Ohio State Cancer Researchers Learn How Resistance Develops in a Lethal Bile Duct Cancer With Novel FGFR Inhibitor

September 24, 2019
Sameek Roychowdhury
  • Cholangiocarcinoma is a rare, lethal cancer of the liver bile ducts that has few treatment option
  • This study examines multiple tumors from one patient for mutations in FGFR genes, which are targeted by a family of promising new drugs
  • The study identified gene changes that can render the new drugs ineffective
  • The findings could help improve drugs that target FGFR gene mutations and prevent or overcome treatment resistance in cholangiocarcinoma

COLUMBUS, Ohio – New research from The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has identified gene mutations that cause resistance to promising new drugs in patients with a rare, lethal form of bile duct cancer.

The disease, called cholangiocarcinoma, has few treatment options and a five-year survival rate of less than two percent for patients with advanced disease. A new group of drugs called FGFR inhibitors offers a promising new treatment for the disease, but tumors can develop resistance to the agents, rendering them ineffective. 

In this new study, OSUCCC – James researchers describe secondary gene mutations – those that arise during treatment and that were not present in the original primary tumor – which caused resistance to an FGFR inhibitor that had initially helped the patient. They also showed that the acquired mutations occurred in subgroups of tumor cells that arose within the metastatic tumors.

The findings are published in the journal Molecular Case Studies.

“Our results demonstrate the emergence of drug-resistance mutations in subgroups of tumor cells from a patient with cholangiocarcinoma,” says Melanie Krook, PhD, senior postdoctoral researcher at the OSUCCC – James and first author of the paper.

About 20 percent of patients with this bile duct cancer have mutations in FGFR genes. The mutated genes contribute to tumor development. FGFR inhibitors are designed to block the effects of the mutated genes.

“Ten FGFR inhibitors are currently in development, and it’s critically important for us to understand how cancer cells develop resistance to them,” says Sameek Roychowdhury, MD, PhD, senior author of the study and medical oncologist-scientist with the OSUCCC – James Translational Therapeutics Research Program.

This research was conducted through a unique Body Donation for Cancer Research study that allows patients to donate their organs and tissue for cancer research.

“Studying how drug resistance develops is challenging, since it is hard to study every tumor in a person’s body. We were able to make this discovery because the patient had consented to a organ donation and research autopsy, which can yield unprecedented insights into how cancer evolves and changes during the course of the disease. We are so grateful to our patients and hope to honor their support through research that can help others,” adds Roychowdhury.

For this study, the OSUCCC – James team examined tumor samples from a patient with FGFR-fusion-positive cholangiocarcinoma.

Researchers compared the cancer genomes from 11 metastatic tumors and from the pretreatment primary tumor. The tissue was obtained within eight hours of death, minimizing the molecular changes that occur in cells after death.

Key findings include:

  • Cell studies identified a novel FGFR alteration and secondary FGFR2 mutation that conferred resistance to the FGFR inhibitor INCB054828 (also called pemigatinib);
  • Identification of four tumor subclones in metastatic tumors;
  • A particular mutation that might be a clinically useful marker of resistance to INCB054828.

“Evaluating the cancer profiles of other cholangiocarcinoma patients through organ donation and research autopsy will be critical for understanding how drug resistance develops to these agents and for the development of therapies that prevent or overcome resistant to them,” says Roychowdhury.

This study was supported by funding from the American Cancer Society (MRSG-12-194-01-TBG), the Prostate Cancer Foundation, the National Cancer Institute (CA202971, CA216432, CA009338), the National Center for Advancing Translational Sciences (TL1TR002735), American Lung Association and Pelotonia, a grassroots cycling movement in Columbus, Ohio, that has raised more than $200 million for cancer research at the OSUCCC-James. Incyte Corporation provided INCB054828 for cell studies.

Other OSUCCC – James researchers involved in this study were Melanie A. Krook, PhD; Russell Bonneville; Hui-Zi Chen, MD, PhD; Julie W. Reeser, PhD; Michele R. Wing, PhD; Dorrelyn M. Martin, MS; Amy M. Smith; Thuy Dao; Eric Samorodnitsky, PhD; Anoosha Paruchuri, PhD; Jharna Miya, MS; Kaitlin R. Baker; Lianbo Yu, PhD; Cynthia Timmers, PhD; Kristin Dittmar, MD; Aharon G. Freud, MD, PhD and Patricia Allenby, MD.

About the OSUCCC – James
The OSUCCC – James strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program’s 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors and with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, visit cancer.osu.edu.

Media Contact:
Amanda J. Harper
OSUCCC-James Media Relations
614-685-5420
Amanda.Harper2@osumc.edu

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