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Cutaneous Oncology Program |
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Program Director: Basic Research: Brian J. Nickoloff , M.D., Ph.D., Director, Oncology Institute  Brian J. Nickoloff, MD, PhD Department of Pathology
Project No. 1 involves the regulation of keratinocyte senescence in normal skin aging and skin cancer. Specific items of interest include defining the molecular phenotype of senescent keratinocytes and the function of senescent keratinocytes. Determining the key elements in the promoter region of the INK4A gene and regulation of p16, p12, and p14 expression, as well as senescent-bypass mechanisms in squamous cell carcinoma are important aspects of this project. Project No. 2 involves the regulation of keratinocyte cell death in normal and diseased human skin samples. This project centers on the concept of “planned cell death” for the epidermis, in which normal keratinocytes delay the onset of cell death, to create the stratum corneum, until after terminal differentiation has occurred. These studies highlight specific death receptors and decoy receptors related to the TNF family, as well as effector caspases that regulate keratinocyte cell death. Besides studies involving normal keratinocytes, we also are interested in establishing the molecular basis for the death-defying phenotype of squamous cell carcinomas. Project No. 3 involves the clinical use of immunocyte derived dendritic cells that are pulsed with autologous melanoma cell lysates, and then matured with CD40L, followed by intranodal injection in stage IV melanoma patients. This phase I study is approved by the U.S. Food and Drug Administration and is open for accrual in advanced melanoma patients with subcutaneous tumors that can be removed to prepare the vaccine. Sequential fine needle aspirations and molecular analysis complement the immunological monitoring of patients in this trial. Melanoma cell lines are being generated as well as tumor infiltrating T cell lines for future studies. Project No. 4 involves the immunopathogenesis of psoriasis in which the etiology and pathophysiology of this common and enigmatic disease are primary goals. This project involves the use of SCID-Human skin xenografts and emphasizes both innate and adaptive immune reactions. Specific areas of interest include defining the role of NK-T cells in psoriasis, as well as various resident dendritic cell subsets including dermal dendritic cells and epidermal Langerhans cells. Nickoloff representative publications
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Mitchell
Denning, PhD
Denning’s laboratory studies the role of the protein kinase C (PKC) family of serine/threonine kinases in skin cancer formation. PKC is a central regulator of normal keratinocyte differentiation and cell cycle withdrawal. PKC also is the major receptor for the phorbol ester tumor promoting agents commonly used in mouse skin carcinogenesis experiments. The lab is investigating the effects of PKC activation on cell cycle machinery to understand how PKC activation triggers irreversible growth arrest in normal, but not neoplastic, human keratinocytes. The lab also is exploring the role of PKC activation in the ultraviolet radiation death effector pathway. UV radiation from the sun is the main causative agent for human skin cancers. They have found that the delta isoform of PKC becomes aberrantly activated in human keratinocytes exposed to UV radiation, resulting in apoptosis. PKC delta activation is both necessary and sufficient for apoptosis, however PKC delta is inactivated or down-regulated in transformed keratinocytes. Denning’s lab is investigating if the loss of PKC delta function provides a selective survival advantage from UV-induced apoptosis. Finally, the lab is studying altered PKC signaling in melanoma. Activation of PKC has opposite effects on the growth of normal and malignant melanoma cells, causing growth stimulation in normal melanocytes and growth inhibition in malignant melanoma cells. The selective growth inhibition of malignant cells makes PKC an attractive therapeutic target for melanoma. The long-term goal of these studies is to identify critical signaling molecules to target for cancer prevention and treatment. Denning representative publications _______________________________________________________________________________________________________
Caroline Le Poole, PhD Department of Pathology Dr. Le Poole studies the immune response to melanocytic cells in vitiligo and melanoma. Autoimmune vitiligo strikes approximately 1% of the world population. Progressive depigmentation of the skin, the primary hallmark of this disease, can also occur in patients with malignant melanoma and is regarded as a positive prognostic factor for melanoma patients. A better understanding of the immune response that eliminates normal melanocytes from the skin in vitiligo can help us design new treatment strategies for both vitiligo and melanoma. In project 1, the effects of stress on the induction of an immune response to melanocytes are studied. Stress imposed on the skin by excessive sun-exposure, contact with bleaching phenols or mechanical trauma will result in upregulation of stress proteins, some of which will enhance local immune responses. The project entails studying stress protein expression and secretion and its effects on DC, T cells and melanocytes in vitro as well as in mouse models. In project 2, T cells are isolated from vitiligo skin and their reactivity to melanocytic cells is compared to that of T cells isolated from melanoma tumors. The TCR from highly reactive T cells are analyzed and cloned from transfection into melanoma patient PBL to redirect lymphocytes to the tumor. In project 3, we are testing the efficacy of dendritic cell effector functions against HPV infected epithelial cells. Such effector functions have been described for dendritic cells against full blown tumors, and here we are assessing the role of HPV encoded genes in sensitizing target cells to dendritic cell mediated killing in vitro and in vivo. Similar effector functions can participate in eliminating stressed epithelial cells from the skin in vitiligo. Le Poole representative publications ________________________________________________________________________________________________________
Jian-Zhong Qin, MD, PhD Department of Pathology Dr. Jian-zhong Qin works together with Dr. Brian J. Nickoloff studying the molecular mechanisms of drug resistance and pursuing novel therapeutic targets in melanoma. Malignant melanoma presents a therapeutic challenge. At present no effective therapy exists for metastatic melanoma because at this stage the tumor cells are highly resistant the conventional chemotherapy. This drug resistance in melanoma is most likely caused by dysregulation of apoptotic processes. Therefore, identification of novel treatment agents targeting critical apoptotic pathways in melanoma is urgently needed. Our current work focuses on two projects: 1. Overcoming melanoma drug resistance by targeting proteasomes. We have observed that proteasome inhibitors preferentially induced significant apoptosis in human melanoma cells, both in-vitro and in-vivo, whilst sparing normal melanocytes. They selectively induce the BH3-only protein NOXA in melanoma cells, but not normal melanocytes, and this induction of NOXA occurred in a p53-independent fashion. The kinetics of NOXA induction correlate with the activation of apoptotic machinery in melanoma cells. Blocking induction of NOXA using an antisense oligonucleotide significantly reduces the apoptotic response. We are now further characterizing the signal pathways leading to tumor selective killing and Noxa induction by targeting proteasome in melanoma. 2. Targeting the Notch signal pathway for melanoma treatment. The Notch receptor and signal pathway controls differentiation, proliferation and apoptosis in a variety of different cellular contexts. Our preliminary data revealed strong expression of Notch 1, 2, 4 receptors in most primary and metastatic melanoma tissues, indicating that Notch signaling may play a role in human melanoma. Strategies targeting the Notch pathway could potentially be used to improve the effectiveness of melanoma treatment. We are currently studying the validity of the Notch pathway as a new therapeutic target in melanoma. By inhibiting the Notch signal pathway with a variety gamma secretase inhibitors and specific RNA interference (RNAi) techniques, we detect melanoma cell viability both in vitro and in vivo. We also dissect the signal pathways of tumor cell death after interrupting Notch signaling. Qin representative publications ________________________________________________________________________________________________________ Leonid Sitailo, PhD Department of Pathology Dr. Leonid Sitailo works together with Dr. Mitchell Denning on the signal transduction pathway(s) of UV induced apoptosis in human keratinocytes. A deep understanding of the molecular details of UV induced apoptosis is the foundation for our knowledge of skin carcinogenesis. Our undergoing work focuses on:
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The role of protein kinase PKC delta in apoptosis, the
regulation of PKC delta activity by phosphorylation or
caspase cleavage, its substrate specificity and
interaction with binding partners.
Bcl-2 family of proteins, especially the function of
anti-apoptotic Mcl-1 protein in PKC delta-dependent
apoptosis in human keratinocytes.
Sitailo
Representative Publications
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