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Science: “Cancer King” Pancreatic Cancer Finally Has a New Dawn of Treatment

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A new study conducted by scientists at the Perelman School of Medicine at the University of Pennsylvania shows that DNA mutations that frequently occur in the development of many pancreatic tumors appear to make these cancers vulnerable to existing drugs called PARP inhibitors.
The discovery was published in “Science Progress” recently. Studies have shown that in the most common types of pancreatic tumors, as many as two-thirds of patients have a copy of the gene missing in the tumor cells. Scientists at the University of Pennsylvania found that although this deletion seems to help tumor growth, the loss of the remaining copies of MYBBP1A in tumor cells has the opposite effect, thereby greatly reducing cell growth.

Science: "Cancer King" pancreatic cancer finally has a new dawn for treatment
Science: “Cancer King” pancreatic cancer finally has a new dawn for treatment

The team demonstrated through experiments in pancreatic cancer cells and mouse models that they can use certain members of existing drugs called PARP1 inhibitors to exploit this vulnerability, which can already be at the level of MYBBP1A protein. It is inactivated when it is low. Currently, PARP1 inhibitors are mainly used to treat ovarian cancer and breast cancer.
Dr. Kenneth Zaret, professor of cell and developmental sciences, said that certain types of DNA deletions often occur in pancreatic cancer. They have found in cell and animal experiments that this type of DNA deletion makes these cancers effective against existing cancers. The drug has selective sensitivity. This is an exciting discovery, because there is currently no effective treatment method for pancreatic cancer; moreover, this method can in principle be used to find new treatment methods for other cancers with DNA deletion characteristics.

Axial CT images of pancreatic head carcinoma and cystadenocarcinoma with iv contrast
Axial CT images of pancreatic head carcinoma and cystadenocarcinoma with iv contrast (Image source: Science)

The American Cancer Society estimates that nearly 60,000 people are diagnosed with pancreatic cancer in the United States each year, and nearly 50,000 of them die from these cancers. The cure rate of pancreatic cancer is very low, mainly because these cancers are often only discovered when they start to spread in the body at an advanced stage and are relatively resistant to chemotherapy and other therapies. Therefore, there is an urgent need for better pancreatic cancer treatment methods.
Pancreatic cancer, pancreatic duct adenocarcinoma, or PDAC are the most common forms and usually feature partial deletion of chromosome 17. Human cells have 22 pairs of chromosomes and X and Y sex chromosomes. The loss of part of a copy of chromosome 17 in PDAC means that there is only one copy of many genes located on this chromosome, so the level of protein encoded by these genes is reduced. This ultimately promotes the growth of affected cancer cells, partly because one of the affected proteins is the tumor suppressor P53, which often acts as a powerful fail-safe switch to prevent excessive cell division.
During the study, Dr. Antony Hsieh, a postdoctoral researcher in American gastroenterology at the Zaret laboratory, wondered whether the loss of other genes in these chromosome 17 deletions would make PDAC cells vulnerable, so that future or existing drugs can be used for development . He finally chose MYBBP1A.
Hsieh and colleagues found that in PDAC cells lacking chromosome 17, one copy of MYBBP1A is lost, making the cells more cancerous, thereby increasing the growth-promoting effect of partial loss of P53. On the other hand, scientists discovered that the use of genetic engineering technology to inactivate the remaining copies of MYBBP1A effectively blocked the brake on the cancerous growth of PDAC cells.
By reviewing the biological literature and conducting their own experiments, the scientists also discovered that MYBBP1A protein acts on the nuclear DNA to promote the activity of growth genes and closely interacts with the protein called PARP1. This hints at an opportunity for treatment, as researchers have recently developed an anticancer drug called a PARP1 inhibitor.
PARP1 inhibitors are approved for the treatment of breast and ovarian cancer, and its mechanism of action has nothing to do with MYBBP1A. However, some PARP1 inhibitors appear to work in part by trapping the PARP1 protein on the coiled DNA in the nucleus. As the Penn Medicine team discovered, the PARP1 inhibitors that capture PARP1 in this way (the drugs olaparib and niraparib) excrete residual amounts of MYBBP1A protein from the chromosome, thereby destroying its growth-promoting function in the nucleus. These drugs appear to be ineffective in cells with two working copies of the MYBBP1A gene and a sufficient supply of MYBBP1A protein. But in PDAC cells that have lost a copy of MYBBP1A, these drugs have the effect of stopping growth, such as completely knocking out the MYBBP1A gene.
The team proved this in a laboratory dish experiment using PDAC cells and showed that in mice transplanted with human PDAC cells lacking a copy of MYBBP1A, the tumors of mice treated with olaparib were better than those of untreated mice. The transplanted mice are much smaller.
The results indicate that olaparib and niraparib may have substantial benefits for thousands of patients with pancreatic tumor cells containing only one copy of MYBBP1A. Researchers hope that these findings can encourage others to reduce the loss of genetic material in cancer. Seen as an opportunity to develop new strategies against these cancers.
Researchers will accelerate the development of their PARP1 inhibitor strategy through further preclinical experiments and clinical trials of PARP1 inhibitors in selected pancreatic cancer patients. As part of this work, scientists are collaborating with Kojo Elenitoba-Johnson, MD, Professor Peter C. Nowell, MD, University of Pennsylvania, and the director of the Pennsylvania Center for Personalized Diagnosis to develop a method that can reveal when pancreatic cancer patients are sick. Diagnostic test.

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