Research Shows Molecular Engine That Drives Pancreatic Cancer and Ways to Turn It Off

Research supported by the National Institutes of Health (NIH), a Stanley and Linda Sher research grant and Georgetown Lombardi Comprehensive Cancer Center, a NCI-designated Comprehensive Cancer Center in Washington, DC, shows how scientists at Georgetown Lombardi have decoded a chain of molecules that are critical for the growth and survival of pancreatic ductal adenocarcinoma (PDAC)—the most common and also the most lethal form of pancreatic cancer.

Today, complete surgical removal of the tumor remains the only chance for cure. However, an estimated 80% to 90% of all patients have disease that is surgically incurable at the time of clinical presentation.

According to the American Cancer Society, an estimated 56,770 people (29,940 men and 26,830 women) new cases and 45,750 people (23,800 men and 21,950 women) deaths are attributable to pancreatic cancer in the United States in 2019 and PDAC represents the vast majority of disease occurrence. [1] And although the disease is the 12th most common cancer in the U.S., it is the 4th leading cause of cancer death, according to the National Cancer Institute.

PDAC is an epithelial tumor that arises from the cells of the pancreatic duct or ductules. In healthy people the pancreatic duct(s) serve as the conduit through which digestive enzymes and bicarbonate ion produced in acinar cells reach the small intestine. Ductal cells and acinar cells together represent the ‘exocrine’ pancreas, from which the vast majority of pancreatic neoplasms arise.

New findings
The study results study builds upon Georgetown Lombardi earlier research that identified Yes-associated protein (YAP) as an oncogene central to the initiation of PDAC as well as a variety of other cancers, a main component of the Hippo pathway, which not only regulates organ size, but also plays an important role in the development of human cancers.

YAP is a transforming gene of the chromosome 11q22 amplicon, and its expression is elevated at high frequency in human cancers, including liver, breast, ovarian and stomach cancer. [2] It is also up-regulated in pancreatic ductal adenocarcinoma (PDAC) where it is associated with the worse possible prognosis for patients. [3]

The researchers note that their findings, published in Developmental Cell, a peer-reviewed scientific journal of cell and developmental biology, suggest that inhibiting Yap’s biological network may effectively regress early stage PDAC and could be paired with other drugs to halt more advanced stage tumors.

Yap inhibitors have been developed and are moving from (early) preclinical development into clinical trials.

In the current study employing advanced animal models, they have managed to switch off Yap in pre-established PDAC tumors, and discovered that suppressing Yap blocks the metabolic pathways that provide the fuel and building materials for maintaining the growth of the cancer.

This study revealed the “flow chart” of key molecules in the Yap signaling network, which could be used to design novel and more effective therapies for advanced pancreatic cancer, says the study’s senior investigator, Chunling Yi, PhD, associate professor of oncology at Georgetown Lombardi.

“Our research suggests that inhibiting Yap as well as Sox2, a molecule that gets turned on when Yap is inhibited, could be very important to long-term control of pancreatic cancer,” says Yi.

“In later stages of this cancer, when a Yap inhibitor is used, Sox2 could takes its place to allow PDAC to survive and grow, so therapy that targets both molecules would be ideal,” Yi added.

Survival
Five-year survival for PDAC is in the single digits because 80% of patients are diagnosed with late-stage disease. The vast majority PDAC (95%) is caused by a mutation in an oncogene known as Kras, which keeps cell growth switched on. There is no approved treatment for tumors with Kras mutations, which are found in a number of cancers.

Kras mutations activate the Yap pathway. Yi and her colleagues, which include investigators from Germany and France, show, in animal models, that the Yap protein is required for the maintenance of Kras mutant PDAC tumors.

In preclinical work, Yi demonstrated that inhibiting Yap can force PDAC tumors to regress into cells that resemble what are normally found within the organ. Eventually, however, Sox2 is activated to compensate for loss of Yap, causing some tumors to relapse.

“To effectively control tumor growth, you have to know the molecular network that drives that growth. This study takes a good look under the hood and gives us the key drivers that could be targeted to shut that engine down,” Yi says.

Reference
[1] Key Statistics for Pancreatic Cancer | How common is pancreatic cancer? American Cancer Society. Online. Last accessed August 16, 2019.
[2] Sudol M. The Role of YAP Oncogene in Metastasis and Mechano-medicine. The FASEB Journal 2019 33:1_supplement, 620.12-620.12
[3] Jiang Z, Zhou C, Cheng L, Yan B, Chen K, Chen X, Zong L, Lei J, et al. Inhibiting YAP expression suppresses pancreatic cancer progression by disrupting tumor-stromal interactions. J Exp Clin Cancer Res. 2018 Mar 27;37(1):69. doi: 10.1186/s13046-018-0740-4.