Scientists at the Perelman School of Medicine at the University of Pennsylvania (United States) have revealed a promising new strategy to combat pancreatic cancer
A DNA mutation that occurs frequently in the development of many pancreatic tumors appears to make these cancers vulnerable to a class of existing drugs known as PARP inhibitors, according to a new study by scientists from the aforementioned School.
The discovery, published in Science Advances, focuses on a gene called MYBBP1A.
Studies suggest that up to two-thirds of patients with the most common type of pancreatic tumor have one copy of this gene deleted in tumor cells. The Penn Medicine scientists found that while this deficiency appears to contribute to tumor growth, the loss of the remaining copy of MYBBP1A in tumor cells has the opposite effect, dramatically reducing cell growth.
The team demonstrated, with experiments in pancreatic cancer cells and in mouse models, that they could exploit this vulnerability with certain drugs called PARP1 inhibitors, which have the effect of inactivating the MYBBP1A protein when its levels are already low in cells.
Currently, PARP1 inhibitors are used primarily to treat ovarian and breast cancers. “A certain type of DNA suppression occurs frequently in pancreatic cancer, and we found in cell and animal tests that this DNA suppression makes these cancers selectively susceptible to existing drugs,” said Kenneth Zaret, Ph.D. , Professor of Cells and Developmental Biology.
“This is an encouraging finding because there are currently no highly effective treatments for pancreatic cancer, and this approach could in principle be used to find new treatments for other cancers that have DNA deletions or missing parts.”
The American Cancer Society estimates that nearly 60,000 people in the United States are diagnosed with pancreatic cancers each year, and nearly 50,000 die from these cancers. The cure rate for pancreatic cancers is very low, largely because these cancers tend to be found only in late stages, when they have begun to spread throughout the body and are relatively resistant to chemotherapies and other treatments.
Better therapeutic approaches for pancreatic cancers are desperately needed.
The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma or PDAC, often has a partial absence of one copy of chromosome 17. Human cells have 22 pairs of chromosomes plus the X and Y sex chromosomes. The loss of one part of a copy of chromosome 17 in PDAC means that many genes located on that chromosome have only one copy remaining, so the levels of the proteins that these genes encode are reduced.
This ends up driving the growth of affected cancer cells, in part because one of the affected proteins is the tumor suppressor P53, which normally functions as a powerful fail-safe switch that protects against excessive cell division.
Antony Hsieh, Ph.D., an American College of Gastroenterology postdoctoral fellow in the Zaret lab, wondered if the loss of other genes in these chromosome 17 deletions could make PDAC cells vulnerable in ways that existing or future drugs could take advantage of it ..
He finally focused on MYBBP1A. Hsieh and colleagues found that the loss of one copy of MYBBP1A, in PDAC cells lacking chromosome 17, somehow made the cells more cancerous and thus added to the progrowth effect of the partial loss of P53.
On the other hand, the scientists found that deactivating the remaining copy of MYBBP1A, using genetic engineering techniques, effectively slowed the cancerous growth of PDAC cells.
The scientists also found, by reviewing the biology literature and conducting their own experiments, that MYBBP1A proteins work on DNA in the nucleus of cells to promote the activity of growth genes, and in this function they interact closely with proteins called PARP1 proteins.
This hinted at a therapeutic opportunity, because researchers recently developed a class of anticancer drugs called PARP1 inhibitors.
PARP1 inhibitors are approved for the treatment of breast and ovarian cancers, and their mechanisms of action are largely unrelated to MYBBP1A. However, some PARP1 inhibitors appear to work in part by trapping the PARP1 proteins in DNA coiled in the cell nucleus. As the Penn Medicine team discovered, PARP1 inhibitors that trap PARP1 in this way – the drugs olaparib and niraparib – flush the residual amount of MYBBP1A protein from the chromosomes, disrupting their growth-promoting function in the cell nucleus. .
In cells that have two working copies of the MYBBP1A gene and abundant supplies of the MYBBP1A protein, drugs appear to have no effect; but in PDAC cells that have lost a copy of MYBBP1A, these drugs have an effective growth arrest impact such as total inactivation of the MYBBP1A gene.
The team demonstrated this in laboratory plate experiments with PDAC cells, and showed that in a mouse transplanted with human PDAC cells lacking a copy of MYBBP1A, treatment with olaparib made tumors much smaller than those in mice. transplanted untreated.
The results suggest that olaparib and niraparib could have substantial benefit in the many thousands of patients whose pancreatic tumor cells have only one copy of MYBBP1A. “We hope that these findings will encourage others to view the loss of genetic material in cancers as an opportunity to develop new strategies against these cancers,” Hsieh said.
Zaret and his colleagues are now working with other Penn Medicine researchers to accelerate the development of their PARP1 inhibitor strategy with more preclinical experiments and one day, hopefully, clinical trials of PARP1 inhibitors in select patients with pancreatic cancer.
As part of that effort, the scientists are working with Kojo Elenitoba-Johnson, MD, Professor Peter C. Nowell MD, and director of the Center for Personalized Diagnosis at Penn Medicine, to develop a diagnostic test that would reveal in patients with pancreatic cancer. if a copy of MYBBP1A is missing and therefore treatment with PARP1 inhibitors could contribute to its cure.
Fuente: Antony Hsieh et al. Growth of pancreatic cancers with hemizygous chromosomal 17p loss of MYBBP1A can be preferentially targeted by PARP inhibitors, Science Advances (2020). dx.doi.org/10.1126/sciadv.abc4517
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