Mechanisms and therapeutic targeting of lethal prostate cancer master regulator transcription factors

SUMMARY Prostate cancer (PCa) is the most frequent malignancy and a leading cause of cancer death in men in the United States. Once PCa progresses to an advanced metastatic therapy-resistant stage, it becomes a lethal disease. To date, the understanding of mechanisms involved in the pathobiology of lethal PCa remain limited. Transcriptional rewiring of the cancer cell plays a fundamental role in enabling disease progression. GATA2 is a master regulator transcription factor that participates in prostate development and PCa pathogenesis. In PCa, GATA2 levels increase during disease progression and are elevated in almost all (~100%) of metastatic therapy- resistant tumors. We and others have shown that GATA2 is essential to enable androgen receptor (AR) transcriptional activity, as well as control the transcription of other genes independently of AR that participate through distinct mechanisms in the pathogenesis of lethal PCa. Most relevant to this proposal, our preliminary studies point to a key role of GATA2 in disease progression and in conferring plasticity to PCa cells. Indeed, our computational and functional studies suggest that elevated GATA2 levels increase the metastatic potential of PCa cells by transcriptionally regulating a subset of genes regulating the motility and invasiveness of PCa cells. Moreover, our transcriptomic single-cell analysis and functional studies indicate that PCa cells expressing high levels of GATA2 develop an undifferentiated stem cell-like phenotype. In addition, we have identified a novel therapeutic that significantly disrupts GATA2 transcriptional activity and demonstrates in vivo anti-cancer efficacy. Based upon these novel preliminary data, we hypothesize that transcriptional rewiring caused by elevated GATA2 expression contributes to PCa progression to lethal disease stages and that this mechanism can be targeted. We will investigate this hypothesis as follows: In Aim 1, we will define the extent and mechanisms by which GATA2 elevation enhances PCa metastasis, focusing on defining a GATA2 motility regulated molecules, as well as determine the role of GATA2 in disease progression using a transgenic conditional knock-in mouse model. In Aim 2, we will determine the impact of GATA2 in PCa cell plasticity and disease progression at the single-cell level, focusing on functionally validating the cistrome changes induced by increased GATA2 levels. We will also assess in human samples the clinical relevance of the GATA2-induced stem-like phenotype during disease progression in circulating tumor cells. Finally, in Aim 3, we will investigate the efficacy of targeting GATA2 in combination with standard therapy in pre-clinical PCa models. At its completion, results from this innovative proposal will not only enhance our understanding of how elevated GATA2 expression transcriptionally rewires the cancer cell and contributes to the pathobiology of lethal PCa, but will also have significant impact by identifying new therapeutic strategies to treat this lethal disease.