Researchers at Dana-Farber Cancer Institute have developed the first clinical-grade drug to directly inhibit cyclins in the cell cycle, launching a nationwide phase 1 clinical trial for patients with small cell lung cancer, triple negative breast cancer, and other cancers. The breakthrough, published in Nature, represents a novel therapeutic approach targeting a specific vulnerability in cancers with disabled quality control mechanisms.
Targeting Cell Cycle Vulnerabilities
The research, led by Dr. Matthew Oser, a thoracic oncologist and researcher at Dana-Farber, focuses on exploiting weaknesses in small cell lung cancer (SCLC) cells. Approximately 90 percent of these cancers are driven by mutations causing the loss of two critical tumor suppressors: RB1 and TP53. These proteins normally function as cellular "brakes," with RB1 helping pause the cell cycle at the G1/S checkpoint for quality control checks and repairs.
"It's more like losing the brakes on a car than having something that is driving growth and can be blocked," Oser explains. The challenge has been that directly targeting these losses with small molecule drugs is not possible, creating an urgent need for alternative therapeutic strategies.
Novel Mechanism of Action
The new class of drugs, called direct cyclin inhibitors (specifically cyclin A/B RxL inhibitors), was developed through collaboration between the Oser Lab and Circle Pharma, a San Francisco-based biotechnology company. First author and post-doctoral fellow Shilpa Singh led the mechanistic studies that uncovered how these compounds selectively target cancer cells.
The drug works through a two-step mechanism that leads to cell death specifically in cells with elevated E2F activity, a characteristic of cancers that have lost RB1 and TP53. The compound interrupts protein-protein interactions of cyclins A and B, which normally ensure quality control and proper cell cycle progression.
The first interaction involves cyclin A and E2F. When this interaction is blocked in the presence of elevated E2F activity, it results in increased DNA damage. The second interaction is between cyclin B and MYT1, and its inhibition causes cancer cells to die during mitosis, the cell division phase of the cell cycle.
Selective Cancer Cell Targeting
A critical finding of the research is the drug's selectivity for cancer cells over normal cells. "Normal cells are about 100 to 1000-fold less sensitive to the drug than cancer cells," Oser notes. This dramatic difference occurs because normal cells don't have elevated levels of E2F activity and are therefore not as susceptible to DNA damage and cell death.
"If the drug had had the same effect in normal cells, it would not be a feasible treatment," Oser emphasizes. This selectivity creates the potential to find a therapeutic dose that works against cancer without unmanageable side effects.
Preclinical Evidence and Clinical Translation
The research team tested the drug in patient-derived xenografts and found that small cell lung cancer tumors treated with the compound stopped growing. Additional preclinical experiments suggested the drug has activity in other cancers that have disabled the G1/S cell cycle checkpoint, supporting its broader therapeutic potential.
The concept of targeting cyclins in cancer cells with high E2F activity was originally proposed in the late 1990s by Nobel Laureate William G. Kaelin Jr.'s laboratory. However, it wasn't until the late 2010s that Circle Pharma discovered the chemistry needed to create drugs that could precisely target cyclins, making this therapeutic approach tractable.
Clinical Trial Launch
Based on the mechanistic and preclinical evidence, a phase 1 clinical trial is now open at Dana-Farber and across the United States. The trial will test a related compound called CID-078 in patients with small cell lung cancer, triple negative breast cancer, and other cancers with disabled G1/S checkpoints.
"This is the first clinical grade drug to directly inhibit cyclins in the cell cycle," Oser states. "Our research using cell biology and genetic screening reveals a two-step mechanism of cell death specifically in cancer cells that does not occur in normal cells."
The clinical trial represents a significant milestone in translating decades of cell cycle research into a potential new treatment option for patients with cancers that have historically been difficult to treat due to their underlying genetic characteristics.
