A recently published study led by researchers at the Barbara Ann Karmanos Cancer Institute investigates the molecular mechanism of action of Selinexor in pancreatic ductal adenocarcinoma and the tumor’s surrounding microenvironment. Asfar Azmi, Ph.D., Molecular Therapeutics (MT) Research Program Leader and Pancreas Cancer Research Director at Karmanos, guided this study titled “Molecular analysis of XPO1 inhibitor and gemcitabine-nab-paclitaxel combination in KPC pancreatic cancer mouse model,” published in Clinical and Translational Medicine in December 2023. Md. Hafiz Uddin, Ph.D., MT Research Program member, was the first author.
Pancreatic cancer can be deadly because the tumor and the microenvironment work collectively to maintain growth and promote drug resistance, meaning most patients experience disease progression. Researchers at Karmanos have been studying the drug Selinexor for quite some time. Earlier studies from Dr. Azmi’s group showed that pancreatic cancer cells have excessive protein export signaling, causing the tumor suppressor proteins to mislocate leading to uncontrolled cell growth. Selinexor blocks nuclear protein transport to retain good proteins in the correct compartment of cancer cells, thus killing tumor cells.
“Our team used spatial transcriptomics and spatial proteomics to investigate anti-tumor changes by Selinexor in pancreatic cancer cells and stromal cells using the gold standard, KRAS-p53-Cre (KPC) model,” explained Dr. Uddin. “The KPC mice model replicates the human disease with the same amount of high stroma surrounding the tumors. In return, we learned that Selinexor causes a broad penetration in the pancreatic tumor and stroma supporting pathway in KPC tumors.”
Karmanos investigators identified a key molecule called Chitinase-3 like-protein-1 (CHIL3), which was downregulated in both cancer and stromal cells. The publication also includes other traditional techniques, such as single nuclear RNA sequencing.
“Digital spatial profiling is a powerful new technology that gives us much deeper insight into the molecular changes happening simultaneously in the entire tumor and surrounding stromal tissue. We anticipate that these findings will help the enhanced use of Selinexor in tumors beyond pancreatic cancer, especially in cancers with dense stroma,” concluded Dr. Azmi.
Additional Karmanos and Wayne State University authors of the study include Najeeb Al-Hallak, M.D., MS, Husain Yar Khan, Ph.D., Amro Aboukameel, MS, Yiwei Li, M.D., Sahar Bannoura, MS, Gregory Dyson, Ph.D., Seongho Kim, Ph.D., Yosef Mazannar, Ibrahim Azar, M.D., Steve Kim, M.D., FACS, Rafic Beydoun, M.D., Ramzi Mohammad, Ph.D., and Anthony Shields, M.D., Ph.D.
Read the study here.