Clinical Trial Protocol for VIOLET: A Single-Center, Phase I/II Trial Evaluation of Radioligand Treatment in Patients with Metastatic Castration-Resistant Prostate Cancer with [Tb]Tb-PSMA-I&T.

[Lu]Lu-PSMA is an effective class of therapy for patients with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response may be partially explained by the presence of micrometastatic deposits, which are energy-sheltered and receive low absorbed radiation with Lu due to the approximately 0.7-mm mean pathlength.

YBX1 integration of oncogenic PI3K/mTOR signalling regulates the fitness of malignant epithelial cells.

In heterogeneous head and neck cancer (HNC), subtype-specific treatment regimens are currently missing. An integrated analysis of patient HNC subtypes using single-cell sequencing and proteome profiles reveals an epithelial-mesenchymal transition (EMT) signature within the epithelial cancer-cell population. The EMT signature coincides with PI3K/mTOR inactivation in the mesenchymal subtype.

Arginine-rich C9ORF72 ALS proteins stall ribosomes in a manner distinct from a canonical ribosome-associated quality control substrate.

Hexanucleotide expansion mutations in C9ORF72 are a frequent cause of amyotrophic lateral sclerosis. We previously reported that long arginine-rich dipeptide repeats (DPRs), mimicking abnormal proteins expressed from the hexanucleotide expansion, caused translation stalling when expressed in cell culture models. Whether this stalling provides a mechanism of pathogenicity remains to be determined.

AlphaBet: Combination of Radium-223 and [ Lu]Lu-PSMA-I&T in men with metastatic castration-resistant prostate cancer (clinical trial protocol).

Background: [Lu]Lu-PSMA is a radioligand therapy used in metastatic castration-resistant prostate cancer (mCRPC). Despite a survival benefit, the responses for many patients receiving [Lu]Lu-PSMA are not durable, and all patients eventually develop progressive disease. The bone marrow is the most common site of progression.

Regulation of gene expression via translational buffering.

Translation of an mRNA represents a critical step during the expression of protein-coding genes. As mechanisms governing post-transcriptional regulation of gene expression are progressively unveiled, it is becoming apparent that transcriptional programs are not fully reflected in the proteome. Herein, we highlight a previously underappreciated post-transcriptional mode of regulation of gene expression termed translational buffering.

The MURAL collection of prostate cancer patient-derived xenografts enables discovery through preclinical models of uro-oncology.

Preclinical testing is a crucial step in evaluating cancer therapeutics. We aimed to establish a significant resource of patient-derived xenografts (PDXs) of prostate cancer for rapid and systematic evaluation of candidate therapies. The PDX collection comprises 59 tumors collected from 30 patients between 2012-2020, coinciding with availability of abiraterone and enzalutamide.

CX-5461 Sensitizes DNA Damage Repair-proficient Castrate-resistant Prostate Cancer to PARP Inhibition.

Monotherapy with PARP inhibitors is effective for the subset of castrate-resistant prostate cancer (CRPC) with defects in homologous recombination (HR) DNA repair. New treatments are required for the remaining tumors, and an emerging strategy is to combine PARP inhibitors with other therapies that induce DNA damage. Here we tested whether PARP inhibitors are effective for HR-proficient CRPC, including androgen receptor (AR)-null tumors, when used in combination with CX-5461, a small molecule that inhibits RNA polymerase I transcription and activates the DNA damage response, and has antitumor activity in early phase I trials.

Regulation of mRNA Translation by Hormone Receptors in Breast and Prostate Cancer.

Breast and prostate cancer are the second and third leading causes of death amongst all cancer types, respectively. Pathogenesis of these malignancies is characterised by dysregulation of sex hormone signalling pathways, mediated by the estrogen receptor-α (ER) in breast cancer and androgen receptor (AR) in prostate cancer. ER and AR are transcription factors whose aberrant function drives oncogenic transcriptional programs to promote cancer growth and progression.

Mast Cell-Derived SAMD14 Is a Novel Regulator of the Human Prostate Tumor Microenvironment.

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood.

Inhibition of the Lysophosphatidylinositol Transporter ABCC1 Reduces Prostate Cancer Cell Growth and Sensitizes to Chemotherapy.

Expression of ATP-binding cassette (ABC) transporters has long been implicated in cancer chemotherapy resistance. Increased expression of the ABCC subfamily transporters has been reported in prostate cancer, especially in androgen-resistant cases. ABCC transporters are known to efflux drugs but, recently, we have demonstrated that they can also have a more direct role in cancer progression.

CRISP3 expression drives prostate cancer invasion and progression.

Identifying the factors stimulating prostate cancer cells migration and invasion has the potential to bring new therapeutic targets to the clinic. Cysteine-rich secretory protein 3 (CRISP3) is one of the most highly upregulated proteins during the transition of a healthy human prostatic epithelium to prostate cancer. Here we show using a genetically engineered mouse model of prostate cancer that CRISP3 production greatly facilitates disease progression from carcinoma in situ to invasive prostate cancer in vivo.

Translational offsetting as a mode of estrogen receptor α-dependent regulation of gene expression.

Estrogen receptor alpha (ERα) activity is associated with increased cancer cell proliferation. Studies aiming to understand the impact of ERα on cancer-associated phenotypes have largely been limited to its transcriptional activity. Herein, we demonstrate that ERα coordinates its transcriptional output with selective modulation of mRNA translation.

mTOR-mediated podocyte hypertrophy regulates glomerular integrity in mice and humans.

The cellular origins of glomerulosclerosis involve activation of parietal epithelial cells (PECs) and progressive podocyte depletion. While mammalian target of rapamycin-mediated (mTOR-mediated) podocyte hypertrophy is recognized as an important signaling pathway in the context of glomerular disease, the role of podocyte hypertrophy as a compensatory mechanism preventing PEC activation and glomerulosclerosis remains poorly understood. In this study, we show that glomerular mTOR and PEC activation-related genes were both upregulated and intercorrelated in biopsies from patients with focal segmental glomerulosclerosis (FSGS) and diabetic nephropathy, suggesting both compensatory and pathological roles.

V-ATPase-associated prorenin receptor is upregulated in prostate cancer after PTEN loss.

Phosphatase and tensin homolog (PTEN) tumor suppressor protein loss is common in prostate cancer (PCa). PTEN loss increases PI3K/Akt signaling, which promotes cell growth and survival. To find secreted biomarkers of PTEN loss, a proteomic screen was used to compare secretomes of cells with and without PTEN expression.

A balancing act: PHLPP2 fine tunes AKT activity and MYC stability in prostate cancer.

PTEN loss stimulates prostate tumor progression by sustaining AKT activation. Nowak et al. (2019.

Generally applicable transcriptome-wide analysis of translation using anota2seq.

mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated contributes to various disorders including metabolic and neurological diseases and cancer. Notwithstanding that optimal and universally applicable methods are critical for understanding the complex role of translational control under physiological and pathological conditions, approaches to analyze translatomes are largely underdeveloped. To address this, we developed the anota2seq algorithm which outperforms current methods for statistical identification of changes in translation.

AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965.

Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor.

Identification of Mutation as a Genetic Driver of Prostate Cancer That Cooperates with Loss to Accelerate Progression and Castration-Resistant Growth.

Genetic alterations that potentiate PI3K signaling are frequent in prostate cancer, yet how different genetic drivers of the PI3K cascade contribute to prostate cancer is unclear. Here, we report mutation/amplification correlates with poor survival of patients with prostate cancer. To interrogate the requirement of different PI3K genetic drivers in prostate cancer, we employed a genetic approach to mutate in mouse prostate epithelium.

Epididymal cysteine-rich secretory proteins are required for epididymal sperm maturation and optimal sperm function.

Study Question: What is the role of epididymal cysteine-rich secretory proteins (CRISPs) in male fertility?

Summary Answer: While epididymal CRISPs are not absolutely required for male fertility, they are required for optimal sperm function.

What Is Known Already: CRISPs are members of the CRISP, Antigen 5 and Pathogenesis related protein 1 (CAP) superfamily and are characterized by the presence of an N-terminal CAP domain and a C-terminal CRISP domain. CRISPs are highly enriched in the male reproductive tract of mammals, including in the epididymis.

Cross-talk between protein synthesis, energy metabolism and autophagy in cancer.

Translation is a pivotal step in the regulation of gene expression as well as one of the most energy consuming processes in the cell. Dysregulation of translation caused by the aberrant function of upstream signaling pathways and/or perturbations in the expression or function of components of the translation machinery is frequent in cancer. In this review, we discuss emerging findings that highlight hitherto unappreciated aspects of signaling to the translation apparatus with the particular focus on emerging connections between protein synthesis, autophagy and energy homeostasis in cancer.

mTOR-sensitive translation: Cleared fog reveals more trees.

Translation is fundamental for many biologic processes as it enables cells to rapidly respond to stimuli without requiring de novo mRNA synthesis. The mammalian/mechanistic target of rapamycin (mTOR) is a key regulator of translation. Although mTOR affects global protein synthesis, translation of a subset of mRNAs appears to be exceptionally sensitive to changes in mTOR activity.