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Diagnosis and treatment of cancerRelated Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic AcidDiagnosis and treatment of cancer description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060166194, Diagnosis and treatment of cancer. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] 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 prostate cancer. [0002] 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. [0003] Cancer is a genetic disease and in most cases involves mutations in one or more genes. There are believed to be around 60,000 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 and have many different functions. [0004] Carcinoma of the prostate has become a most significant disease in many countries and it is the most commonly diagnosed malignancy in men in the western world, its occurrence increasing significantly with age. Over the last 20 years the mortality rates have doubled and it is now the second commonest cause of male cancer deaths in the Western world (Wingo et al (1995) Cancer J. Clin. 45, 8-30; Mortality Statistics: Cause England and Wales. OPCS DH2 19, 1993, Her Majesty's Stationery Office). The prevalence of prostate cancer has increased by 28% in the last decade and this disease now accounts for 12% of the total cancers of men in England and Wales (Cancer Statistics: Registrations England and Wales. OPCS MBI No 22, 1994, Her Majesty's Stationery Office; Foster et al (1999) Br. J. Urol. 83, 171-194). By the year 2018 it is expected to be the biggest killer with 50% of the male population suffering from it (80% by age 80 years). Recent evidence suggests that prostate cancer is also increasing amongst younger men as well (Br J Cancer (1999) 79, 13-17). These increases and the recent deaths of many public figures from prostatic cancer have served to highlight the need to do something about this cancer. It has been suggested that the wider availability of screening may limit mortality from prostate cancer. [0005] Prostate cancer screening currently consists of a rectal examination and measurement of prostate specific antigen (PSA) levels. These methods lack specificity as digital rectal examination has considerable inter-examiner variability (Smith & Catalona (1995) Urology 45, 70-74). Measurement of serum prostate specific antigen (PSA), synthesised by the epithelial cells of the prostatic acini and ducts and secreted as a normal constituent of seminal fluid, is currently the most commonly applied diagnostic marker of the cancer (e.g. Gao et al (1997) The Prostate 31, 264-281). However, PSA measurements can give inconsistent information so that some patients with prostate cancer have low levels of PSA, while PSA levels may be elevated in the presence of non-malignant prostatic disease, for example benign prostatic hyperplasia (BPH), prostatic inflammation and other conditions (e.g. Mandelson et al (1995) Annu. Rev. Public Health 16, 283-306; Flood et al (1996) J. Gen. Int. Med. 11, 342-349; Morgan et al (1996) The Prostate 57, 58-63; Chan & Sulmasy (1998) Am. J. Med. 108, 226-274. The comparative failure of PSA as a diagnostic test was shown in 366 men who developed prostate cancer while being included in the Physicians Health Study, a prospective study of over 22,000 men. PSA levels were measured in serum, which was stored at the start of the study, and elevated levels were found in only 47% of men developing prostate cancer within the subsequent four years (Gann et al (1995) JAMA b 4 273, 289-294). [0006] 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. [0007] Grimes et al (1995) FEBS Lett. 369, 290-294 describes the differential expression of voltage-activated Na.sup.+ 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 Na.sup.+ channels may be involved. [0008] Laniado et al (1997) Am J. Pathol. 150, 1213-1221 describes the expression and functional analysis of voltage-activated Na.sup.+ channels in human prostate cancer cell lines and discusses their contribution to invasion in vitro. There is no indication of which particular Na.sup.+ channels may be involved. [0009] Smith et al (1998) FEBS Lett. 423, 19-24 suggests that Na.sup.+ channel protein expression enhances the invasiveness of rat and human prostate cancer cell lines. [0010] Grimes & Djamgoz (1998) J. Cell. Physiol. 175, 50-58 describes the electrophysiological and pharmacological characterisation of voltage-gated Na.sup.+ current expressed in the highly metastatic Mat-LyLu cell line of rat prostate cancer. [0011] Dawes et al (1995) Visual Neuroscience 12, 1001-1005 describes the identification of Na.sup.+ channel subtypes induced in cultured retinal pigment epithelium cells. [0012] Reviews of Na.sup.+ 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); and Marban et al (1998) J. Physiol. 508, 647-657. Some Na.sup.+ 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. However, no Na.sup.+ channel sequence is used presently for diagnostic purposes. [0013] Thus, although previous work may have suggested some general role for voltage-gated Na.sup.+ channels (VGSCs) in prostate cancer and its metastasis based on work in cell lines, until now it has not been possible to make use of this information effectively since the involvement of VGSCs in prostate cancer in vivo has not been demonstrated, and the particular VGSC(s) involved in human prostate cancer have not been identified. [0014] We have now found, surprisingly, that VGSC expression correlates with pathological progression and that the VGSC which is associated with human cancer, particularly prostate cancer and its metastases, is hNe--Na (also termed Na.sub.v1.7). As noted above, this is a known VGSC (although not previously known to be associated with human cancer or cancer cell lines, in particular human prostate cancer) and an amino acid sequence of the protein, and cDNA of the mRNA encoding it has been reported (Klugbauer et al (1995) EMBO J. 14, 1084-1090). hNe--Na (human) and PN1(rat) correspond to the SCN9A gene, as discussed in Example 1. Recently, a new VGSC nomenclature has been adopted (Goldin et al (2000) Neuron 28(2), 365-368). In this system hNe--Na and PN1 are the human and rat orthologs, respectively, of Na.sub.v1.7. [0015] The chromosomal location of hNe--Na has not yet been determined. However, the mouse equivalent has been located to the voltage-gated Na.sup.+ channel cluster on mouse chromosome 2 (Beckers et al (1997) Genomics 36, 202-205). This cluster is also present in human chromosome 2 where hNe--Na may similarly be present (Malo et al (1994) Cytogen. Cell. Genet. 67, 178-186; Malo et al (1994) Proc. Natl. Acad. Sci. USA 91, 2975-2979; George et al (1994) Genomics 19, 395-397). The hNe--Na gene (human SCN9A) intron/exon organisation has not yet been determined but could be inferred from other known, conserved VGSC intron positions (Loughey et al (1989) Cell 58, 1143-1154; George et al (1993) Genomics 15, 598-606; Wang et al (1996) Genomics 34, 9-16; and Sonslova et al (1997) Genomics 41, 201-209). [0016] The brain-type Na.sup.+ channels (rat brain I-III (Noda et al (1986) Nature 322, 826-828; Kayano et al (1988) FEBS Lett. 228, 187-194) that are most similar to hNe--Na are 20% different over the whole sequence (human skeletal, 30%; heart 34% different). However, (i) if sequence comparison is made within specific structural/fiinctional domains this homology is much reduced (eg first one-third of DII-DIII cytoplasmic linker region is only 45% homologous to the most similar channel (RBII/HBII); (ii) hNe--Na has sufficiently different regions (eg residues 446-460: EYTSIRRSRIMGLSE) to make specific antibodies (see, for example, Toledo-Aral et al (1997) Proc. Natl. Acad. Sci. USA 94, 1527-1532). [0017] It is an object of the invention to provide methods useful in providing diagnoses and prognoses of cancer, especially prostate cancer, and for aiding the clinician in the management of cancer, particularly prostate cancer. In particular, an object of the invention is to provide a method of assessing the metastatic potential of cancer, in particular prostate cancer. [0018] Further objects of the invention include the provision of methods of treatment of cancer, in particular prostate cancer, and methods of identifying compounds which selectively inhibit the VGSC associated with human cancer, particularly prostate cancer, since these may be useful in treating cancer. [0019] A first aspect of the invention provides a method of determining the susceptibility of a human patient to cancer comprising the steps of (i) obtaining a sample containing nucleic acid and/or protein from the patient; and (ii) determining whether the sample contains a level of hNe--Na voltage-gated Na.sup.+ channel nucleic acid or protein associated with cancer. [0020] A second aspect of the invention provides a method of diagnosing cancer in a human patient comprising the steps of (i) obtaining a sample containing nucleic acid and/or protein from the patient; and (ii) determining whether the sample contains a level of hNe--Na voltage-gated Na.sup.+ channel nucleic acid or protein associated with cancer. [0021] It will be appreciated that determining whether the sample contains a level of hNe--Na VGSC nucleic acid or protein associated with cancer may in itself be diagnostic of cancer or it may be used by the clinician as an aid in reaching a diagnosis. [0022] For example, in relation to prostate cancer, it is useful if the clinician undertakes a histopathological examination of biopsy tissue or measures plasma PSA level or carries out external digital examination or carries out imaging. Recently, the possibility of using the blood IGF-1 level has also been suggested (Chan et al (1998) Science 279, 563-566). It will be appreciated that the clinician will wish to take in to account these or other factors, as well as consider the level of said VGSC, before making a diagnosis. [0023] A third aspect of the invention provides a method of predicting the relative prospects of a particular outcome of a cancer in a human patient comprising the steps of (i) obtaining a sample containing nucleic acid and/or protein from the patient; and (ii) determining whether the sample contains a level of hNe--Na voltage-gated Na.sup.+ channel nucleic acid or protein associated with cancer. [0024] Thus, the method of the third aspect of the invention may be useful in prognosis or aiding prognosis. The method may be used as an adjunct to known prognostic methods such as histopathological examination of biopsy tissue, or measurement of plasma PSA levels, external digital examination or imaging. Continue reading about Diagnosis and treatment of cancer... 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