Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antigenics is developing a therapeutic cancer vaccine based on heat-shock proteins (HSPs). The vaccine [HSPPC-96, Oncophage] is in a pivotal phase III clinical trial for renal cancer at 80 clinical sites worldwide. The trial is enrolling at least 500 patients who are randomised to receive surgical removal of the primary tumour followed by out-patient treatment with Oncophage((R)) or surgery only. This study was initiated on the basis of results from a pilot phase I/II study and preliminary results from a phase II study in patients with renal cell cancer. In October 2001, Oncophage was designated as a fast-track product by the Food and Drug Administration in the US for the treatment of renal cell carcinoma. Oncophage is in phase I/II trials in Italy for colorectal cancer (30 patients) and melanoma. The trials in Italy are being conducted at the Istituto dei Tumouri, Milan (in association with Sigma-Tau). Preliminary data from the phase II trial for melanoma was presented at the AACR-NCI-EORTC International Conference in Florida, USA, in October 2001. Oncophage is also in a phase I/II (42 patients) and a phase II trial (84 patients) in the US for renal cell cancer, a phase II trial in the US for non-Hodgkin's lymphoma (35 patients), a phase II trial in the US for sarcoma (20-35 patients), a phase I/II trial in the US for melanoma (36 patients), and phase I/II trials in Germany for gastric (30 patients) and pancreatic cancers. A pilot phase I trial in patients with pancreatic cancer began in the US in 1997 with 5 patients enrolled. In November 2000, Antigenics announced that this trial had been expanded to a phase I/II study which would now include survival as an endpoint and would enroll 5 additional patients. The US trials are being performed at Memorial Sloan-Kettering Cancer Center and the M.D. Anderson Cancer Center. The trials in Germany are being carried out at Johannes Gutenberg-University Hospital, Mainz. Oncophage is an autologous vaccine consisting of purified complexes of tumour-derived HSPs linked to tumour antigen peptides. When these HSPPC are readministered to a patient following surgery or biopsy of the tumour, the antigenic tumour peptides are expressed on the surface of potent antigen-presenting cells of the immune system, such as macrophages and dendritic cells. This stimulates a much more powerful anti-tumour immune response than that generated by expression of the same antigens by the tumour cell. Thus, Antigenics autologous HSP technology is attractive because it is highly specific for individual patients and circumvents the need for identification of specific antigens for individual cancers (i.e. it does not require definition of the antigenic epitopes on cancer cells) and it overcomes the immune tolerance associated with various tumours. Oncophage is manufactured in a 10-hour process from surgically resected autologous tumour. A minimum of 1-3g of tumour tissue is required to produce enough Oncophage for a course of treatment. The major limiting factor for producing Oncophage from a particular cancer is the ability to purify HSP from that cancer. From clinical studies to date, Antigenics has been able to produce HSP from 100, 98, 90, 71 and 30% of colorectal carcinoma, renal cell carcinoma, melanoma, gastric cancer and pancreatic cancer tumours, respectively. The low success rate with pancreatic cancers is because of the high concentration of proteases in that tissue type. HSPs are a family of highly conserved proteins present in the cells of all organisms. They function as molecular chaperones, assisting the correct folding of polypeptides and aiding intracellular protein transport. In addition, HSPs associate with a broad range of peptides derived from intracellular protein degradation, including antigenic peptides produced in tumour cells. Antigenics has exclusively licensed worldwide rights to its HSP immunotherapeutic complexes from Mount Sinai School of Medicine and Fordham University in the USA. On 3 November 1998, Antigenics was issued a US patent (5,830,464) covering immunotherapy in which antigen-presenting cells are isolated and mixed with heat shock protein-antigen complexes purified from patients' tumours. The patent was issued to Fordham University, New York, US, who subsequently licensed it to Antigenics. Antigenics has an agreement with Sigma Tau, under the terms of which the latter company will fund 2 clinical trials in return for an option to market Oncophage in Italy, Portugal, Spain and Switzerland. Antigenics also has an agreement with Medison for marketing of Oncophage in Israel.
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PMID:Cancer vaccine--Antigenics. 1190 4

T lymphocytes play an important role in tumor rejection and their response to human malignant melanoma has been well documented. In contrast, the existence of cytotoxic T lymphocytes (CTL) to pancreatic cancer remains unclear. Tumor-associated lymphocytes (TAL) and peripheral blood monocytes (PBMC) were isolated from pancreatic cancer patients. Tumor-specific CTL were generated from TAL and PBMC using solid-phase anti-CD3, low-dose IL-2 (50 IU/ml) and repetitive autologous tumor stimulation. The specificity of CTL was tested in standard cytotoxicity assays using autologous tumor cells, autologous fibroblasts when available, several allogeneic pancreatic tumor cells and the NK-sensitive cell line K562. Anti-HLA-Class I MAb, W6/32, was used to demonstrate that tumor-specific CTL were HLA-Class I restricted. HLA-molecules of human pancreatic cancer cells were washed out using acid elution. Eight consecutive, histologically confirmed pancreatic cancer specimen as well as peripheral blood mononuclear cells were analyzed. CTL were capable of lysing autologous tumor cells significantly after 3 stimulations with autologous tumor cells. T cell mediated recognition was HLA-Class I restricted as shown by incubation with MAb anti-HLA-Class I. In case of HLA-A2 positivity, incubation of tumor cells in cytotoxicity assays resulted in significant inhibition. Autologous fibroblasts or K562 cells were lysed significantly less. HLA-Class I molecule elution resulted in significantly lower recognition of these cells by CTL. These results show for the first time in a larger series the possibility of generating CTL in human pancreatic cancer. The identification of new tumor associated antigens or tumor antigens will be crucial for establishing new treatment strategies.
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PMID:Cytotoxic T lymphocyte mediated recognition of human pancreatic cancer cells. 1194 97

Strabismus 1 (STB1/VANGL2) and Strabismus 2 (STB2/VANGL1), which have been cloned and characterized using bioinformatics and cDNA-PCR, are human homologues of Drosophila tissue polarity gene strabismus (stbm)/Van Gogh (Vang). STB1 and STB2 are tetra-membrane-spanning proteins with 73.1% total-amino-acid identity. Serine-rich domain and Strabismus-homology (STH1 and STH2) domains are conserved among human STB1, STB2, Xenopus Stbm, and Drosophila Stbm. STH2 domain with the C-terminal Ser/Thr-X-Val motif is implicated in binding with Dishevelled (DVL) proteins. STB1 gene is clustered with CASQ1 gene on human chromosome 1q21-q23, while STB2 gene is clustered with CASQ2 gene on human chromosome 1p13. STB1 and STB2 genes are located around cancer susceptibility loci or recombination hot spots in the human genome. STB1 is moderately expressed in K-562 (leukemia), G-361 (melanoma), and MKN7 (gastric cancer) cells. STB2 is highly expressed in MKN28, MKN74 (gastric cancer), BxPC-3, PSN-1, and Hs766T (pancreatic cancer) cells. On the other hand, STB1 and STB2 are significantly down-regulated in several cancer cell lines and primary tumors. Xenopus homologue of human STB1 and STB2 regulates negatively the WNT - beta-catenin signaling pathway. Loss-of-function mutations of genes encoding negative regulators of WNT - beta-catenin signaling pathway lead to carcinogenesis. Based on functional aspects and human chromosomal loci, STB1 gene and STB2 gene are predicted to be potent tumor suppressor gene candidates. STB1 and STB2 might be suitable targets for tissue engineering in the field of re-generative medicine and for chemoprevention and treatment in the field of clinical oncology.
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PMID:Strabismus (STB)/Vang-like (VANGL) gene family (Review). 1206 Aug 45

Hereditary pancreatic cancer (PC) appears to be exceedingly heterogeneous, as evidenced by its association with a variety of integrally associated diverse cancers and/or differing mendelian inherited cancer syndromes, which include the Lynch syndrome II variant of hereditary nonpolyposis colorectal cancer, hereditary breast-ovarian cancer syndrome in families with the BRCA2 mutation, hereditary pancreatitis, Peutz-Jeghers polyposis and the familial atypical multiple-mole melanoma syndrome in families with the CDKN2A (p16) germline mutation. Because of this heterogeneity, we provide a conservative estimate that about 5% (1,460) of PC cases in the US annually are hereditary. Although this number is relatively small, members of hereditary PC families serve as excellent models for studying the etiology, natural history, biomarkers, pathogenesis, potential carcinogenic exposures and their perturbation of underlying genetic events, and treatment of PC. These individuals would benefit greatly from method(s) capable of detecting cancer at an early stage, and such knowledge would also be useful for improving the diagnosis of the much more common 'sporadic' form of PC.
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PMID:Hereditary pancreatic cancer. 1212 Feb 26

Family history of pancreatic cancer, the fifth leading cause of cancer death in the United States, confers a 1.5-13-fold higher risk of developing pancreatic cancer. Pancreatic cancer is associated with several genetic syndromes, including hereditary breast cancer (BRCA2), familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary nonpolyposis colorectal cancer (HNPCC). However, these syndromes explain little of the observed familial aggregation of pancreatic cancer. We performed complex segregation analysis on 287 families ascertained through an index case diagnosed with pancreatic cancer at the Johns Hopkins Medical Institutions between January 1, 1994 and December 31, 1999. We tested for the presence of a major gene controlling either the "age-at-onset of pancreatic cancer" of "susceptibility to pancreatic cancer," and incorporated smoking data on kindred members as a covariate. We found evidence for involvement of a major gene in the etiology of pancreatic cancer. Whether inheritance was modeled as "age-at-onset" or "susceptibility," nongenetic transmission models were strongly rejected. However, modeling "age-at-onset" provided a better fit to the observed data than did modeling "susceptibility." The most parsimonious models included autosomal-dominant inheritance of a rare allele. Under the age-at-onset model, approximately 0.7% of the population appears to be at high risk of developing pancreatic cancer due to this putative gene, whereas 0.4% of the population is at high risk under the susceptibility model. Inclusion of smoking as a covariate did not significantly improve the fit of these models. This hospital-based segregation analysis of pancreatic cancer found evidence supporting the role of a rare major gene influencing risk of pancreatic cancer.
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PMID:Evidence for a major gene influencing risk of pancreatic cancer. 1221 7

Virulizin, a biological response modifier, is a mixture of proteins and peptides that have been extracted from bovine reticuloendothelial tissue that activates macrophages. It is being developed by Lorus Therapeutics (formerly Imutec Pharma) for the treatment of various cancers and had completed phase II clinical trials in Canada for the treatment of pancreatic cancer and advanced malignant melanoma. The commencement of phase III clinical trials in Canada, for the treatment of pancreatic cancer, was delayed due to quality control problems with batches of virulizin and all clinical trials of virulizin were suspended as Lorus underwent a major restructuring programme. However, phase I/II clinical trials are now underway again in Canada in HIV-positive patients with Kaposi's sarcoma and for the treatment of pancreatic cancer. A phase I/II clinical trial is also underway in patients with pancreatic cancer in the USA. Lorus announced in June 2000 that it had completed a meta analysis of three phase I/II studies of virulizin that showed the drug increased survival and improved quality of life for pancreatic cancer patients. Based on these positive results, Lorus initiated a phase III trial to be conducted at 40 sites in North America in November 2001. The study aims to enrol 350 patients with advanced pancreatic cancer and will test the effectiveness of virulizin as first- and second-line treatment of pancreatic cancer. The study will compare virulizin + gemcitabine with gemcitabine alone as first-line therapy, while second-line treatment will involve patients who have failed to respond to gemcitabine. Some of these patients will receive virulizin + fluorouracil while another group will receive only fluorouracil. The study is scheduled to complete in 2004 or early 2005. Virulizin received orphan drug status for this indication from the US FDA in February 2001. Lorus received fast track designation from the FDA in June 2002 for virulizin for the treatment of pancreatic cancer. Virulizin is registered for the treatment of malignant melanoma in Mexico and is due to be launched there in 2002. Lorus has entered into an exclusive 7-year distribution agreement with Faulding Canada Inc., giving Faulding (now part of Mayne Group) the right to market and sell virulizin in Mexico for the treatment of melanoma. Lorus will receive royalties from sales of the product and will be responsible for its manufacture. In April 2002, Mayne exercised its option to acquire the distribution rights for virulizin in Brazil. Lorus Therapeutics has signed a collaborative agreement with NaPro BioTherapeutics, USA, to study the efficacy of virulizin in combination with paclitaxel for the treatment of lung adenocarcinoma. Lorus is conducting preclinical studies of virulizin in human breast cancer, lung, ovarian and prostate cancer, and has reported successful activity of the agent in these indications. Lorus was awarded a patent by the US Patent and Trademark Office to protect the only known process used to create virulizin. This patent, in conjunction with the patents issued in Australia, South Africa, New Zealand, Korea and Singapore, broadens and strengthens the protection of Lorus' intellectual property rights regarding the process, composition and use of virulizin.
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PMID:Virulizin. 1240 41

Germ-line mutations of the CDKN2A tumour suppressor gene have been reported in association with familial melanoma, sporadic melanoma with multiple primary lesions and also pancreatic cancer. We studied the hypothesis that patients with melanoma and additional unrelated cancers may harbour mutations in the CDKN2A gene. Twenty seven patients with histologically confirmed melanoma who also had additional cancers such as breast, colorectal, lymphoma and other neoplasms were studied. We also examined 17 additional patients, 13 of whom had a first-degree relative with melanoma and four who had two or more primary melanomas. Some patients belonged to more than one of these categories. No mutations of the CDKN2A tumour suppressor gene were detected among patients with melanoma and additional cancers. The previously described Met53Ile CDKN2A mutation located in exon 2 was detected in a female patient with melanoma metastatic to the regional lymph nodes, multiple primary cutaneous lesions, atypical naevi and a first-degree relative with melanoma. The studied cohort is too small for firm conclusions. However, it would appear that melanoma and additional, apparently unrelated, cancers developing in the same individual are likely to be related to a combination of low-risk susceptibility genes and environmental factors.
Melanoma Res 2002 Dec
PMID:The CDKN2A tumour suppressor gene: no mutations detected in patients with melanoma and additional unrelated cancers. 1245 45

Familial risk of pancreatic cancer has been mainly assessed through case-control studies based on reported but not medically verified cancers in family members. We used the nationwide Swedish Family-Cancer Database on 10.2 million individuals and 21,000 pancreatic cancers to calculate standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) for pancreatic cancer in 0- to 66-year-old offspring of parents with pancreatic or other specified tumors. Additionally, SIRs for second primary pancreatic cancers were analyzed after any first neoplasm. SIRs for pancreatic cancer (1.68, 95% CI 1.16-2.35) and pancreatic adenocarcinoma (1.73, 95% CI 1.13-2.54) were increased when a parent presented with pancreatic cancer. The risk was not dependent on diagnostic age of offspring or parents. Pancreatic cancer was associated with parental lung, rectal or endometrial cancer and with melanoma. SIRs for pancreatic cancer were 10.01 and 7.96 among offspring who were diagnosed before age 50 years when parents were diagnosed with squamous cell and adenocarcinoma of the lung, respectively, before age 60 years. The population-attributable proportion of familial pancreatic cancer was 1.1%. Risks for second pancreatic cancers were increased in men and women after small intestinal, colon and bladder cancer. The degree of familial clustering for pancreatic cancer and its population-attributable proportion were lower than the data cited in the literature. Clustering of pancreatic cancer with sites presenting in hereditary nonpolyposis colorectal cancer was noted. The strong association of pancreatic and lung cancers is puzzling, and it remains unclear to what extent this represents familial sharing of smoking habits.
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PMID:Familial and second primary pancreatic cancers: a nationwide epidemiologic study from Sweden. 1247 70

Oncolytic herpes simplex virus type 1 (HSV-1) vectors are emerging as an effective and powerful therapeutic approach for cancer. Replication-competent HSV-1 vectors with mutations in genes that affect viral replication, neuropathogenicity, and immune evasiveness have been developed and tested for their safety and efficacy in a variety of mouse models. Evidence to-date following administration into the brain attests to their safety, an important observation in light of the neuropathogenicity of the virus. Phase I clinical traits of three vectors, G207, 1716, and NV1020, are either ongoing or completed, with no adverse events attributed to the virus. These and other HSV-1 vectors are effective against a myriad of solid tumors in mice, including glioma, melanoma, breast, prostate, colon, ovarian, and pancreatic cancer. Enhancement of activity was observed when HSV-1 vectors were used in combination with traditional therapies such as radiotherapy and chemotherapy, providing an attractive strategy to pursue in the clinic. Oncolytic HSV-1 vectors expressing "suicide" genes (thymidine kinase, cytosine deaminase, rat cytochrome P450) or immunostimulatory genes (IL-12, GM-CSF, etc.) have been constructed to maximize tumor destruction through multimodal therapeutic mechanisms. Further advances in virus delivery and tumor specificity should improve the likelihood for successful translation to the clinic.
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PMID:Oncolytic herpes simplex virus vectors for cancer virotherapy. 1252 36

Using differential cDNA library screening techniques based on metastatic and nonmetastatic rat mammary adenocarcinoma cell lines, we previously cloned and sequenced the metastasis-associated gene mta1. Using homology to the rat mta1 gene, we cloned the human MTA1 gene and found it to be over-expressed in a variety of human cell lines (breast, ovarian, lung, gastric and colorectal cancer but not melanoma or sarcoma) and cancerous tissues (breast, esophageal, colorectal, gastric and pancreatic cancer). We found a close similarity between the human MTA1 and rat mta1 genes (88% and 96% identities of the nucleotide and predicted amino acid sequences, respectively). Both genes encode novel proteins that contain a proline rich region (SH3-binding motif), a putative zinc finger motif, a leucine zipper motif and 5 copies of the SPXX motif found in gene regulatory proteins. Using Southern blot analysis the MTA1 gene was highly conserved, and using Northern blot analysis MTA1 transcripts were found in virtually all human cell lines (melanoma, breast, cervix and ovarian carcinoma cells and normal breast epithelial cells). However, the expression level of the MTA1 gene in normal breast epithelial cells was approximately 50% of that found in rapidly growing adenocarcinoma and atypical epithelial cell lines. Experimental inhibition of MTA1 protein expression using antisense phosphorothioate oligonucleotides resulted in inhibition of growth and invasion of human MDA-MB-231 breast cancer cells with relatively high MTA1 expression. Furthermore, the MTA1 protein was localized in the nuclei of cells transfected with a mammalian expression vector containing a full-length MTA1 gene. Although some MTA1 protein was found in the cytoplasm, the vast majority of MTA1 protein was localized in the nucleus. Examination of recombinate MTA1 and related MTA2 proteins suggests that MTA1 protein is a histone deacetylase. It also appears to behave like a GATA-element transcription factor, since transfection of a GATA-element reporter into MTA1-expressing cells resulted in 10-20-fold increase in reporter expression over poorly MTA1-expressing cells. Since it was reported that nucleosome remodeling histone deacetylase complex (NuRD complex) involved in chromatin remodeling contains MTA1 protein and a MTA1-related protein (MTA2), we examined NuRD complexes for the presence of MTA1 protein and found an association of this protein with histone deacetylase. The results suggest that the MTA1 protein may serve multiple functions in cellular signaling, chromosome remodeling and transcription processes that are important in the progression, invasion and growth of metastatic epithelial cells.
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PMID:Tumor metastasis-associated human MTA1 gene and its MTA1 protein product: role in epithelial cancer cell invasion, proliferation and nuclear regulation. 1265 Jun 3


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