Cancer is one of the leading causes of premature death worldwide. Furthermore, colorectal cancer is the second leading cause of death from cancer in the western world. Colorectal cancer is curable if diagnosed early. One of the major treatment protocols for colorectal cancer is surgery. With no additional therapy, surgery typically cures Duke's A colon cancer that invades the submucosa and Duke's B1 disease that invades the muscularis propria (Cohen et al., In: DeVita et al. (eds.), Cancer Principles and Practice of Oncology, Ed. 5, pp. 1144-1197. New York: Lippincott-Raven.).
The primary prognostic approach to identify differences among patients in early stages of the disease is the Tumor-Node-Metastasis (TNM) system (Graziano et al. (2003) Ann Oncol. 14, 1026-1038). However, the survival outcome varies among patients with similar pathological disease stages. There have been increasing demands to specify the molecular markers for more aggressive colorectal cancer in order to identify the disease well in advance and prescribe appropriate patient therapy. In response, new therapeutic strategies are needed to combat colorectal cancer.
It is known that the activity of N-myristoyltransferase (NMT) is highly elevated in colorectal cancer (Magnuson et al. 1995, J. Natl. Cancer Inst. 87, 1630-1635). NMT is an enzyme that catalyzes the myristoylation of proteins involved in diverse biological functions including oncogenesis (Rajala et al. (2000) Mol. Cell. Biochem. 204, 135-155; Selvakumar et al., (2002) Int. J. Mol. Med. 10, 493-500).
N-myristoyltransferase activity is increased in rat colonic tumors compared to those of normal appearing colonic mucosa (Magnuson et al., (1995) J. Natl. Cancer Inst. 87, 1630-1635.). Interestingly, NMT activity in the normal appearing mucosa of colon cancer bearing rats was similar to the activity found in colonic mucosa of control rats, suggesting that elevated NMT activity is restricted to the tumor site. Higher NMT activity is observed in rat colonic tumors when compared with the corresponding normal-appearing or normal mucosa. Furthermore, a several fold increase in NMT activity as compared to adjacent normal-appearing mucosa, was observed in polyps and stage B1 tumors located in the descending colon close to the rectum.
In addition to the rat model, elevated NMT activity and expression was also observed in human adenocarcinoma compared to that of normal appearing mucosa (Magnuson et al., (1995) J. Natl. Cancer Inst. 87, 1630-1635; Raju et al., (1997) Exp. Cell Res. 235, 145-154.). NMT activity in normal appearing mucosa is similar to that of Crohn's disease and the volvulus, indicating that elevated NMT activity is specific to cancer and is not a non-specific response to inflammatory conditions or noncancerous lesions. Rajala et al. (Cancer 2000; 88(9):1992-1999) showed increased expression on NMT in gall bladder tissue of patients with gall bladder cancer.
Previous work, however, has not established NMT as a marker for cancer, given the limitation that the elevated expression and activity of NMT in the tumor region is not accessible for prognostic/diagnostic purposes until a colonoscopy is performed and a tissue sample is available for protein analysis.
There is a need for non-invasive or minimally invasive technologies that can be used to detect cancer.