Colorectal cancer (CRC): is a term used to refer to colon and rectal cancers. The major differences between the two are the sites where the malignant growths occur and the fact that treatments may differ based on the location of the tumors. Colon cancer is the second leading casue of cancer deaths in the US. Each year over 100,000 new cases are diagnosed, and 50,000 patients die from the disease. In large part this death rate is due to the inability to diagnose the disease at an early stage. CRC is one of the most frequently diagnosed cancers and cancer related mortality remains unacceptably high despite improvements in understanding the events leading to malignant transformation of the colorectal epithelium. The lifetime risk of developing CRC is about 1 in 18 person (Cancer Statistics 2009: A Presentation from the American Cancer Society, 2009).
How CRC starts:
Colorectal carcinogenesis occurs as a multstep process that requires sequential or concomitant damage to several genes within and across cellular generations. The pathogenesis of CRC is characterized by a well defined sequence of events – from aberrant crypt proliferation or hperplasia over benign adenomas to carcinoma in situ and, finally, metastatic carcinoma.
Classification: Pathologists classify abnormal mucosal growth into 4 categories with increasing severity: 1) low-grade intraepithelial neoplasia (LIEN) or adenoma, which occurs in more than 30%, 2) high-grade intraepithelial neoplasia (HIEN) or advanced adenoma, occuring in more than 2%, 3) carcinoma in situs, where the cancerous growth is still confined to the mucosa, and 4) CRC, where the cancerous growth has invaded the submucosa.
Diagnosis:
CRC is diagnosed with an incidence rate of about 1% in persons over the age of 55 years with an average risk of the disease. Current technologies to detect CRC include:
1) in vitro diagnostics where a specimen is taken from the test person and analyzed for one or mroe biomarkers. Exemplary tests include guaic fecal occult blood test (gFOBT) or immunological fecal occult blood test (iFOBT).
2) imaging methods without interventional capabilites such as X ray.
3) imaging methods with interventional capabilities such as colonoscopy.
Treatment:
The prognosis for a case of colon cancer is vastly enhanced when malignant tissue is detected at the early stage known as polyps. Simply removal of malignant polyps (polypectomy) through colonoscopy is now routine, and curing the condition from this procedure is effectively guaranteed. Noramlly a malignant colon cancer will not cause noticeable symptoms (e.g., bowel obstruction, abdominal pain, anemia) until it has reached an advanced and far mroe serious stage of malignancy. At these stages, only risky and invasive procedures are available, including chemotherapy, radiation therapy, and colonectomy.
Adjuvant chemotherapy, radiation therapy and immunotherapy have shown some usefulness in the treatment of primary and advanced colorectal carcinoma. Chemotherapy alone has limiations in that the cancer cells often become resistant to a broad spectrum of structurally unrelated chemotherapeutic agents. In immunotherapy, immunoglobulin molecules are preferably specific for an antigen expressed on the cancer cells. For example, in the case of colorectal cancers, radiolabelled antibodies specific for A33 antigen have shown promise for targeting colon cancer cells (US2002/0187144A1).
Antibodies
Monoclona antibody (mAb) A33 recognizes a cell surface differentiation antigen (A33) of normal human gastrointestinal epithelium that is expressed in 95% of primary and metastatic colorectal cancerl cells, but is absent in most other normal tissues and tumor types. Consequently, the A33 antigenic system is the focus of several clinical studies in patients with colon cancer. Damasceno (Protein Expression and Purification 37 (2004) 18-26)
The anti-epidermal growth factor receptor (EGFR) mAbs cetuximab and panitumumab are effective in a subset of RAS/BRAF wild-type metastatic colorectal cancers (mCRCs). However, the onset of secondary resistance limits their clinical benefit. After EGFR blockage, about 20% of CRCs develop mutations in the EGFR extracellular domain (ECD) that impair antibody binding and are associated with clinical relapse. EGFR extracellular domain that impair antibody binding and are associated with clinical replace can be targeted more efficiently with antiboies that bind multiple regions of the EGFR ECD. Arena, Science Translational Medicine, 8(324) 324ra14).
Anti-PD-1 mAb: A small study showed incredible results against rectal cancer. All patietns had mismatch repair-deficient locally advanced rectal cancer and were given dostarlimab, an anti-PD-1 monoclonal antibody, every three weeks for six months. After at least six months of follow-up, all 14 pateints ahceived remission, with no evidence of tumors on medical scans and tests, digital rectal exam or biopsy.
—-Jemperli (dostarlimab -Glaxo Smith): is an anti-PD1 mAb for endometrail, colorectal, ehad and neck and lung cancers. In combination with chemotherpay, Jemperli was approved for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer. Phase III RUBY trail data showed that Jemperli and chemotherapty led to a 31% lower risk of death than those treated onoy with chemotherapy. In 2024, the FDA exapnded approval for Jemperli plus chemotherapy to include all pateints with primary advanced or recurrent endomethrial cancer.
Glaxo Smith’s targeted approach identified a specific biomarker, known as dMMR/MSI-H, that is present in some gynaecologic and other cancer types, such as colorectal cancer.
In 2024, Glaxo Smith announced updated resutls form a phase II study of dostarlimab in locally advanced dMMR rectal cancer, with all 42 patients showing no evidence of disease after treatment. This was a collaborative study with Memorial Sloan Kettering Cancer Center evaluating dostarlimab as a first line treatment and alternative to life altering surgery. The AZUR-1 trial is an ongoing global phase II registrational clinical trail taht aims to confirm these promising findings. Beased on this data, the FDA granted breathrough tehrpay designation for dostarlimab.