Yale Cancer Center scientists have built a powerful genomic research platform to study cervical cancer, a disease that often is untreatable if it progresses after surgery or primary chemo-radiation treatment. The work is described in a study published today in the Proceedings of the National Academy of Sciences (PNAS). “We have identified many driving genetic mutations in cervical cancer and are beginning preclinical validation of drug candidates that target and block the activities of these mutations,” said Alessandro Santin, M.D., leader of the Disease Aligned Research Team for the Gynecologic Oncology Program at YCC and Smilow Cancer Hospital at Yale New Haven and the study’s senior author. Among the results, researchers discovered a combination of two drugs, copanlisib and neratinib, that proved effective in cervical cancer cells and animal models for one biological pathway in which mutations were seen in more than 70% of the tumor samples. Santin assembled a team with expertise in gynecological cancer, genomics, pathology, pharmacology, and computational biology from the U.S. and Italy. The team began by collecting fresh-frozen tumor samples from 69 patients with cervical cancer and performing whole-exome sequencing to identify genetic mutations that might drive the cancer. DNA sequencing identified numerous genetic mutations in a number of critical cellular pathways. More than 70% of the sample tumors included at least one mutated gene in a cellular signaling pathway known as ERBB2/PI3K/AKT/mTOR. Mutations in components of this pathway have been implicated in many types of cancer and are potentially targetable by drugs approved by the U.S. Food & Drug Administration for other tumors. The DNA sequencing database also identified gene copy number variations in the tumor samples—looking for genes that are not mutated but when amplified in tumors can give them a growth advantage over normal tissues, researchers said. Unlike previous genomic surveys of cervical cancer, Yale scientists then went on to examine whether any of the mutations identified in this comprehensive analysis could be targeted by drugs in cancer cells and animal models. The team’s first step was to establish 15 primary cell lines from the fresh-frozen cervical tumors and to perform whole-exome sequencing of the cell lines. The scientists then did pre-clinical validation of driving genetic mutations by testing candidate therapies in both the cervical cell lines and in xenograft models (in which the cells were transplanted into mice). Their strategy was to test drugs that target those genetic mutations and are approved for other types of cancer. The researchers were particularly interested in examining combinations of drugs, since combination therapies often work much better among cancer patients than treatments with single agents. The combination of the drugs copanlisib and neratinib showed significant promise and will soon be taken into an early clinical study. “This is only the first step,” Santin added. “Many other potentially ‘druggable’ mutations and deranged pathways were identified in our work that may now go through preclinical validation using agents highly specific for these targets.” Gilead Sciences and Puma Biotechnology provided leading support for the research. The study also was funded by grants from the National Institutes of Health, the National Cancer Institute, the Deborah Bunn Alley Ovarian Cancer Research Foundation, the Honorable Tina Brozman Foundation, the Discovery to Cure Foundation, the Stand Up to Cancer Foundation and the Guido Berlucchi Foundation. Luca Zammataro and Salvatore Lopez are co-lead authors on the paper. Other Yale contributors include Stefania Bellone, Francesca Pettinella, Elena Bonazzoli, Emanuele Perrone, Valentina Pirazzoli, Gulden Menderes, Gary Altwerger, Chanhee Han, Burak Zeybek, Anna Bianchi, Aranzazu Manzano, Paola Manara, Dan-Arin Silasi, Gloria Huang, Elena Ratner, Masoud Azodi, Peter Schwartz, Natalia Buza, Pei Hui, Serena Wong, Kaya Bilguvar, Amy Stiegler, and Titus Boggon.