Researchers from Baylor College of Medicine have created an experimental drug, CS18, which could potentially enhance the effectiveness of cancer treatments against tumors that have developed resistance. Published in Science Advances, the study offers preliminary evidence that supports further exploration of CS18 as a future option for cancer therapy.
“One of the biggest challenges in achieving successful and lasting cancer treatment is therapeutic resistance,” stated Dr. Weei-Chin Lin, the study’s corresponding author and a professor of medicine with specialties in hematology and oncology and molecular and cellular biology at Baylor. “Though some therapies can work well initially, many patients face relapse as cancer cells adapt, activating biological pathways that help them evade the toxic effects of treatment and survive.”
Addressing Cancer’s Survival Mechanisms
Instead of concentrating on a single cancer pathway, the researchers aimed to create a drug that could target a wider regulatory center involved in various cancer-related processes simultaneously. Their focus was on topoisomerase IIß-binding protein 1 (TopBP1), which they refer to as a ‘biological switchboard’ due to its role in managing multiple pathways linked to cancer growth and survival.
The goal was to see if disrupting this central mechanism could lead to longer-lasting responses to treatments and potentially help overcome resistance.
“Among the various ‘biological switches’ within TopBP1, the BRCT7/8 switch interacts with several critical regulators of cancer growth, such as MIZ1, which inhibits the oncogene MYC; the mutant p53, which may take on cancer-promoting roles; and PLK1 and CIP2A, which support cancer cell proliferation and survival,” Lin explained, noting TopBP1-BRCT7/8’s intriguing potential as a therapeutic target.
The Development of CS18
To identify a compound that could effectively block BRCT7/8, the research team analyzed thousands of chemicals using a combination of computer simulations and lab tests. This led to the discovery of a compound named 3B6.
The team then refined 3B6 and tested various iterations of the molecule, finally pinpointing CS18 as the most promising candidate.
“When CS18 attaches to BRCT7/8, it diminishes the cancer-promoting effects of MYC and mutant p53, reduces the activity of DNA repair proteins, and increases the likelihood of cancer cell death,” Lin noted. “In addition, CS18 boosts the activity of genes that inhibit unchecked cancer growth. Overall, CS18 seems to weaken several of the protective measures cancer cells use to survive treatments.”
Effects of CS18 Across Various Cancers
The researchers found these beneficial effects across numerous cancer types, including triple-negative breast cancer, ovarian cancer, lung adenocarcinoma, lung squamous cell carcinoma, and acute myeloid leukemia, with CS18 demonstrating lower toxicity toward healthy cells.
Combining CS18 with existing cancer therapies showed particularly promising results. For example, when CS18 was paired with PARP inhibitors or osimertinib, the ability to kill cancer cells proved significantly more effective than using those treatments alone.
“In cases involving lung cancer cells resistant to osimertinib, introducing CS18 restored the cells’ sensitivity to the drug, ultimately leading to increased cancer cell death,” Lin said. “We noted a meaningful decrease in tumor growth in animal models, with no significant weight loss or other signs of toxicity.”
A Strategy to Combat Drug Resistance
Given these findings, the researchers propose that CS18 should be further developed as a possible element of combination therapies for cancer. This approach could help prevent the emergence of resistance or potentially make previously resistant cancers responsive to treatment once again.
