A recent search by HudsonAlpha Center for Biotechnology (HudsonAlpha) scientists has yielded the discovery of a gene that holds the potential to reverse chemoresistance in pancreatic cancer.

In the United States, cancer treatments and survival rates are met with two significant challenges: metastasis and chemoresistance. Additionally, cancer is the second leading cause of death, falling just behind heart disease.

Metastasis is the process by which cancer cells spread from the primary tumor to other parts of the body, whereas chemoresistance is the ability of cancer cells to become resistant to chemotherapy drugs, making them less effective in fighting the disease altogether.

“This resistance can occur due to various factors, such as genetic mutations within the cancer cells or protective mechanisms that prevent the drugs from effectively targeting the cancerous growth. Both chemoresistance and metastasis pose considerable hurdles in cancer treatment, highlighting the need for ongoing research and innovative approaches to improve patient outcomes,” explained HudsonAlpha in a recent press statement.

Pancreatic cancer often runs a higher risk of being plagued by chemoresistance, and metastatic complications. As many as half of the patients diagnosed with pancreatic cancer already have cancer spread beyond the area of the pancreas.

“Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a five-year survival rate of only 11 percent, due to the lack of early diagnostic markers for PDAC to catch the disease early and its high rate of treatment resistance,” according to research performed by HudsonAlpha.

HudsonAlpha Institute for Biotechnology Faculty Investigator Sara Cooper, PhD, and her lab focus on identifying novel targets to prevent cancer chemoresistance, especially in pancreatic cancer. The lab recently published results in BMC Cancer from a promising study led by senior scientist Emily Gordon, PhD, identifying several potential targets for reversing chemoresistance in PDAC.

In 2016, Cooper and colleagues at HudsonAlpha identified genes whose expression positively or negatively correlated with PDAC patient survival. High expression of a gene called ANGPTL4 was linked with poor patient survival and, when knocked down in cell lines, increased their sensitivity to a common pancreatic cancer treatment. ANGPTL4 has a defined role in cardiovascular disease and lipid metabolism, but its role in cancer is unclear.

“This work builds upon an earlier finding that highlighted ANGPTL4 as a possible drug target,” said Dr. Cooper. “We are considering ANGPTL4 as a possible drug target based on its link to patient outcomes and the evidence that inhibition can improve response to treatment.”

The ANGPTL4 gene is not alone in its ability to influence patient survival. The expression of several genes downstream of ANGPTL4 was altered by its overexpression. The genes were linked to epithelial to mesenchymal transition, a phenomenon that allows cancer cells to detach from the main tumor site and move to other parts of the body. Overexpression of genes downstream of ANGPTL4 also predicts patient outcomes, providing more potential targets to study.

Using CRISPR to knock down factors downstream of ANGPTL4 in cell lines, the scientists showed that the chemoresistance could be reversed. It also reduced the migratory potential of cells. This means that targeting ANGPTL4 or its downstream partners with a drug could be a potential solution to reverse chemoresistance in PDAC.

The data from this study suggests that ANGPTL4 and its downstream pathway are potential therapeutic targets for the reversal of treatment resistance in pancreatic cancer.

“These data help us understand the function of ANGPTL4 in pancreatic cancer and provide evidence to support advancing ANGPTL4 and its targets as potential drug targets and aid in developing much-needed treatments for pancreatic cancer,” said Dr. Cooper.