.

With more than 300 publications, Dr. Mills has authored papers in such prestigious journals as Nature, Cell, Oncogene, Nature Genetics, Nature Medicine, Nature Cell Biology, Nature Cancer Reviews, Cancer Research, Proceedings of the National Academy of Sciences and Clinical Cancer Research. A testament to the quality of his research, Dr. Mills' work in ovarian cancer, breast cancer and tumor immunology has been continuously funded by major peer-reviewed grants for over 20 years. He serves as principal investigator or project investigator on ten national peer review grants including NIH/NCI SPOREs and PPGs, Department of Defence, and Komen Foundation grants, and collaborator on multiple other national peer-reviewed grants.

Dr. Mills has made significant contributions to the understanding of ovarian tumorigenesis, including the identification and development of lysophosphatidic acid (LPA) and sphingosine 1 phosphate (S1P) as possible markers for early-stage ovarian cancer and as a potential targets for therapy. He also has played a major role in increasing our understanding of the genetic aberrations in the phosphatidylinositol 3 kinase/PTEN/AKT pathway, forwarding this cascade as a major target for the therapy of multiple types of cancer. Dr. Mills has also extensively explored the genomics and genetics of ovarian and breast cancer identifying and characterizing a number of potential oncogenes and tumor suppressor genes including ARHI, Rab25, EVI1 and PKCi. These are being explored both as markers and targets for therapy.

Dr. Mills is the holder of more than 20 patents related to novel technologies and molecular markers. He was a co founder of an early diagnostics company. He currently sits on the scientific advisory boards of multiple different companies and venture capital groups. Based on his expertise in technology development, he is the head of the MD Anderson Cancer Center Technology Review Committee.

Dr. Mills now heads the Kleberg Center for Molecular Markers. This Center holds the responsibility for developing personalized molecular medicine at the MD Anderson Cancer Center. Specifically, this center will implement a series of novel technologies to for the first time explore the genetic changes and their consequences at the DNA, RNA and protein levels in human tumors. This information will be used to identify patients at high risk for tumor development so they can be triaged to early screening and chemoprevention, identify markers to use in early screening, and to determine approaches to ensure that patients receive the most effective and least toxic therapies targeting the underlying genetic aberrations in tumors.

Dr. Mills is the inaugural chair of the Department of Systems Biology. The mission of the Department of Systems Biology to understand how a process, a cell, a group of cells, or an organism works at a global level and how different components of the process cooperate to attain the "correct" functional outcome. It is now recognized that component-by-component analysis is not sufficient for the study of signal transduction, gene regulatory and biochemical networks, oncogenic transformation, and other processes in which many genes and proteins interact. Understanding the dynamics of such systems, both qualitatively and quantitatively, and constructing mathematical models with robust predictive capabilities will be necessary for the realization of the promise of personalized molecular medicine and the efficient implementation of targeted therapeutics.