Oxidative stress, metabolic adaptation and therapeutic resistance of cancer:
We discovered that non small cell lung cancer frequently develop gain of function in Nrf2 due to KEAP1 mutations, which increases antioxidants and alters metabolism to drive tumor growth and cause therapeutic resistance. This has changed the paradigm in cancer biology and develop our understanding of dark side of antioxidants in cancer cells. Our current effort will help unravel mechanisms of oncogenic cooperation and metabolic adaptation using patient-derived xenografts in humanized immunocompetent mice and GEM models.
Chemical and biochemical approaches in the study of signal transduction, gene regulation, and metabolism
Dr. Ewald has spent the past decade developing imaging, genetic, and 3D organotypic culture techniques to enable real-time analysis of cell behavior and molecular function in breast cancer. As a graduate student in Scott Fraser’s Lab at Caltech he utilized his physics training to develop and apply novel light microscopy approaches to reveal cellular interactions within intact tissues in real-time. During Dr. Ewald’s postdoctoral studies in Zena Werb’s Lab at UCSF, he developed novel 3D organotypic culture and imaging techniques to reveal the cellular mechanisms and molecular regulation of morphogenesis in primary normal and neoplastic mammary epithelia. His laboratory seeks to understand how epithelial cancer cells escape their normal developmental constraints and acquire the ability to invade and disseminate into normal tissues.
The research in my program involves the development and application of molecular biomarkers of exposure, dose, and effect from environmental carcinogens. The environmental carcinogens studied include agents that are naturally occurring in the diet as well as those produced as a result of cooking practices. A major emphasis of the research has been in the elucidation of the role of aflatoxins, a common contaminate of the food supply, in the induction of liver cancer in high-risk populations living in Asia and Africa. This work has led to the identification of a very strong chemical-viral interaction between aflatoxin and the human hepatitis B virus in the induction of liver cancer. These biomarkers have also been used in many collaborative molecular epidemiology studies of liver cancer risk and recently employed to assess the efficacy of a number of chemopreventive agents in trials in high-risk aflatoxin-hepatitis B virus exposed populations. This research is now being extended to develop genetic biomarkers of p53 mutations and viral alterations in human samples as early detection of disease biomarkers using a novel mass spectroscopy based method for genotyping developed in the laboratory. Thus, the research in our laboratory focuses on the translation of mechanistic research to public health based prevention strategies.
The Laiho lab seeks to understand the regulatory events that are derailed in cancers, and to detect and exploit cancer cell characteristics that could be used as basis of new cancer therapies. Our major focus is on RNA polymerase I transcription and new therapeutic agents targeting this abundantly deregulated process in cancers.
Our primary research interest lies at the interface between chemistry, biology, and medicine. We employ high-throughput screening to identify modulators of various cellular processes and pathways that have been implicated in human diseases from cancer to autoimmune diseases. Once biologically active inhibitors are identified, they will serve both as probes of the biological processes of interest and as leads for the development of new drugs for treating human diseases.
Among the biological processes of interest are cancer cell growth and apoptosis, angiogenesis, calcium-dependent signaling pathways, eukaryotic transcription and translation.
The Meeker laboratory is located at the Johns Hopkins University School of Medicine. Utilizing a combination of tissue-based, cell-based, and molecular approaches, our research goals focus on abnormal telomere biology as it relates to cancer initiation and tumor progression, with a particular interest in the Alternative Lengthening of Telomeres (ALT) phenotype. In addition, our laboratories focus on cancer biomarker discovery and validation with the ultimate aim to utilize these novel tissue-based biomarkers to improve individualized prevention, detection, and treatment strategies.
Dr. Pienta is involved in research to define the tumor microenvironment of prostate cancer metastases, as well as developing new therapies for prostate cancer. Current research projects in the lab are studying why prostate cancer preferentially disseminate to the bone and can remain dormant for many years before returning to a proliferative phenotype that results in metastatic disease. Additionally, his research team is looking at ways to isolate, identify, and characterize these disseminated tumor cells so that new therapies can be designed to target them prior to becoming “reactivated” and metastatic.
My research work focuses on various aspects of breast carcinogenesis, particularly the molecular and hormonal mechanisms underlying breast tumor growth, epithelial-mesenchymal transition, invasion, migration and breast cancer prevention. My studies have established important markers for development of acquired tamoxifen resistance. We are actively investigating novel molecular targets and pathways involved in chemopreventive role of bioactive components.
Neurodegeneration is a poorly understood biomedical phenomenon and a major public health challenge in our increasingly aging society. Our goal is to describe at the molecular and cellular levels how specific neurons degenerate, how protein folding and misfolding operate in the cell, and how protective systems fail at disease stages.