Browsing by Subject "skin cancer"

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    Basal Cell Skin Cancer: Information for patients and their families
    (2010-09-15) Johnson, Rebecca
    Basal cell skin cancer is the most common type of skin cancer in America. It can be cured with early diagnosis and treatment. Appropriate treatment depends on the appearance and location of the growth, with simple surgery being a common treatment. This pamphlet describes risk factors, tips for detecting skin cancers and treatment options.
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    Improving the Delivery of Molecularly-Targeted Agents to Effectively Treat Melanoma Brain Metastases
    (2015-03) Vaidhyanathan, Shruthi
    The FDA approval of molecularly-targeted drugs that specifically targeted aberrant signaling proteins has brought about new hope for the treatment of advanced melanoma. Historically, metastatic melanoma has been an untreatable devastating disease. Two BRAF inhibitors (vemurafenib and dabrafenib), a MEK inhibitor (trametinib), and a combination of dabrafenib and trametinib are currently in use and several other drugs are in clinical development. Melanoma is known to metastasize to distant organs such as the lung, liver and brain. A critical challenge in the successful treatment of metastatic melanoma is the effective treatment of brain metastases. A significant proportion of melanoma patients have brain metastases at autopsy. It is also known that once patients develop clinical signs of CNS disease, they have an abysmally poor survival (less than 6 months). This brings about an important question about the efficacy of current drugs in treating brain metastases. The blood-brain barrier is comprised of a tight network of endothelial cells that are sealed together by tight-junction (TJ) protein complexes. The BBB also expresses several efflux transport proteins that utilize ATP to pump drug molecules against a concentration gradient. Together, the TJ proteins and ATP-dependent efflux transport proteins are known to effectively limit the permeability of several chemotherapeutics across the blood-brain barrier. Of particular interest are two efflux transporters, P-glycoprotein (P-gp) and breast-cancer resistance protein (BCRP) that are known to be highly expressed at the BBB. One of the aims of this thesis project was to understand the factors that potentially limit the efficacy of molecularly-targeted drugs in treating deadly melanoma brain metastases. Through this work, we have shown that several molecularly-targeted agents are substrates for active efflux by P-gp and BCRP. Through a series of carefully planned in vitro experiments and elegant pharmacokinetic studies in mice we conclude that the limited brain distribution of vemurafenib, dabrafenib, trametinib, and GSK2126458 (a Pi3K/mTOR inhibitor) is due to their interaction with P-gp and BCRP. We also investigated potential differences in pharmacokinetics and pharmacodynamics of vemurafenib when administered as pharmacy grade Zelboraf; versus non-pharmacy grade vemurafenib. We observed that formulation differences that affect the solubility of a drug are extremely critical to designing and interpreting meaningful pre-clinical studies. Currently, we are conducting studies in a novel melanoma mouse model in order to understand the efficacy of molecularly- targeted drugs in treating brain metastases (single agent or in-combination). The findings of this thesis provide significant insight into the selection of rational drug combinations and are highly relevant to improving the treatment of melanoma brain metastases
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    Innate Immunogenetics Of Keratinocyte Carcinomas
    (2014-12) Vineretsky, Karin
    Keratinocyte carcinomas (KC) which include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin represent the most common malignancies in the world. UVR is the major risk factor associated with KC, and contributes to skin cancer carcinogenesis both as a mutagen and an immune suppressing agent. Exposures to arsenic, immunosupressive medications, beta-HPV, and individual susceptibility risk factors including genetic variability have also been implicated in KC development. Previous research was largely focused on the role of adaptive immunity in KC, while the role of innate immunity has not been fully investigated. Recent studies, including those on the action of Imiquimod, point to the centrality of innate immunity in KC pathogenesis. Natural killer (NK) cells of the innate immune system are the first line of defense against transformed and infected cells. NK cell killing capacity is determined by multiple inhibitory and activating cell surface receptors, including broad cellular-stress sensing natural killer group 2 member D (NKG2D) receptors, and highly diverse in gene content, copy number, and allelic polymorphisms killer-cell immunoglobulin-like receptors (KIR) that recognize self-human leukocyte antigen class I (HLA-I) ligands. Inter-individual variability of the KIR locus, and its interaction with cognate HLA-I, has been increasingly implicated in various disease settings including cancer. Genetic variability of NKG2D receptor activity has also been described in epithelial cancers. Given that NK cell function is influenced by these two classes of receptors, we hypothesized that genetic variability at these loci impacts innate immunity and BCC and SCC risk. Using a large population-based case-control study, a three part investigation was conducted. First investigation examined whether two genetic variants related to high natural cytotoxic activity of the NKG2D receptor decrease risk of KC and are modified by susceptibility and exposure factors including: sex, skin type, number of severe sunburns, glucocorticoids, and arsenic. This revealed differential effects of NKG2D genotype on KC risk by sex and skin type. The second study, determined whether KIR gene content alone and in combination with HLA-I ligands was associated with KC risk. The results suggested interactions of the activating KIR and HLA-I ligands may be implicated in control of BCC and to a lesser degree of SCC. The third study investigated the combined effects of KIR and NKG2D. NKG2D activity was assigned based on the number of alleles with high cytotoxic activity, and activating KIR were grouped based on the presence of 2DS1, 3DS1 and 2DS5 that were previously associated with reduced KC risk. The results showed reduced KC risk with the highest activating profile (containing 3 activating KIR and 2 or more NKG2D high activity alleles). Taken together, the results suggest a greater involvement of the innate immune response in the etiology of BCC, and to a lesser extent of SCC. In the context of SCC, these data suggest increased inflammation may deregulate the innate immune response.