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Different therapies for the treatment of colorectal cancer

Feb 26th 2020 at 1:32 AM

Although the advent of a series of innovative therapies has led to a rise in the survival rate of patients with advanced colorectal cancer, this type of cancer—colorectal cancer—is still one of the top five cancers in the world, with its morbidity and mortality ranking fourth and second, respectively. About one in every 20 people will develop colorectal cancer in their lifetime.

Gene is to be blamed.

At the end of the 20th century and the beginning of the 21st century, scientists has gained a thorough and better understanding of colorectal cancer as a result of development of disciplines and technologies such as molecular biology and gene sequencing, thus gradually found the root cause of this disease.

In 1987, Professor Walter Bodmer of the University of Oxford discovered the formation of Familial Adenomatous Polyposis (FAP) in hereditary colorectal cancer is related to a type of APC on chromosome 5. Later, it was found that APC is a tumor suppressor gene, which normally prevents the cell from proliferating. When it is mutated, the cell will become out of control and become a cancer cell.

Thanks to the development of genomics, in 2006-2007, American scientists successfully mapped the gene sequence of cancers such as colon cancer and identified nearly 200 genes associated with these diseases. These milestones have laid a solid foundation for researchers to develop targeted therapies.

Targeted therapy

Until 2004, colorectal cancer ushered in two targeted drugs: the EGFR inhibitor Erbitux (cetuximab) and the VEGF inhibitor Avastin (bevacizumab). The EGFR regulates cell proliferation, differentiation, apoptosis, invasion, and angiogenesis by binding signaling to the nucleus. The study found that 49%-82% of colorectal cancers have EGFR overexpression, so Erbitux can kill cancer cells by inhibiting EGFR on the surface of cancer cells.

The mechanism of action of Avastin is different from that of Erbitux. The study found that tumor cells acquire the "nutrition" needed for growth and reproduction by establishing their own vascular network, which is a protein essential for tumor blood vessel growth. Thus, Avastin prevents their binding to the VEGF receptor (VEGFR) by binding to VEGF, cutting off the "feeding channel" of the tumor to inhibit its growth and metastasis. It is worth mentioning that Avastin is also the first targeted drug in the history of cancer treatment to "stop tumor growth by inhibiting blood vessel growth."

At present, targeted drugs targeting EGFR and VEGF/VEGFR have become a new direction for the treatment of metastatic colorectal cancer. Before the advent of targeted therapy, the median overall survival of metastatic colorectal cancer with chemotherapy alone was about 20 months. By contrast, targeted drugs, when combined with chemotherapy, can increase this number to about 30 months, making the risk of death drop by 56%.

Gene therapy

In the 21st century, with the deepening of research on colorectal cancer, researchers realize that this disease is a complex, highly molecularly heterogeneous disease, and found more genes related to colorectal cancer, such as KRAS gene mutations, BRAF gene mutations, PIK3CA mutations, HER2 amplification, and NTRK gene fusion.

When these genes are surfaced, the treatment of colorectal cancer has begun to enter the era of precise treatment of the "drugs" of genes. At present, several innovative therapies for specific gene mutations have been approved for marketing, such as Bristol-Myers Squibb's PD-1 inhibitor Opdivo (nivolumab) and Opdivo and CTLA-4 inhibitor Yervoy (ipilimumab). The combination therapy has been approved by the US FDA for patients with metastatic colorectal cancer carrying MSI-H or dMMR. In addition, researchers are currently developing targeted drugs for colorectal cancer patients with mutations in BRAF, KRAS and other genes.

Prevention is even more important than treatment.

Treatment itself is of course very important, but some intestinal adenomatous polyps can take ten years or even longer to develop into cancer, and there are no obvious symptoms in the early stage. Therefore, prevention is more important for colorectal cancer.

Today, many advanced examinations such as sigmoidoscopy, colonoscopy, and virtual colonoscopy are used in the screening of colorectal cancer. The American Cancer Society recommends regular screening for colorectal cancer in the general population aged 45-75. In addition to colonoscopy, genetic testing also plays an important role in the prevention of colorectal cancer. At the same time, studies also found that colorectal cancer is related to age, gender, and long-term smoking, excessive drinking as well as intake of large amounts of fat or red meat.

Conclusion

The high molecular heterogeneity of colorectal cancer determines that an innovative targeted therapy can only benefit some patient. Many patients have no targeted drugs. Therefore, scientists are also trying to explore innovative treatments such as new targeted drugs, vaccines, and stem cell therapies. BOC Sciences is a major supplier of small molecules like EGFR inhibitor, VEGF inhibitor and PD-1 inhibitor, as well as other chemicals like impurities, metabolites, APIs, intermediates and pharmaceutical excipients. Meanwhile, BOC Sciences is dedicated to offering solutions to the industry’s most pressing drug development issues throughout lead discovery, lead optimization to synthesis, purification and formulation, using techniques and platforms like screening libraries, computer aided drug discovery.

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