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Huntsville BUSINESS JOURNAL
BIOTECHNOLOGY
HudsonAlpha Scientists Identify Genes Involved in Chemotherapy Resistance in Pancreatic Cancer Imagine a world where science can unlock the mystery of cancer cells that are fighting against the very drugs used to combat its spread. HudsonAlpha Faculty Investigator Dr. Sara Cooper and her team, in collaboration with the Myers Lab, are focused on discovering genetic bases for chemotherapy resistance in pancreatic cancer to help identify treatment options. Pancreatic ductal carcinoma, also known as pancreatic adenocarcinoma, is the most common type of pancreatic cancer. PDAC accounts for more than 90% of pancreatic cancer diagnoses. It is frequently diagnosed in its late stages because symptoms are often vague, mimicking less serious illnesses. For these patients, chemotherapy and radiation are usually their sole course of treatment. PDAC is also one of the most lethal cancers, with an average of less than 10% survival rate after five years. This low survival rate can partly be
attributed to chemotherapy resistance. Cooper and her lab recently published a paper in BMC Cancer that describes the results of the study, which identified genes involved in resistance to chemotherapy. Using CRISPR DNA editing, Cooper and her team of Emily Gordon, Drew Hardigan, and Ryne Ramaker applied this technology to activate and knock out genes in the pancreatic cancer cell lines.
Four CRISPR activation and knockout screens were performed. These screens were used to identify genes that could alter sensitivity to the four most common chemotherapies used to treat pancreatic cancer. Widespread closed chromatin has been previously associated with poor prognosis in pancreatic cancer patients and was one of the most consistent mechanisms of drug resistance identified in the screens. Activation of chromatin remodeling pathways, which is the dynamic modification of tightly wound DNA from its closed state to an open state, allows access to the machinery necessary to turn genes on. The team then focused on a gene that codes for an enzyme called histone deacetylase 1 (HDAC1) that is involved in chromatin remodeling.
By Lori J. Connors / Photo courtesy of HudsonAlpha
High expression of HDAC1 is also associated with poor patient prognosis in pancreatic cancer. By overexpressing HDAC1 in cell lines, the team discovered that it regulated genes that are part of the epithelial-to-mesenchymal transition, a pathway known to be involved in multidrug resistance. By predicting a patient’s response to treatment, a physician can avoid administering a medication that has the potential to be ineffective. For example, if a patient’s tumor expressed high levels of a gene implicated in gemcitabine resistance, then the doctor could prescribe a different treatment regimen. “The ultimate goal in cancer treatment is to prescribe patients a treatment that will work to eliminate their cancer with minimal side effects,” said Cooper. “Now that we have narrowed in on HDAC1 and its involvement in drug resistance, we hope to look at all the genes that are regulated by HDAC1 to see if one or a small subset of them are driving the resistance.” u
