Scientists from Stanford University and the University of Texas MD Anderson Cancer Center have discovered a class of molecules that use endogenous proteins to modulate genetic pathways involved in cell death. These molecules, which are called transcriptional/epigenetic chemical inducers of proximity (TCIPs), use local transcription factors or epigenetic regulators to restart the expression of genes responsible for instigating apoptosis in cancer cells. Full details of the study are described in a Nature paper titled “Rewiring cancer drivers to activated apoptosis” published this week.
“The coexistence of cell death pathways with driver mutations suggest that the cancer driver could be rewired to activate cell death using chemical inducers of proximity (CIPs),” the researchers wrote in the paper. Previous studies involving these molecules have rewired genes in signal transduction pathways and in protein localization and transcription pathways.
“To rewire transcriptional circuits within a genetically unmodified cell or organism, we developed small molecules that the recruitment of cancer-driving translational or epigenetic regulators to the regulatory regions of target therapeutic genes,” the study authors said. “[B]y making use of the intrinsic driving pathways of the cancer cell and rewiring them to activate pathways of cell death, we have introduced an approach to cancer chemotherapy that is analogous to a dominant gain-of-function mutation in genetics.”
The study focused on cells from a diffuse large B cell lymphoma, a type of non-Hodgkin lymphoma where the body produces abnormally sized B cells, and a transcription factor called B-cell lymphoma 6 (BCL6). The team generated a small library of TCIPs for testing on B-cell lymphoma cells lines alongside other types of cancer. The TCIPs combined small molecules that bind to and inhibit BCL6, with molecules that bind protein domains of B-cell transcription activators like BRD4. The linked molecules and proteins formed a complex that targets and activates some of the pathways that lead to cells’ death.
The research team generated a small library of TCIPs and tested them against various cancer cell lines. One TCIP, labeled TCIP1, selectively killed B cell lymphoma cell lines including some that were resistant to chemotherapy. The researchers tested TCIP1’s potency on a larger panel of 906 cancer cell lines culled from various lineages. The results showed that TCIP1 had the strongest effect on cancer cells that originated from hematopoietic and lymphoid tissues and had high levels of BCL6. It was less effective, however, in cell lines without BCL6. Further analysis showed that TCIP1 targets multiple death pathways including popular ones like TNF signaling and the p53 pathway.
A bonus of the treatment is that it remains robust even at low concentrations. “TCIPs produce their effect by activating cell death signaling and rewiring only a fraction of the cancer driver molecules per cell to drive the phenotype,” the scientists noted in the paper. “A gain-of-function mechanism would also explain the far more robust cell killing seen with substantially lower concentrations of TCIP1” compared to other small-molecule inhibitors of BCL6.
Although this study focused on cancers specifically, TCIPs are versatile and can be used to activate gene expression in a broader range of contexts. For example, they could be used to modulate gene expression in organisms used in synthetic biology projects. Importantly, these complexes are better suited for therapies than their predecessors, according to the study authors. Earlier CIP studies used genetically modified transcription factors in their complexes, which reduced their potential for use in therapeutic applications. In contrast TCIP’s use native proteins, and that opens several possible therapeutic applications. For example, scientists could design TCIPs for use in human immunotherapies or to induce apoptosis in aging cells.
