Currently, my time at Oregon Health and Sciences University(OHSU) is spent investigating the molecular and cellular mechanisms that regulate leukocyte recruitment into neoplastic tissue, and the subsequent regulation those leukocytes exert on evolving cancer cells. To address these issues, we have taken several approaches to investigate mechanisms involved in the induction and maintenance of chronic inflammatory microenvironments in premalignant, malignant and metastatic tissues using murine models of human cancer development, and clinical samples obtained fresh from the operating room from patients with cancer. We investigate the role of leukocytes in regulating tissue remodeling, angiogenesis, immune suppression and cancer development and we research the development of novel non-invasive imaging reagents to monitor immune response in tissues/tumors. The long-term goal of this work is to translate basic observations made in the mouse, toward rational design of novel therapeutics whose aim will be to block and/or alter rate-limiting events critical for solid tumor growth, maintenance or recurrence in humans, and/or therapeutics that enhance the efficacy of standard-of-care cytotoxic therapy. Currently, we are actively utilizing transgenic mouse models of solid tumor development (non-small cell lung cancer, non-melanoma squamous, pancreatic and breast adenocarcinoma, and mesothelioma) to reveal the functional roles of adaptive and innate leukocytes during tumor development. These experimental studies are conducted in parallel with evaluation of representative human cancer specimens to affirm that mechanisms revealed in the experimental setting represent fundamental parameters of multi-stage cancer development in humans.
During my time at Washington University, we sought to find an improved method for diagnosing myelodysplastic syndrome(MDS). MDS is characterized by low blood cell counts, fatigue and shortness of breath. It can be fatal, but people with low-risk MDS may live for years with the disease and never realize they have it. Patients are diagnosed based on the appearance of their abnormal blood cells, and doctors often take a watchful waiting approach to see if their blood cell counts decrease or the number of abnormal blood cells increases before taking steps to intervene. In about one-third of MDS patients, the slow-growing disease takes an aggressive turn and progresses to acute myeloid leukemia (AML), a fast-growing cancer of the blood that is fatal unless successfully treated with a stem cell transplant. Even so, long-term prognosis for almost all AML patients is poor. About 40,000 people are diagnosed with MDS in the U.S. each year. Our group at Washington University was interested in identifying healthy individuals with normal blood counts and mutations in a few key genes that are linked to MDS but who don’t have any symptoms. This condition is called age-related clonal hematopoiesis (ARCH). Individuals with ARCH have a higher than average but still relatively low risk of developing MDS — about 1% per year, as well as a higher risk of developing other age-related conditions, such as cardiovascular disease. Although relatively few will end up with MDS, by studying this group of patients we are trying to help doctors understand the differences between those patients who go on to develop disease and those who don’t.
Our research group at the University of New Mexico(UNM) focused primarily on the characterization and targeted therapies of human leukemia. The bulk of the characterization work centered on the integration of gene expression patterns with underlying genetic events to identify groups of patients with targetable characteristics. By taking advantage of the specific features of these expression groups we found it possible to develop focused therapies to treat patients with maximum efficacy and minimal side effects. Over the several years I was working in this lab, our discovery effort has branched over into targeted therapeutics as well. In conjunction with UNM and Sandia National Laboratories colleagues our group was just starting to explore the application of nanotechnology as targeted delivery vectors for therapeutic agents. The discoveries stemming from these efforts may likely be applicable to many other types of cancers.