Cancer researchers have discovered a way to target a pivotal driver of drug resistance in ovarian cancer, one of the top causes of cancer death in women.
The experimental compound, called SU056, shrank tumors and stopped the rise of metastatic tumors in animal models of ovarian cancer. When dosed with SU056, cancer cells resistant to paclitaxel became vulnerable to that chemotherapy drug.
“We have subsequently shown its effectiveness in models of six different cancer types,” said the study’s senior author, Sanjay Malhotra, Ph.D. He is a professor of cell, developmental & cancer biology in the OHSU School of Medicine and director of the Center for Experimental Therapeutics in the Knight Cancer Institute.
Ovarian cancer is the fifth most common cause of cancer death in women. Most cases are detected after the disease has spread and tumors can quickly develop resistance to chemotherapy. Overall, less than half of women with this cancer survive more than 5 years.
The new agent blocks a protein called YB-1, known for many years to play a role in tumor progression and the emergence of treatment resistance. The protein is a transcription factor that binds to DNA and RNA to help regulate the activity of specific genes. Until recently, biologists considered transcription factors to be unworkable targets for cancer therapy, but discoveries in recent years have opened eyes to the potential.
Serendipity led Malhotra’s team to YB-1. The researchers started out exploring molecules related to an older cancer drug called etoposide, which has a target different than YB-1 and is limited by its toxicity. “Our idea was to find out if you could change the structure to keep the potency but remove the liability of toxicity.”
‘The possibility of stopping activity of YB-1 provides potential for new treatments for a range of cancers’
They tested a range of candidate molecules for their ability to inhibit ovarian cancer cells grown in the laboratory. One low-toxicity candidate, SU056, was significantly more potent than the rest. “But it was not hitting the target originally sought,” Malhotra said.
Systematic studies of its interaction target revealed six likely proteins. All were known to play a role in driving cancer, but the transcription factor YB-1 stood out because its activity was strongly inhibited by SU056 in a variety of different ovarian cancer cell lines. Further experiments confirmed that SU056 binds to YB-1 and that its anti-cancer effect does not work without the presence of the YB-1 protein in cancer cells.
In a mouse model of ovarian cancer, animals treated with SU056 showed a 2-fold reduction in tumor weight compared with control animals treated with saline solution. SU056-treated mice showed a 3-fold reduction in metastatic tumors arising in the lung. The researchers published their findings in Cell Chemical Biology.
“Development of drug resistance is one of the major challenges for cancer chemotherapy,” said first author Dhanir Tailor, a post doctoral scholar in Malhotra’s lab. “The possibility of stopping activity of YB-1, a key regulator of resistance, with a small molecule drug that helps to restore treatment sensitivity provides potential for new treatments for a range of cancers.”
Knowing that YB-1 is involved in the emergence of resistance to chemotherapy, the researchers explored its effects in combination with the chemo drug paclitaxel. Experiments showed that paclitaxel given alone boosts the expression of YB-1 and another gene, MDR1, in ovarian cancer cell lines. But that effect is reversed by the combined treatment of SU056 and paclitaxel. In mouse studies, paclitaxel and SU056 each reduced tumor growth. But the two combined resulted in a much greater reduction in tumor growth.
Malhotra said the results exceeded expectations with its low toxicity and powerful synergistic effect in combination with paclitaxel. “The compound can do so much,” he said. “We were very excited when we realized there is actually a potential to develop a new therapy.” OHSU holds a joint patent with Stanford University on the findings.
The researchers expect to begin clinical trials as soon as they complete the preliminary studies needed to obtain regulatory approval for human research. “Fingers crossed for now,” Malhotra said. “There does not seem to be any reason for it not to advance.”
Y box binding protein 1 inhibition as a targeted therapy for ovarian cancer by Dhanir Tailor, Angel Resendez, Fernando Jose Garcia-Marques, Mallesh Pandrala, Catherine C. Going, Abel Bermudez, Vineet Kumar, Marjan Rafat, Dhanya K. Nambiar, Alexander Honkala, Quynh-Thu Le, George W. Sledge, Edward Graves, Sharon J.Pitteri, and Sanjay V. Malhotra. Cell Chemical Biology (March 12, 2021)
Y box binding protein 1 (YB-1) oncoprotein at the hub of DNA proliferation, damage and cancer progression by Felicia Sangermano, Antonella Delicato and Viola Calabrò. Biochimie (December 2020)