OVERALL PROJECT SUMMARY The overall goal of this Program is to understand how transcription and splicing regulation is altered and co- opted by cancer cells to promote tumor initiation and progression, and to apply this knowledge towards development of new therapeutic approaches. During the past 50 years, the strong underlying basic science foundation of the Program Project has allowed members to identify vulnerabilities in cancer and develop novel and highly specific therapeutic strategies. This Program continues to take a multi-pronged approach grounded in basic cancer research to identify and disrupt the molecular dependencies underlying cancer. Within this Program, there are three highly integrated Projects (Targeting oncogenic transcription factors; RNA Splicing dysregulation in cancer; Regulatory RNAs as cancer drivers and dependencies) and four innovative Cores that are using cutting edge technologies to study the molecular mechanisms of cancer biology. To achieve the Program's goals, these studies will exploit novel organoid models of human cancers, pioneering imaging modalities in animal models, therapeutic antisense oligonucleotide strategies against otherwise undruggable targets, and cutting-edge methods in biochemistry, cell biology and molecular biology. The researchers will interrogate the basis of two of the most devastating types of tumors, basal-like carcinomas of the breast and pancreas. All of this work is supported by four Cores that provide access to technologies, services, and expertise that all combine to enhance productivity and promote interactions. The interactive and collaborative nature of this Program guides each of these Projects beyond their singular potential. Research in all three Projects touches on overlapping themes and benefits from the expertise of the other Program members. Together, this Program is making significant progress towards its goal of identifying novel therapeutic targets that will substantially impact cancer treatment.