Research from the Dana-Farber Cancer Institute reveals a groundbreaking class of drugs that can induce cancer cell death in small cell lung cancer and other malignancies characterized by a dysfunctional quality control mechanism known as the G1/S checkpoint. The findings, published in the journal Nature, highlight a new therapeutic strategy now entering clinical testing.
A phase 1 clinical trial has been initiated across the United States for patients with small cell lung cancer, triple-negative breast cancer, and other cancers. According to Dr. Matthew Oser, a researcher and thoracic oncologist at Dana-Farber, this represents the first clinical-grade drug designed to inhibit cyclins directly in the cell cycle. “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,” Oser explained.
Targeting Cancer’s Weakness
The urgency for new treatment options for small cell lung cancer is underscored by the fact that approximately 90 percent of these cancers originate from mutations that disable two crucial tumor suppressors, RB1 and TP53. These proteins play a vital role in controlling the cell cycle, which is the process that regulates cell growth and division. Oser likens the situation to a car losing its brakes, indicating that while cancer cells are propelled forward, traditional small molecule drugs cannot effectively target the lost suppressors.
Research led by Nobel Laureate William G. Kaelin Jr., MD in the late 1990s posited that targeting cyclins in cancer cells with heightened E2F activity could be a viable approach. This concept gained traction only in the late 2010s when developers at Circle Pharma, based in San Francisco, discovered innovative chemistry that allowed for the creation of drugs aimed specifically at cyclins. These drugs, known as direct cyclin inhibitors, are designed to exploit the vulnerabilities of cancer cells.
Mechanisms of Action
The study conducted by the Oser Lab, with Shilpa Singh as the first author, collaborated with Circle Pharma to investigate how these drugs impact both cancerous and normal cells. Their research identified a complex mechanism that triggers cell death exclusively in cancer cells exhibiting elevated E2F activity. The direct cyclin inhibitors disrupt protein-protein interactions between cyclins A and B, which are essential for maintaining quality control during the cell cycle.
Inhibiting the interaction between cyclin A and E2F leads to increased DNA damage, while blocking cyclin B’s interaction with MYT1 causes cancer cells to perish during mitosis, the final phase of cell division. Notably, normal cells appear to be significantly less affected by the drug, being approximately 100 to 1,000-fold less sensitive than cancer cells. “If the drug had the same effect in normal cells, it would not be a feasible treatment,” Oser stated.
The promising results from preclinical tests suggest that small cell lung cancer tumors treated with these inhibitors ceased to grow, pointing to the potential of these drugs not only in small cell lung cancer but also in other cancers with impaired G1/S checkpoints. Given this encouraging data, the clinical trial for the related compound CID-078 aims to further assess its safety and efficacy in humans, marking a significant step forward in cancer treatment.
