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Diagnosis and treatment of cancer:i

Diagnosis and treatment of cancer:i description/claims

This application is a divisional application of application Ser. No. 10/474,778, filed Oct. 10, 2003, which claims priority from Application PCT/GB02/01692, filed Apr. 11, 2002 and Provisional Application No. 60/283,295, filed Apr. 12, 2001, all of which are deemed incorporated by reference in their entirety in this application.

Not applicable.

The present invention relates to methods of determining whether a patient has cancer and whether the cancer is likely to metastasise; and it relates to methods of treating cancer, particularly breast cancer.

Cancer is a serious disease and a major killer. Although there have been advances in the diagnosis and treatment of certain cancers in recent years, there is still a need for improvements in diagnosis and treatment.

Cancer is a genetic disease and in most cases involves mutations in one or more genes. There are believed to be around 40,000 genes in the human genome but only a handful of these genes have been shown to be involved in cancer. Although it is surmised that many more genes than have been presently identified will be found to be involved in cancer, progress in this area has remained slow despite the availability of molecular analytical techniques. This may be due to the varied structure and function of genes which have been identified to date which suggests that cancer genes can take many forms, occur in different combinations and have many different functions.

Breast cancer is one of the most significant diseases that affects women. At the current rate, American women have a 1 in 8 risk of developing cancer by the age of 95 (American Cancer Society, Cancer Facts and Figures, 1992, American Cancer Society, Atlanta, Ga., USA). Genetic factors contribute to an ill-defined proportion of breast cancer cases, estimated to be about 5% of all cases but approximately 25% of cases diagnosed before the age of 40 (Claus et al (1991) Am J. Hum. Genet. 48, 232-242). Breast cancer has been divided into two types, early-age onset and late stage onset, based on an inflection in the age-specific incidence curve at around the age of 50. Mutation of one gene, BRCA1, is thought to account for approximately 45% of familial breast cancer, but at least 80% of families with both breast and ovarian cancer (Easton et al (1993) Am. J. Hum. Genet. 52, 678-701).

Breast carcinoma is potentially curable only when truly localised. The most common problem is either late presentation with overt metastases or, more frequently, the development of systemic metastases after apparent local cure. Metastatic breast carcinoma is highly chemosensitive and effective chemotherapy routinely induces disease remission, allowing delay in the onset of secondary disease or amelioration of the symptoms of extensive disease.

Recently, the role of tumour-associated antigens in the biology of cancer has begun to be investigated. Probably the best studied example of tumour-associated antigens are the MAGE antigens which are involved in melanoma and certain other cancers, such as breast cancer. Therapeutic and diagnostic approaches making use of the MAGE antigens are described in Gattoni-Celli & Cole (1996) Seminars in Oncology 23, 754-758, Itoh et al (1996) J. Biochem. 119, 385-390, WO 92/20356, WO 94/23031, WO 94/05304, WO 95/20974 and WO 95/23874. However, other tumour-associated antigens have also been implicated in breast cancer. For example, studies concerning the antigens expressed by breast cancer cells, and in particular how these relate to the antigenic profile of the normal mammary epithelial cell, have been and continue to be a major activity in breast cancer research. The role of certain antigens in breast cancer, especially the role of polymorphic epithelial mucin (PEM; the product of the MUC1 gene) and the c-erbB2 protooncogene, are reviewed in Taylor-Papadimitriou et al (1993) Annals NY Acad. Sci. 698, 31-47. Other breast cancer associated antigens include MAGE-1 and CEA.

Immunotherapeutic strategies and vaccines involving the MUC1 gene or PEM are described in Burchell et al (1996), pp 309-313, In Breast Cancer, Advances in Biology and Therapeutics, Calvo et al (eds), John Libbey Eurotext; Graham et al (1996) Int. J. Cancer 65, 664-670; Graham et al (1995) Tumor Targeting 1, 211-221; Finn et al (1995) Immunol. Rev. 145, 61-89; Burchell et al (1993) Cancer Surveys 18, 135-148; Scholl & Pouillart (1997) Bull. Cancer 84, 61-64; and Zhang et al (1996) Cancer Res. 56, 3315-3319.

Despite the recent interest in the breast cancer predisposing genes, BRCA1 and BRCA2, there remains the need for further information on breast cancer, and the need for further diagnostic markers and targets for therapeutic intervention.

For cancers such as breast cancer, present screening methods are therefore unsatisfactory; there is no reliable method for diagnosing the cancer, or predicting or preventing its possible metastatic spread, which is the main cause of death for most patients.

Grimes et al (1995) FEBS Lett. 369, 290-294 describes the differential expression of voltage-gated Na+ currents in two prostatic tumour cell lines and discusses their contribution to invasiveness in vitro. The cell lines studied were rat cell lines and there is no indication of which particular voltage-gated Na+ channels may be involved.

Laniado et al (1997) Am J. Pathol. 150, 1213-1221 describes the expression and functional analysis of voltage-gated Na+ channels in human prostate cancer cell lines and discusses their contribution to invasion in vitro. There is no indication of which particular voltage-gated Na+ channels may be involved.

Smith et al (1998) FEBS Lett. 423, 19-24 suggests that Na+ channel protein expression enhances the invasiveness of rat and human prostate cancer cell lines.

Grimes & Djamgoz (1998) J. Cell. Physiol. 175, 50-58 describes the electrophysiological and pharmacological characterisation of voltage-gated Na+ current expressed in the highly metastatic Mat-LyLu cell line of rat prostate cancer. The underlying VGSC is identified as belonging to the “tetrodotoxin-sensitive” class.

Dawes et al (1995) Visual Neuroscience 12, 1001-1005 describes the identification of voltage-gated Na+ channel subtypes induced in cultured retinal pigment epithelium cells.

UK Patent application No 0021617.6 entitled “Diagnosis and treatment of cancer” filed on 2 Sep. 2000 relates to methods of treatment and diagnosis of cancer, particularly prostate cancer concerning expression of VGSCs. VGSC expression correlates with pathological progression and a VGSC which is associated with human cancer, particularly prostate cancer and its metastases, is hNe-Na (SCN9A). The amino acid sequence of the protein, and cDNA of the mRNA encoding it is known (Klugbauer et al (1995) EMBO J. 14, 1084-1090).

Reviews of voltage-gated Na+ channels may be found in, for example, Black & Waxman (1996) Develop. Neurosci. 18, 139-152; Fozzard & Hanck (1996) Physiol. Rev. 76, 887-926; Bullman (1997) Hum. Mol. Genet. 6, 1679-1685; Cannon (1999); Marban et al (1998) J. Physiol. 508, 647-657; Catterall (2000) Neuron 26, 13-25; Plummer & Meisler (1999) Genomics 57, 323-331, and Goldin (2001) Ann Rev Physiol 63, 871-894. Some Na+ and other ion channels are well known to underly certain genetic defects as is described in Bullman (1997) Hum. Mol. Genet. 6, 1679-1685; Burgess et al (1995) Nature Genet. 10, 461-465; and Cannon (1998) Mol Neurology (J B Martin, Ed) Scientific American Inc., NY.

The involvement of VGSCs in breast cancer has not been demonstrated, and the particular VGSC(s) involved in human breast cancer have not been identified.

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