Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
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As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e. g., Melan-A/ MART-1, tyrosinase, gp 100). Some target antigens are specifically expressed in tumors of different types but not in normal tissues (e. g., MAGE-3), while other possible targets are antigens that are expressed at low level in normal tissues and are over-expressed in tumors of different types (e. g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (pS3) or tumor-specific post-translational modified proteins (under glycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, these antigens tend to be poorly inmmunogenic by themselves and vaccines containing them generally require the inclusion of potent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Many adjuvants currently under evaluation for use in cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via toll-like receptors (TLRs) and promote effective uptake, processing and presentation of antigen to T-cells in draining lymph nodes.Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for lipid A have allowed for a better understanding of how this immunostimulant functions with regard to induction of innate and adaptive immune responses.Although several lipid A species, including LPS and synthetic analogs, have been developed and tested as monotherapeutics for the treatment of cancer,1-8 only 3-O-desacyl-4'-monophosphoryl lipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL comprises the lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the l-phosphare have been removed by successive acid and base hydrolysis.9 LPS and MPL induce similar cytokine profiles, but MPLis at least 1OO-fold less toxic.9,10 lOMPL has been administered to more than 300, 000 human subjects in studies of next-generation vaccines.11 In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various cancer vaccines containing MPL, either alone or combined with other immunostimulants, Such as cell wall skeleton (CWS) of Mycobacterium phlei in the adjuvant Detox; Biomira, Inc.), the saponin QS-21 (in the adjuvants AS01B and AS02B; GSK Biologicals) or with QS-21 and CpG oligonucleotides (in the adjuvant AS15; GSK Biologicals) will be summarized. Combining MPL with other immunostimulants has been demonstrated to be advantageous in many cases and may be required to elicit the full complement of activities necessary to achieve an effective immune response and overcome the ability of tumors to evade attack by the immune system. In this chapter, information relating to vaccines targeting specific cancers will be presented in the first section, while information relating to vaccines targeting multiple tumor types by the induction of immune responses to shared TAAs is presented in the second section.
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PMID:Monophosphoryl lipid A (MPL) as an adjuvant for anti-cancer vaccines: clinical results. 2066 4

Mammary Paget's disease is rare and comprises about 0.62% of all breast cancer cases, only 1.65% of which occur in male patients. This case report involves a 76-year-old man who presented to his primary care physician with an itching, scaly, unilateral lesion involving the nipple skin. He underwent wide local excision of the lesion for a diagnosis of Bowen's disease (squamous cell carcinoma in situ). Histologic examination of the specimen revealed mammary Paget's disease with ductal carcinoma in situ in the underlying breast tissue. A panel of immunohistochemical stains revealed the Paget cells to be positive for cytokeratin 7, MUC1, GATA3, and androgen receptor and negative for cytokeratins 5/6, p63, SOX10, and MART-1/Melan-A. Paget cells were also negative for estrogen receptor and progesterone receptor, and positive for HER2/neu. However, the underlying ductal carcinoma in situ was positive for both estrogen receptor and progesterone receptor and negative for HER2/neu. This discordance, supported by the current literature, suggests an alternative etiology for Paget's disease in certain cases that cannot be explained by the well-established epidermotropic and transformative theories of Paget's disease evolution.
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PMID:Mammary Paget's Disease of the Male Breast: A Rare Case With an Unusual Immunohistochemical Profile. 3151 89