A Stanford study published July 26 in Nature demonstrates that cancer cells can be prompted to activate cellular death, a finding that has therapeutic applications in cancer treatment, regenerative medicine, and developmental disorders. The study was led by Stanford Cancer Institute members Nathanael Gray, PhD, and Gerald Crabtree, MD.

Previous research showed that mutations that drive cancer growth, known as cancer drivers, can coexist with cellular death pathways. Additionally, cell death, or apoptosis, can be induced by chemical inducers of proximity (CIPs). These small molecules can play a part in transcribing DNA to RNA, maintaining proteins, and transmitting signals through cells when near a target gene. 

“There was the thought that we may be able to use CIPs with genes that regulate cellular death to kill cancer cells,” said Crabtree. “However, CIPs are limited in their functionality because they’re not very gene-specific, so it’s hard to control where they go in the cell, and the desired outcome may not happen.”  

The study innovates a new class of molecules termed transcriptional/epigenetic CIPs (TCIPs). This approach relies on the cell’s natural transcription and epigenetic factors to bring the cancer driver to an apoptosis-regulating gene and facilitate the cancer cell’s destruction. 

“TCIPs give us better specificity and control over the genes we want to activate or deactivate, so we have a better chance at inducing apoptosis in the cancer cell,” said Gray.

This study focused on diffuse large B cell lymphoma cancer cells where the transcription factor B cell lymphoma 6 (BCL6) is deregulated and prevents apoptosis genes from being expressed. Cancer cells continue to divide and multiply as a result. However, another transcription factor, BRD4, can negate deregulated BCL6 by activating the cell’s pro-apoptotic genes.

To produce an interaction between these transcription factors, the researchers created a potent molecule named TCIP1 by linking small intracellular molecules that bind BCL6 to BRD4. Putting TCIP1 close to both BCL6 and BRD4 induces an interaction that allows apoptosis to occur. 

“We found that it was necessary to combine these three parts, termed an intracellular ternary complex, within the cell to prompt apoptosis,” said Crabtree. 

BRD4 increased its activity by 50% in pro-apoptotic genes and decreased its activity by 10% in enhancers, which aid in gene activation and deactivation. MYC, an essential gene in diffuse large B cell lymphoma growth, was one of the most reduced enhancers. 

“What’s amazing about this approach is that it only affects cancer cells. Healthy cells are left alone,” said Gray. “It’s not only an improvement on chemotherapy, but we also found that it has the potential to kill cancer cells resistant to chemotherapy.”

“There is a wealth of regulators involved in cell death. This presents many opportunities to use diverse cancer drivers to generalize this strategy of killing cancer cells by rewiring the cancer driver circuitry. Further, this approach might be applicable to other areas of biology and medicine. It’s an exciting approach that offers a lot of promise,” said Crabtree. 

An editorial about the study appeared in Nature, and the study was covered in the New York Times.