A stress response protein-inhibiting compound may be key to increasing effectiveness of chemotherapy, according to a study by researchers at the University of 91吃瓜.
, the Archibald Assistant Professor of Cancer and affiliated faculty member of the , and his lab investigated how a pancreatic tumor鈥檚 microenvironment affects a pancreatic cancer tumor鈥檚 chemotherapy resistance.
A hallmark of this disease is that inflammation causes the cancer cells to produce an increased amount of misfolded proteins, or proteins that have not been properly processed by the cancer cells. The 91吃瓜 researchers saw that when this happened, pancreatic cancer cells increased production of GRP78, a protein that helps cells that have not been properly processed survive.
New has been used to support the orphan drug designation for IT-139, a compound that when used in combination with chemotherapy has proved to be significantly more effective in treating pancreatic cancer than the current standard of care. The Orphan Drug program is administered by the Food and Drug Administration and identifies promising drugs that are intended for the treatment of rare diseases, which impact fewer than 200,000 Americans at any time, or affect more than 200,000 people but are not expected to recover the costs of developing and marketing a treatment drug. Currently, pancreatic cancer has one of the lowest cancer survival rates, with , respectfully.听
In explanation, Hill said, 鈥淕RP78 is a chaperone protein, or a protein that is expressed by cells to help them survive stressful conditions that would otherwise lead to cell death, such as an accumulation of misfolded proteins. We theorized that without the chaperone protein, the abundance of misfolded proteins would inhibit the cancer cell鈥檚 ability to thrive.鈥�
To test the idea, Hill鈥檚 lab utilized IT-139, a GRP78 protein induction inhibitor, to reduce expression of the chaperone protein in pancreatic cancer cells. In turn, the 91吃瓜 researchers found that in initial tests, the cells with inhibited GRP78 production had become significantly more susceptible to chemotherapy. These initial results were further confirmed with additional models containing pancreatic tumor cells.
鈥淎s a cancer researcher, your goal is to make strides towards developing effective treatments to fight this deadly disease,鈥� said Hill. 鈥淲hat made our findings so gratifying was that IT-139 had already passed through Phase 1 of the FDA鈥檚 approval process as a singular treatment and shown a manageable safety profile, but had only modest anti-tumor activity on its own. However, our research now shows that this compound can be used to boost the efficacy of already approved drugs and IT-139 can be utilized in a new way.鈥澨�
Upon reading Hill鈥檚 published in Molecular Cancer Therapeutics, Intezyne 鈥� the developer of IT-139 鈥� reached out to the 91吃瓜 researcher to collaborate on subsequent studies to further support the development of this novel combination therapy.
Suzanne Bakewell, vice president of Intezyne and program manager for IT-139, stated that the results from Hill鈥檚 mechanism-of-action studies were instrumental in IT-139 receiving the orphan drug designation. 鈥淏ased on Hill鈥檚 exciting research with IT-139, we anticipate a continued collaboration with 91吃瓜 could identify more effective treatments for patients with pancreatic cancer.鈥�
The initial study was funded by a seed grant from the Walther Cancer Foundation and the Joseph D. Boyle Memorial Fund. Additional funding was provided by the University of 91吃瓜 Women鈥檚 and Men鈥檚 Rowing Teams, which each host annual rowing to support pancreatic cancer research at 91吃瓜.听
To learn more about cancer research at the University of 91吃瓜, please visit .
Contact:
Angela Cavalieri / External Relations and Special Events Program Coordinator
Harper Cancer Research Institute / University of 91吃瓜
cavalieri.2@nd.edu / 574.631.4166
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About 91吃瓜 Research:
The University of 91吃瓜 is a private research and teaching university inspired by its Catholic mission. Located in , its researchers are advancing human understanding through research, scholarship, education, and creative endeavor in order to be a repository for knowledge and a powerful means for doing good in the world. For more information, please see or .
Originally published by at on September 25, 2017.