Research conducted at the Dana-Farber Cancer Institute has unveiled a promising new approach to treating small cell lung cancer (SCLC) through a novel class of drugs. These drugs induce cancer cell death by targeting a compromised cell cycle checkpoint known as the G1/S checkpoint, which is often disabled in SCLC. The findings, published in the journal Nature, indicate that clinical trials for this strategy are now underway.
A phase 1 clinical trial has opened nationwide for patients with SCLC, as well as triple negative breast cancer and other malignancies. The trial aims to assess the efficacy of a compound called CID-078, developed in collaboration with Circle Pharma, a biotechnology firm based in San Francisco. Dr. Matthew Oser, a researcher and thoracic oncologist at Dana-Farber, is the senior author of the study and emphasizes the significance of this breakthrough.
“This is the first clinical-grade drug to directly inhibit cyclins in the cell cycle,” says Dr. Oser. His research, which utilizes cell biology and genetic screening, reveals a two-step mechanism leading to cell death specifically in cancer cells, while sparing normal cells.
The urgent need for new therapeutic options in SCLC is underscored by the fact that approximately 90 percent of these cancers are driven by mutations that disable two crucial tumor suppressors: RB1 and TP53. These proteins are essential for regulating the cell cycle and preventing uncontrolled cell division. Dr. Oser likens the loss of these suppressors to “losing the brakes on a car,” highlighting the challenge of directly targeting these mutations with traditional small molecule drugs.
The RB1 protein is responsible for pausing the cell cycle at the G1/S checkpoint, allowing time for quality control checks and repairs. TP53 plays a supportive role in this process. Research from the lab of Nobel Laureate William G. Kaelin Jr., MD, proposed in the late 1990s, suggested that targeting cyclins could be beneficial for cancer cells exhibiting elevated activity of a factor known as E2F, which occurs in cells lacking both RB1 and TP53.
Despite this early insight, it wasn’t until the late 2010s that scientists at Circle Pharma made significant strides in creating drugs that could effectively target cyclins. The Oser Lab, led by post-doctoral fellow Shilpa Singh, collaborated with Circle Pharma to investigate how these direct cyclin inhibitors, specifically cyclin A/B RxL inhibitors, impact cancer and normal cells.
The lab’s research uncovered a complex mechanism of action. The direct cyclin inhibitors disrupt protein-protein interactions between cyclins A and B, which are critical for ensuring quality control and proper cell cycle progression. By interrupting these interactions, the drugs induce a cascade of errors leading to cell death. The first interaction involves cyclin A and E2F; when inhibited, this results in increased DNA damage. The second interaction, between cyclin B and MYT1, causes the cancer cell to perish during mitosis, the phase of cell division.
Importantly, Dr. Oser found that normal cells treated with the drug are significantly less vulnerable to DNA damage and cell death. “Normal cells are about 100 to 1000-fold less sensitive to the drug than cancer cells,” he notes. This differential sensitivity suggests the potential for an effective dosage that could combat cancer without severe side effects.
In preclinical studies, treatment with the drug halted the growth of small cell lung cancer tumors in patient-derived xenografts. Additional experiments suggest the drug may also be effective against other cancers characterized by a disabled G1/S checkpoint.
As the phase 1 clinical trial progresses at Dana-Farber and other locations across the United States, there is cautious optimism regarding this innovative approach to small cell lung cancer treatment. The results could pave the way for new therapies that specifically target the vulnerabilities of cancer cells while minimizing harm to normal tissues.