Scientists Discover New Cancer Therapies by Exploring the Coexistence of Cell Death and Mutation Pathways

Scientists are exploring the coexistence of cell death and mutation pathways to develop new cancer therapies Credit: Freepik

Genes involved in cell proliferation, survival, invasion, and metastasis have been identified for several human cancers. Independent studies have identified death pathways that kill cells for the benefit of the body. The coexistence of cell death and mutational pathways suggests that causes of cancer can be reconfigured to activate cell death using chemical affinity triggers.

In this sense, now scientists from Stanford University and the University of Texas MD Anderson Cancer Center have discovered a class of molecules that proteins use to modify genetic pathways involved in cell death.

Called chemical inducers/proximal epigenetics (TCIPs), these factors use local transcription factors or epigenetic regulators to re-express genes responsible for initiating apoptosis (a type of cell death in which a series of molecular processes within the cell causes its destruction) in cancer cells. Full details of this study are described in an article by alam which was just published.

The coexistence of cell death pathways with driver mutations suggests that cancer drivers can be rearranged to trigger cell death using chemical proximity inducers (CIPs),” said Gerald R. Crabtree, a specialist in the Department of Pathology at Stanford University. Previous studies of this molecule have reconfigured genes in signal transduction pathways and in protein localization and transcription pathways.”

The TCIP molecule provides new hope for anaplastic large B-cell lymphoma patients, showing promising results in laboratory tests (Freepik)

Described by Nathaniel S. Gray, of the Department of Systems Chemistry and Systems: “To repair transcriptional circuits within genetically modified cells or organisms, we have developed small molecules that recruit cancer-causing epigenetic or multi-translational regulators to regulatory regions of therapeutic genes that are targeted.” Biology at Stanford Cancer Institute.

“By harnessing the intrinsic delivery pathways of cancer cells and remodeling them to activate cell death pathways, we have introduced approaches to cancer chemotherapy that mimic function mutations in genes,” he added.

Studies focused on Diffuse large B-cell lymphoma, which is a type of non-Hodgkin lymphoma in which the body produces abnormally sized B cells, and a transcription factor called B-cell lymphoma 6 (BCL6). The team created a small library of TCIP for testing in B-cell lymphoma cell lines along with other cancers.

TCIP combines a small molecule that binds to and inhibits BCL6, with another molecule that binds to the domain of a B-cell transcription activator protein such as BRD4. The molecules and related proteins form complexes that target and activate several pathways that lead to cell death. Professionals take a small library of TCIPs and test them against various cancer cell lines.

Endogenous proteins modulate genetic pathways in malignant cells, representing an innovative approach to inducing cell death (peterschreiber.media/Adobe Stock)

One TCIP, called TCIP1, selectively kills B-cell lymphoma cell lines, including some that are resistant to chemotherapy. The researchers tested the effectiveness of TCIP1 in a larger group of 906 cancer cell lines selected from different lineages. The results show that TCIP1 has the strongest effect on cancer cells of hematopoietic origin (responsible for blood cells) and lymphoid tissue and has high levels of BCL6.

However, it was less effective in cell lines without BCL6. Additional analyzes demonstrated that TCIP1 targets multiple death pathways, including common pathways such as TNF signaling and the p53 pathway. The advantage of this treatment is that it remains strong even at low concentrations.

Gray explains, “TCIP produces its effect by activating cell death signals and recombining only a small portion of each cell’s cancer-promoting molecules to drive the phenotype.” concentration level of TCIP1 is significantly lower compared to other small molecule inhibitors of BCL6″.

Although this research focuses specifically on cancer, TCIP is extremely versatile and can be used to activate gene expression in a wider context. For example, they can be used to modify gene expression in organisms used in synthetic biology projects. This complex is better suited for therapy than its predecessors, according to the study authors.

Previous papers have used transgenic transcription factors in their complexes, which has reduced their potential for therapeutic applications. In contrast, TCIP uses native proteins, and this opens up many potential therapeutic applications. For example, scientists could design TCIP for use in human immunotherapy or to induce apoptosis in senescent cells.

Tim peneliti dilengkapi oleh: Sai Gourisankar, Andrey Krokhotin, Wenzhi Ji, Xiaofan Liu, Chiung-Ying Chang, Samuel H. Kim, Zhengnian Li, Wendy Wenderski, Juste M. Simanauskaite, Haopeng Yang, Hannes Vogel, Tinghu Zhang, Michael R. hijau.

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2023-08-12 10:43:40
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