Reprogramming malignant gene expression with chemical inducers of proximity

Описание: Abstract: "Contemporary targeted cancer therapy centers on silencing oncogenic programs. While this paradigm has revolutionized the treatment of numerous malignancies, its impact is frequently curtailed by dose-limiting toxicities and resistance, by either reactivation of the original driver or acquisition of additional, secondary drivers. In contrast, the success of CAR-T and other immunotherapies highlights the critical need for inducing robust death of tumor cells for a potent and durable clinical response.
We provide the molecular and structural underpinnings of a small molecule approach that leverages chemically induced proximity to produce specific cell killing of diffuse large B cell lymphoma. We develop bifunctional molecules that re-localize cancer-driving transcriptional activators to activate pro-apoptotic genes ordinarily repressed by the BCL6 transcription factor. Despite their large size, these molecules are cell-permeable and induce potent and lineage-specific induction of pro-apoptotic genes and killing of cancer cells that overexpress BCL6. Genomic and proteomic evidence corroborates a gain-of-function mechanism where, instead of target-centric, global inhibition, a small fraction of target activity is borrowed and re-localized. Together, we show that the aberrant function of oncogenic drivers can be co-opted to activate robust cell death, with implications for precision cancer therapy.
We further develop a chemical blueprint for rewiring oncogenic gene expression beyond lymphoma, specifically in acute pediatric leukemia and demonstrate that induced proximity is a privileged approach for addressing transcription factors, which previously have escaped modulation with conventional small-molecule pharmacology."

Within the MtL Lecture Series, usually faculty members from the MPS MtL introduce their research to everyone interested via Zoom. Each talk is followed by a Q&A session.