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Principal Investigator: Qianben Wang
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $516,712
Funding agency: National Cancer Institute
Project Summary/Abstract
Patients with lethal castration-resistant prostate cancer (CRPC) are currently treated with agents targeting
androgen receptor (AR) signaling. However, AR inhibition has not dramatically improved CRPC patient survival,
underscoring the need to discover novel oncogenic mechanisms in CRPC and develop new therapies targeting
these mechanisms. Cancer cells are addicted to aberrant RNA polymerase II (Pol II) transcription, which includes
initiation, elongation, and termination phases, as well as a recycling step critical to repeated Pol II transcription
of the same gene after the initial transcription cycle. While studies have already indicated that uncontrolled
transcriptional initiation and elongation have oncogenic roles, it is unknown whether other Pol II transcription
processes contribute to cancer-relevant transcriptional outcomes and cancer growth. In preliminary studies, our
newly developed in vitro and cell-based transcription recycling assays have found that Pol II recycling is a key
yet overlooked transcription process with relevance to prostate cancer. We have found that Mediator complex
subunit 31 (MED31) drives Pol II recycling in CRPC cells, enhancing mRNA output during the recycling process.
Importantly, high expression of MED31 is both sufficient and necessary for prostate cancer castration-resistant
growth and is associated with poor prognosis of CRPC patients. While these findings identify the oncogenic
MED31 as a new therapeutic target for CRPC, transcription regulators such as MED31 are generally considered
untargetable by traditional, small molecule-based drug design. We have developed a safe lipid nanoparticle
(LNP) system for targeted delivery of the CRISPR/Cas13d system to efficiently and specifically knock down
oncogenic transcription regulators at the mRNA level. In preliminary studies, we have demonstrated that the
LNP-Cas13d system effectively and safely knocks down MED31 mRNA and decreases CRPC cell growth in vivo,
establishing the proof of the concept that the therapeutic window exists for targeting MED31 in CRPC. Together,
our preliminary findings support the hypothesis that MED31-governed transcription recycling is a novel
oncogenic driver for CRPC progression and that an LNP-Cas13d-based RNA targeting system can counteract
oncogenic transcription driven by MED31 in CRPC with safety, specificity, and efficacy. In Aim 1, we will delineate
the molecular mechanism, biological function, and clinical relevance of MED31-mediated transcription recycling.
In Aim 2, we will target MED31-mediated transcription recycling using a CRISPR/Cas13d-based nanoparticle
system. The successful completion of these aims will significantly elucidate the critical role of Pol II recycling in
lethal prostate cancer and will provide an experimental basis for future clinical trials testing the utility of an LNP-
Cas13d RNA targeting system to target this novel oncogenic mechanism in CRPC patients.
Terms: <Amino Acids><Androgen Receptor><Assay><Bioassay><Biochemical><Biological Assay><Biological Function><Biological Process><Body Tissues><CRISPR><CRISPR/Cas system><Cancer Cell Growth><Cancer Patient><Cancers><Castration><Cell Body><Cell Culture Techniques><Cells><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Complex><DNA><DNA-Dependent RNA Polymerase II><Deoxyribonucleic Acid><Disease><Disorder><Drug Design><European><Future><Gene Transcription><Generalized Growth><Genes><Genetic Transcription><Genomics><Growth><Guide RNA><Hepatic Neoplasm Secondary><Hepatic metastasis><Heterograft><Heterologous Transplantation><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Invaded><Legal patent><Liver secondaries><Liver secondary cancer><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic nodes><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Mediating><Mediator><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Mice><Mice Mammals><Modeling><Molecular><Murine><Mus><Neoplasm Metastasis><Non-Polyadenylated RNA><Non-Visceral><Nonvisceral><Nucleic Acids><Oncogenesis><Oncogenic><Organ><Outcome><Output><PDX model><Patents><Patient derived xenograft><Patients><Phase><Polymerase><Process><Prognosis><Prostate><Prostate CA><Prostate Cancer><Prostate Gland><Prostate malignancy><Prostatic Cancer><Prostatic Gland><Proteins><Proteomics><RNA><RNA Expression><RNA Gene Products><RNA Polymerase B><RNA Polymerase II><Receptor Inhibition><Receptor Signaling><Recycling><Resistance><Ribonucleic Acid><Role><Safety><Sampling><Secondary Neoplasm><Secondary Tumor><Specificity><Surface><Surgical Castration><System><Testing><Therapeutic><Tissue Arrays><Tissue Chip><Tissue Growth><Tissue Microarray><Tissues><Toxic effect><Toxicities><Transcription><Transcription Elongation><Transcription Initiation><Transcription Process><Treatment Efficacy><Xenograft><Xenograft procedure><Xenotransplantation><aminoacid><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><aptamer><bone><cancer cell><cancer metastasis><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cell culture><cell cultures><clinical relevance><clinically relevant><domain mapping><gRNA><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><hormone refractory prostate cancer><human tissue><improved><in vivo><insight><intervention efficacy><knock-down><knockdown><lipid based nanoparticle><lipid nanoparticle><liver metastases><lymph gland><lymph nodes><lymphnodes><mRNA><malignancy><malignant liver neoplasm, specified as secondary><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic liver><metastatic liver neoplasm><nano particle><nano therapy><nano-sized particle><nanoparticle><nanosized particle><nanotherapy><neoplasm/cancer><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><patient derived xenograft model><pre-clinical development><preclinical development><prostate cancer cell><prostate cancer cell line><prostate cancer progression><prostate cancer resistant to androgen><prostate tumor cell><protein expression><resistant><response><secondary liver malignancy><secondary malignant liver neoplasm><site targeted delivery><small molecule><social role><targeted agent><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic efficacy><therapy efficacy><tumor cell metastasis><tumorigenesis><xeno-transplant><xeno-transplantation>