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Principal Investigator: Andrew Caleb Hsieh
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $412,243
Funding agency: National Cancer Institute
ABSTRACT (from parental grant)
The recent advent of highly potent inhibitors of the androgen receptor and androgen biosynthesis has had the
unfortunate iatrogenic effect of fueling new lethal prostate cancer phenotypes in patients. In particular, non-
neuroendocrine androgen receptor-low castration resistant prostate cancer (CRPC), an aggressive form of this
disease, is increasing in occurrence amongst patients and is uniformly fatal. The main barriers against
therapeutic advances are a paucity of relevant disease models and a very poor understanding of the
mechanisms that give rise to this phenotype. The process of protein synthesis has long been considered
subordinate to alterations at the levels of DNA and RNA in cancer etiology. However, work from our laboratory
and others have revealed that protein synthesis control is a dynamic process that coordinates not only bulk
mRNA translation, but also the specialized translation of distinct mRNAs important for cancer phenotypes.
Recently, our laboratory has developed and characterized a new in vitro and in vivo toolkit of both human and
murine androgen receptor-low CRPC. We have used these models to discover a critical link between androgen
receptor signaling and the process of mRNA translation initiation, which is critical for androgen receptor-low
CRPC growth. We hypothesize that androgen receptor-low CRPC is driven by the specific translation of
distinct mRNA networks, thereby leading to persistent tumor growth, which may represent a therapeutic
vulnerability. Our long-term objective is to utilize state-of-the-art mouse models, ribosome profiling, and patient
derived xenografts to definitively investigate the fundamental link between the androgen receptor and protein
synthesis control in a highly relevant and newly emerging disease course for prostate cancer patients. To do
so, we will address the following aims: 1) determine the mechanism by which the androgen receptor
communicates with the translation apparatus, 2) delineate how aberrant protein synthesis drives the translation
of distinct oncogenic mRNAs, and 3) elucidate the therapeutic efficacy of targeting translation initiation in
androgen receptor-low CRPC.
Ultimately, these studies are poised to uncover a new paradigm for gene regulation in androgen receptor-low
prostate cancer and provide the preclinical basis for targeting the protein synthesis apparatus in an
increasingly common highly aggressive disease.
Terms: <Androgen Antagonists><Androgen Receptor><Androgenic Agents><Androgenic Compounds><Androgens><Anti-Androgen><Anti-Androgen Agents><Binding Proteins><Body Tissues><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Patient><Cancer-Promoting Gene><Cancers><Cell Communication and Signaling><Cell Function><Cell Growth in Number><Cell Line><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><CellLine><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cessation of life><Collection><Communication><DNA><Data><Death><Deoxyribonucleic Acid><Development><Disease><Disorder><Drug resistance><Exhibits><Experimental Genetics><Gene Action Regulation><Gene Expression Process><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Generalized Growth><Generations><Genes><Genetic Models><Goals><Grant><Growth><Human><Hyperactivity><Iatrogenesis><In Vitro><Individual><Initiation Factors><International><Intracellular Communication and Signaling><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Link><Maintenance><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Measures><Mediating><Messenger RNA><Methods><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Neuroendocrine><Neuroendocrine System><Neurosecretory Systems><Non-Polyadenylated RNA><Oncogenes><Oncogenic><Organoids><PDX model><Pathogenesis><Patient derived xenograft><Patients><Peptide Initiation Factors><Phenotype><Process><Proliferating><Prostate CA><Prostate Cancer><Prostate malignancy><Prostatic Cancer><Protein Binding><Protein Biosynthesis><Proteins><RNA><RNA Gene Products><Receptor Protein><Receptor Signaling><Regulatory Element><Ribo-seq><Ribonucleic Acid><Ribosomal Peptide Biosynthesis><Ribosomal Protein Biosynthesis><Ribosomal Protein Synthesis><Role><Sampling><Seminal><Series><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Strains Cell Lines><Study models><Subcellular Process><Testing><Therapeutic><Therapeutic Androgen><Tissue Growth><Tissues><Transforming Genes><Translation Initiation><Translation Initiation Factor><Translational Initiation Factor><Translational Regulation><Translations><Treatment Efficacy><United States><Work><Xtandi><abiraterone><advanced prostate cancer><androgen ablation therapy><androgen biosynthesis><androgen blockade therapy><androgen deprivation therapy><androgen deprivation treatment><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen inhibitor><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><biological signal transduction><bound protein><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><cohort><cultured cell line><develop therapy><developmental><disease model><disorder model><drug resistant><enzalutamide><global gene expression><global transcription profile><hormonal signals><hormone refractory prostate cancer><hormone signals><human model><human tissue><iatrogenic><iatrogenically><iatrogenicity><in vivo><inhibitor><intervention development><intervention efficacy><intratumoral androgen><mRNA><mRNA Translation><malignancy><men><model of human><mouse model><murine model><neoplasm/cancer><new technology><novel technologies><ontogeny><patient derived xenograft model><pre-clinical><pre-clinical study><preclinical><preclinical study><prognostic><programs><prostate cancer cell><prostate cancer resistant to androgen><prostate tumor cell><protein synthesis><receptor><resistance to Drug><resistant to Drug><response><response to therapy><response to treatment><ribosome footprint profiling><ribosome profiling><social role><therapeutic efficacy><therapeutic response><therapy development><therapy efficacy><therapy response><transcriptome><translation><treatment development><treatment response><treatment responsiveness><tumor growth>