Researchers at Baylor College of Medicine have developed an experimental drug called CS18 that may help cancer treatments work against tumors that have become resistant to the therapy. The study, published in Scientific advancesprovides early evidence supporting further investigation of CS18 as a potential future cancer treatment.
“Therapeutic resistance is the main obstacle to effective and long-lasting cancer treatments,” said corresponding author Dr. Weei-Chin Lin, professor of medicine, hematology and oncology and of molecular and cellular biology at Baylor. “While some therapies are effective initially, many patients eventually relapse because cancer cells can activate compensatory and convergent biological pathways that allow them to overcome the toxic effects of the therapy, promoting survival.”
Targeting the cancer survival network
Instead of focusing on a single cancer pathway, researchers set out to develop a drug that could interfere with a broader control center involved in several cancer-promoting processes at once. Their target was topoisomerase IIß-binding protein 1 (TopBP1), which the team describes as a “biological switchboard” because it helps regulate multiple pathways associated with cancer growth and survival.
The researchers wanted to determine whether altering this central control point could produce longer-lasting treatment responses and help overcome resistance.
“Of all the ‘biological switches’ in TopBP1, the BRCT7/8 switch interacts with several key regulators of cancer growth, including MIZ1, a suppressor of the cancer driver MYC; mutant p53, which can acquire cancer-promoting functions; and PLK1 and CIP2A, proteins that help cancer cells survive and divide,” said Lin, a member of Baylor’s Dan L Duncan Comprehensive Cancer Center. “Together, these diverse functions position TopBP1-BRCT7/8 as a promising target for intervention.”
Developing CS18
To find a compound capable of blocking BRCT7/8, the researchers screened thousands of chemicals with a combination of computer models and laboratory experiments. This search identified a compound known as 3B6.
The team then modified 3B6 and tested numerous versions of the molecule, eventually identifying CS18 as the most effective candidate.
“When CS18 binds to BRCT7/8, the cancer-promoting activities of MYC and mutant p53 decreased, proteins involved in DNA repair became less active, and cancer cells were more likely to die,” Lin said. “In addition, CS18 increased the activity of genes that stop uncontrolled cancer growth. Taken together, CS18 appears to reduce several of the defenses that help cancer cells survive therapy.”
Testing CS18 in multiple cancers
The researchers observed these effects in several types of cancer cells, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, and acute myeloid leukemia. CS18 was also less toxic to non-cancerous cells.
The results became particularly notable when CS18 was combined with anti-cancer drugs already in use. Combining CS18 with treatments such as PARP inhibitors or osimertinib killed cancer cells more effectively than either treatment used alone.
“For lung cancer cells that were already resistant to osimertinib, adding CS18 restored the cells’ sensitivity to osimertinib, which increased cancer cell death,” Lin said. “We observed a significant reduction in tumor growth in animal models without significant weight loss or other signs of toxicity.”
A possible strategy against drug resistance
Based on these findings, the researchers suggest that CS18 warrants further development as a potential component of combination cancer therapies. These treatments could help prevent the emergence of resistance or make resistant cancers respond to therapy again.
Other contributors to this work include Fang-Tsyr Lin, Kang Liu, Yang Xiao, Lidija A. Wilhelms Garan, and Helena Folly-Kossi, all of Baylor College of Medicine. Shwu-Jiuan Lin is at Taipei Medical University.
This work was supported by grants from the National Institutes of Health (R01CA203824, R01CA269971, T32CA174647, and T32GM136560) and grants from the Department of Defense (W81XWH-18-1-0329, W81XWH-19-1-0369, W81XWH-22-1-0226, W81XWH-22-1-0534 and HT9425-24-1-0045). Additional support was provided by a pilot award from the Rivkin Center for Ovarian Cancer and a grant from the Ministry of Science and Technology of Taiwan (MOST 107-2635-B-038-001).