HOX Gene Dysregulation and Therapeutic Targeting in Neuroendocrine Prostate Cancer
Creators: name: Smith, Christopher
Publisher: name: University of Surrey
Year: 2024

description: Prostate cancer (PCa) is a disease that arises from cells in the prostate and in recent years it has become increasingly evident that current treatment strategies for advanced PCa such potent androgen receptor pathway inhibitors (ARPIs) contribute to the emergence of an aggressive PCa variant termed treatment-emergent neuroendocrine prostate cancer (t-NEPC). This variant is becoming increasingly prevalent as ARPIs are being introduced earlier in the clinical management timeline for advanced PCa. Rarely, NEPC may also present de novo as a primary form of PCa arising from the resident neuroendocrine cells of the prostate. The de novo and t-NEPC variants are associated with shortened survival compared to conventional prostatic adenocarcinoma and are currently underdiagnosed with few available treatment options. Patients manifesting t-NEPC are frequently difficult to biopsy due to inaccessible lesions and high burden of disease. There is therefore a severe unmet clinical need for non-invasive diagnostic biomarkers and novel therapeutics for this aggressive malignancy. The HOX genes encode a family of transcription factor proteins responsible for body axis patterning and tissue identity in the developing embryo. The HOX genes have been shown to be dysregulated in several cancer types where they promote cell proliferation and survival. To date, very few studies have examined the role of HOX gene expression in the context of de novo or t-NEPC and how their expression patterns differ from conventional PCa. Recent pre-clinical studies using the small peptide inhibitors HXR9 and HTL-001 which disrupt HOX function by preventing HOX proteins from forming a heterodimer with their PBX co-factors have revealed this interaction as a therapeutic target in a variety of cancers, including PCa. To address the need for biomarkers, this study aimed to assess whether HOX genes are dysregulated in NEPC with a particular focus on the t-NEPC variant and whether these genes have utility as predictive biomarkers in this context. To address the need for novel therapies, this study assessed the utility of using HOX/PBX heterodimer targeting peptides as a novel therapeutic option for the treatment of NEPC. To achieve these objectives, real-time quantitative polymerase chain reaction experiments were performed alongside the analysis of publicly-available datasets to determine HOX gene expression in NEPC-like and NEPC cell lines, patient-derived xenografts, and patient tissue. Furthermore, novel peptide inhibitors were used for the in vitro and in vivo therapeutic targeting of the oncogenic HOX/PBX heterodimer. This study highlights that HOX genes are aberrantly expressed in NEPC and a comparison between prostate adenocarcinoma and t-NEPC revealed a panel of differentially expressed genes which were associated with t-NEPC and used as a diagnostic biomarker to discriminate t-NEPC samples from other forms of PCa. This study revealed that t-NEPC and NEPC-like cell lines and t-NEPC xenograft models were amenable to HOX/PBX heterodimer inhibition following treatment with HXR9 and HTL-001. Importantly, the HTL-001 peptide caused a rapid reduction of cell viability in NEPC and NEPC-like cell lines and was able to restrict the in vivo tumour growth of a NEPC xenograft model. These results highlighted that targeting the HOX/PBX heterodimer and their transcriptional function represents a useful and valid novel strategy for the treatment of NEPC. Finally, through a collaborative effort, the in vivo delivery strategy of HTL-001 was improved to better its candidacy and use as a focal ablative therapy. The result of these efforts indicate that HTL-001 may represent a novel focal ablative therapy for localised PCa, accessible metastatic t-NEPC lesions and de novo NEPC.