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Attacking Specific Proteins May Help Future Therapies for Colorectal, Lung, and Pancreatic Cancer


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Genetic mutation is the common cause of cancer development and has been a central focus of targeted therapy research. Most common cancer-causing gene mutations are found at the core of cellular function that makes them undruggable. But a new study from the University of California, San Francisco discovered a way to attack specific proteins that cause colorectal, lung, and pancreatic cancer.

 

 

Each cell in the body has DNA that contains genes. Genes are responsible for cell functions such as development, growth, reproduction, and lifespan. Genes can be found in 46 chromosomes, divided into two sets of 23 chromosomes that a person inherited from their parents. One of the sets of 23 chromosomes determines the person’s gender while the other set of 23 determines that person’s physical characteristics which include inherited health conditions from the parents.

In order to control cell functions, genes create proteins that instruct cells. Genes must have the correct code to provide the proper instructions for the cells. In the event of a mutation, one or more genes in the cells may have changed, causing abnormal instruction which triggers uncontrolled cell growth leading to cancer. Genetic mutations are classified into two basic types:

 

 

1. Acquired genetic mutations occur when genes are damaged by external sources, such as subjection to radiation like ultraviolet rays, chronic exposure to certain chemicals and substances, and viral infections. This is the most common cause of cancer growth.

2. Germline genetic mutations are based on the inherited genetic codes from either one or both parents. The mutations can be found in every cell of the person including reproductive cells. An individual can pass germline mutations to their children. Inherited cancer accounts for 5 to 10 percent of all cancer cases. Moreover, this type of mutations can also pass non-cancer disorders, such as Huntington’s disease.

Scientists have dug deeper into cancerous growth triggered by genetic mutations. Studies revealed that many genes are vulnerable to mutations, such as the following:

- Some genes protect the body from abnormal cell growth by monitoring the speed of cell division. These genes are called tumor suppressor genes responsible for managing the life cycle of cells and repairing mismatched DNA. Examples of these genes are BRCA1 and BRCA2 found in breast tissue, and p53 or the “guardian of the genome” found in the chromosome 17. At least 50 percent of all cancer cases are associated with a missing or mutated p53 gene.

- Some repair genes can cause mutations. DNA repair genes fix the mistakes of copied DNA to prevent abnormalities. But errors in the DNA repair genes cannot fix the mistakes of copied DNA which triggers abnormalities and eventually, cancer. One example is Lynch syndrome wherein the mutation in DNA repair genes puts the person at 80 percent risk of colon cancer for life.

- Some genes cause healthy cells to become cancerous. These genes are called oncogenes that specialize in converting normal cells to malignant growths. The most common oncogenes are HER2 that cause breast and ovarian cancers, and the RAS family of genes that causes colorectal, lung, and pancreatic cancers.

The RAS gene family has been the main focus of the new study at UCSF. RAS acts as a major communication hub that transmits information from the outside to the inside of cells through proteins on surfaces of cells. The gene family can carry and pass on information to as many as 12 different signaling pathways within cells, such as the MAPK and PI3K pathways. The information exchange managed by the RAS genes causes changes in affected cells, leading to cell malignancies.

"While there are intense efforts to target signaling pathways within the cell, very little is understood about how RAS signaling can regulate the set of proteins expressed on the surface of a cell at any time. More studies in this area would help us understand how mutations in RAS signaling drive malignancy and may point to novel targets for antibody and cellular-therapy-based treatment in RAS-driven cancers,” said Dr. James Wells, the senior author of the study and a professor of pharmaceutical chemistry at UCSF.

 

 

With that insight, researchers suggest that attacking the proteins made by RAS genes can be a viable therapeutic approach in undruggable cancer types. They used mass spectrometry to analyze the RAS signaling in the cell line MCF10A. They found that a mutation in the KRAS gene, a gene from the RAS family called KRAS G12V, changed the signature of surface proteins, driven by the MAPK pathway signaling.

The researchers then generated and applied a resource of antibodies that targeted seven of RAS-induced proteins. The antibodies revealed that five of the proteins were distributed on cell lines which housed the KRAS mutations. In a parallel study, the team used a CRISPR-based technology called CRISPRi screen to turn off specific genes to unravel their functions. In both studies, the researchers found that one protein called CDCP1 is the common denominator. CDCP1 has been identified as a causal agent to cancer growth, metastasis, and progression. The researchers demonstrated in the lab setting that antibodies targeting CDCP1 could deliver therapeutic compounds to RAS-induced cancer cells.

“While our results provide a large number of interesting proteins to follow up, we decided to focus on targeting CDCP1. Overall, we've presented a novel technological pipeline for the discovery and application of antibodies to surface proteins regulated by cancer-causing signaling pathways,” said Dr. Wells.

[메디컬리포트=​Ralph Chen 기자]


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