Prostate cancer is the most commonly diagnosed malignancy in men in the United States, although our understanding of the molecular basis for this disease remains incomplete. We are interested in characterizing consistent alterations in the structure and expression of the genome of human prostate cancer cells as a means of identifying genes critical in the pathways of prostatic carcinogenesis. We are focusing on somatic genomic alterations occurring in sporadic prostate cancers, as well as germline variations which confer increases in prostate cancer risk. Both genome wide and candidate gene approaches are being pursued, and cancer associated changes in gene expression analyses of normal and malignant prostate cells are being cataloged as a complementary approach in these efforts. It is anticipated that this work will assist in providing more effective methodologies to identify men at high risk for this disease, in general, and in particular, to identify new markers of prognostic and therapeutic significance that could lead to more effective management of this common disease.

Normal and neoplastic cells respond to genome integrity threats in a variety of different ways. Furthermore, the nature of these responses are critical both for cancer pathogenesis and for cancer treatment. DNA damaging agents activate several signal transduction pathways in damaged cells which trigger cell fate decisions such as proliferation, genomic repair, differentiation, and cell death. For normal cells, failure of a DNA damaging agent (i.e., a carcinogen) to activate processes culminating in DNA repair or in cell death might promote neoplastic transformation. For cancer cells, failure of a DNA damaging agent (i.e., an antineoplastic drug) to promote differentiation or cell death might undermine cancer treatment. Our laboratory has discovered the most common known somatic genome alteration in human prostatic carcinoma cells. The DNA lesion, hypermethylation of deoxycytidine nucleotides in the promoter of a carcinogen-defense enzyme gene, appears to result in inactivation of the gene and a resultant increased vulnerability of prostatic cells to carcinogens. Studies underway in the laboratory have been directed at characterizing the genomic abnormality further, and at developing methods to restore expression of epigenetically silenced genes and/or to augment expression of other carcinogen-defense enzymes in prostate cells as prostate cancer prevention strategies. Another major interest pursued in the laboratory is the role of chronic or recurrent inflammation as a cause of prostate cancer. Genetic studies of familial prostate cancer have identified defects in genes regulating host inflammatory responses to infections. A newly described prostate lesion, proliferative inflammatory atrophy (PIA), appears to be an early prostate cancer precursor. Current experimental approaches feature induction of chronic prostate inflammation in laboratory mice and rats, and monitoring the consequences on the development of PIA and prostate cancer.

The Raman laboratory is within the Division of Cancer Imaging Research in the Department of Radiology and Radiological Science. The focus of the laboratory is bench-to-bed side cancer research. We integrate molecular and cellular biology, developmental biology, cancer biology, molecular imaging techniques to study cancer formation and progression. Many of the projects in the lab investigate dysregulated genes in cancer and the translatability of this information to a clinical setting. One such project is to functionally decipher the role of a RNA helicase gene, DDX3, in the biogenesis of multiple cancer types such as breast, lung, brain, sarcoma, colorectal and prostate. Additionally, using a rational drug design approach, a small molecule inhibitor of DDX3 (RK-33) was synthesized and its potential for clinical translation is being investigated.

The lab currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow noninvasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.

Our research results in effective and quality care which has led to the development of new therapies, medications and vaccines, including the HPV vaccine — the first vaccine to prevent gynecologic cancer. Our patient satisfaction scores are among the highest in the nation, due to our commitment to safety and quality.

The Kathryn Carson Lab investigates ways to improve medical research, particularly in the areas of brain and thyroid cancer, Alzheimer’s disease, atherosclerosis, hypertension, HIV and lupus. Our team seeks to help researchers optimize their studies through better study design, protocol and grant writing, data cleaning and analysis, and publication writing. We work with investigators from a wide range of departments through the Johns Hopkins Institute for Clinical and Translational Research.

Research in the Kathleen Gabrielson Laboratory focuses on the signal transduction of cardiovascular toxicities in vitro, in cardiomyocyte culture and in vivo using rodent models. Specifically, the research focuses on understanding the mechanisms of various cancer therapies that induce cardiac toxicities. Currently, we are testing prevention strategies for these toxicities by studying the cardiac effects of the anthracycline doxorubicin (adriamycin) and the immunotherapeutic agent, Herceptin, anti-erbB2. We are focusing on the signal transduction pathways in the heart that are modulated by anti-erbB2 treatment, which in turn, worsens doxorubicin toxicity. Thus, understanding the mechanisms behind the combined toxicity of doxorubicin and anti-erbB2 will pave the way for the design of strategies to reduce toxicity, identify patients at risk and potentially allow higher levels of this effective combination therapy to be used with an improved long-term survival in patients.

The Kenneth J. Pienta laboratory has championed the concept that cancer tumorigenesis and metastasis can best be understood utilizing the principles of Ecology. As a result, the Pienta laboratory is working to develop new treatments for cancer utilizing network disruption.

The Glunde lab is within the Division of Cancer Imaging Research in the Department of Radiology and Radiological Science. The lab is developing mass spectrometry imaging as part of multimodal molecular imaging workflows to image and elucidate hypoxia-driven signaling pathways in breast cancer. They are working to further unravel the molecular basis of the aberrant choline phospholipid metabolism in cancer. The Glunde lab is developing novel optical imaging agents for multi-scale molecular imaging of lysosomes in breast tumors and discovering structural changes in Collagen I matrices and their role in breast cancer and metastasis.

Malfunction and malformation of blood vessels are associated with a broad range of medical conditions, including cancer, cardiovascular diseases, and neurological disorders. The ultimate goal of the Komatsu lab is to find a way to reverse the process of abnormal vessel formation and restore normal function to these vessels. In cancer, normalization of tumor blood vessels facilitates lymphocyte infiltration, potentiating anti-tumor immunity, and enhances the efficacy of immunotherapies as well as conventional cancer treatments. Normalization of regenerating blood vessels is also necessary for reestablishing blood flow to ischemic hearts and limbs, and preventing blindness caused by diabetic retinopathy or macular degeneration. Komatsu lab’s research is uncovering key molecular pathways important for the normalization of pathological vasculature.