Targeting Undruggable Transcription Factor HoxB13 to Inhibit Prostate Cancer Metastasis - Project Summary/Abstract Metastasis is the leading cause of cancer-related deaths. In patients with metastatic castration-resistant prostate cancer (mCRPC), although bone is the most prevalent site of metastasis, the existence of metastases in visceral organs such as the liver and lungs leads to the poorest prognosis. Current androgen receptor signaling-targeted therapies have not vastly improved overall survival in mCRPC patients. There remains an urgent need for the development of novel therapies for mCRPC patients, particularly those visceral and bone mCRPC patients who have the worst prognosis or a high prevalence. We and others have found that mCRPC cells highly express the oncogenic transcription factor (TF) HoxB13, which has been shown to promote CRPC growth, invasion and metastasis, However, the precise molecular and genomic mechanisms that underlie the oncogenic functions of HoxB13 remain largely unknown. Furthermore, like the majority of TFs, HoxB13 is considered untargetable by traditional, small molecule-based drug design. Gene therapy is a critical alternative strategy with the potential to directly target such traditionally undruggable genes. We have developed a lipid nanoparticle (LNP) system for safely delivery of the highly specific RNA-targeting CRISPR/Cas13d (CasRx) system to knock down mRNAs of transcription regulators in prostate cancer. By combing the LNP-CasRx system with the visceral organ-targeting SORT (selective organ targeting) nanotechnology, or incorporating the bone-targeting chemical alendronate into the LNP, and further modifying these visceral- or bone-targeting LNP surfaces with the prostate cancer-specific aptamer E3, we have successfully developed and tested a tri- targeting LNP system, simultaneously targeting 1) specific organs including liver, lungs or bone; 2) metastatic cancerous cells (mCRPC cells); and 3) mRNAs encoding TFs (HoxB13). In this proposal, we hypothesize that HoxB13-driven oncogenic transcription and CRPC metastasis can be counteracted by a CasRx-based LNP system with specificity, efficacy, and safety. In Aim 1, we will uncover molecular and genomic mechanisms by which HoxB13 activates oncogenic transcription in CRPC. In Aim 2, we will assess the therapeutic efficacy, safety and molecular impact of the CasRx-based tri-targeting LNP system in CRPC. The data generated from this proposal will provide key preclinical information about the efficacy and safety of this tri-targeting therapeutic strategy, forming a basis for future medical application of a nanoparticle-delivered RNA targeting system to inhibit HoxB13-driven oncogenic transcription in metastatic CRPC.
