Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.

Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression.

Reproducible preclinical models of androgen receptor driven human prostate cancer bone metastasis.

Background: Preclinical models recapitulating the metastatic phenotypes are essential for developing the next-generation therapies for metastatic prostate cancer (mPC). We aimed to establish a cohort of clinically relevant mPC models, particularly androgen receptor positive (AR) bone metastasis models, from LuCaP patient-derived xenografts (PDX) that reflect the heterogeneity and complexity of mPC.

Methods: PDX tumors were dissociated into single cells, modified to express luciferase, and were inoculated into NSG mice via intracardiac injection.

Localized high-risk prostate cancer harbors an androgen receptor low subpopulation susceptible to HER2 inhibition.

Patients diagnosed with localized high-risk prostate cancer have higher rates of recurrence, and the introduction of neoadjuvant intensive hormonal therapies seeks to treat occult micrometastatic disease by their addition to definitive treatment. Sufficient profiling of baseline disease has remained a challenge in enabling the in-depth assessment of phenotypes associated with exceptional vs. poor pathologic responses after treatment.

Radiogenomic profiling of prostate tumors prior to external beam radiotherapy converges on a transcriptomic signature of TGF-β activity driving tumor recurrence.

Background: Patients with localized prostate cancer have historically been assigned to clinical risk groups based on local disease extent, serum prostate specific antigen (PSA), and tumor grade. Clinical risk grouping is used to determine the intensity of treatment with external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT), yet a substantial proportion of patients with intermediate and high risk localized prostate cancer will develop biochemical recurrence (BCR) and require salvage therapy. Prospective identification of patients destined to experience BCR would allow treatment intensification or selection of alternative therapeutic strategies.

Progression of prostate cancer reprograms MYC-mediated lipid metabolism via lysine methyltransferase 2A.

Background: The activities of MYC, the androgen receptor, and its associated pioneer factors demonstrate substantial reprogramming between early and advanced prostate cancer. Although previous studies have shown a shift in cellular metabolic requirements associated with prostate cancer progression, the epigenetic regulation of these processes is incompletely described. Here, we have integrated chromatin immunoprecipitation sequencing (ChIP-seq) and whole-transcriptome sequencing to identify novel regulators of metabolism in advanced prostate tumors characterized by elevated MYC activity.

Prostate-Specific Membrane Antigen Is a Biomarker for Residual Disease following Neoadjuvant Intense Androgen Deprivation Therapy in Prostate Cancer.

Purpose: Neoadjuvant intense androgen deprivation therapy (iADT) can exert a wide range of histological responses, which in turn are reflected in the final prostatectomy specimen. Accurate identification and measurement of residual tumor volumes are critical for tracking and stratifying patient outcomes.

Materials And Methods: The goal of this current study was to evaluate the ability of antibodies against prostate-specific membrane antigen (PSMA) to specifically detect residual tumor in a cohort of 35 patients treated with iADT plus enzalutamide for 6 months prior to radical prostatectomy.

EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer.

Prostate cancers are considered to be immunologically 'cold' tumors given the very few patients who respond to checkpoint inhibitor (CPI) therapy. Recently, enrichment of interferon-stimulated genes (ISGs) predicted a favorable response to CPI across various disease sites. The enhancer of zeste homolog-2 (EZH2) is overexpressed in prostate cancer and known to negatively regulate ISGs.

Nascent Prostate Cancer Heterogeneity Drives Evolution and Resistance to Intense Hormonal Therapy.

Background: Patients diagnosed with high risk localized prostate cancer have variable outcomes following surgery. Trials of intense neoadjuvant androgen deprivation therapy (NADT) have shown lower rates of recurrence among patients with minimal residual disease after treatment. The molecular features that distinguish exceptional responders from poor responders are not known.

MEIS1 down-regulation by MYC mediates prostate cancer development through elevated HOXB13 expression and AR activity.

Localized prostate cancer develops very slowly in most men, with the androgen receptor (AR) and MYC transcription factors amongst the most well-characterized drivers of prostate tumorigenesis. Canonically, MYC up-regulation in luminal prostate cancer cells functions to oppose the terminally differentiating effects of AR. However, the effects of MYC up-regulation are pleiotropic and inconsistent with a poorly proliferative phenotype.

A case report of multiple primary prostate tumors with differential drug sensitivity.

Localized prostate cancers are genetically variable and frequently multifocal, comprising spatially distinct regions with multiple independently-evolving clones. To date there is no understanding of whether this variability can influence management decisions for patients with prostate tumors. Here, we present a single case from a clinical trial of neoadjuvant intense androgen deprivation therapy.

Low Abundance of Circulating Tumor DNA in Localized Prostate Cancer.

Purpose: Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease.

Methods: We applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases.

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins.

The paradigm that microtubule-targeting agents (MTAs) cause cell death via mitotic arrest applies to rapidly dividing cells but cannot explain MTA activity in slowly growing human cancers. Many preferred cancer regimens combine a MTA with a DNA-damaging agent (DDA). We hypothesized that MTAs synergize with DDAs by interfering with trafficking of DNA repair proteins on interphase microtubules.

Histone deacetylase inhibitors influence chemotherapy transport by modulating expression and trafficking of a common polymorphic variant of the ABCG2 efflux transporter.

Histone deacetylase inhibitors (HDI) have exhibited some efficacy in clinical trials, but it is clear that their most effective applications have yet to be fully determined. In this study, we show that HDIs influence the expression of a common polymorphic variant of the chemotherapy drug efflux transporter ABCG2, which contributes to normal tissue protection. As one of the most frequent variants in human ABCG2, the polymorphism Q141K impairs expression, localization, and function, thereby reducing drug clearance and increasing chemotherapy toxicity.

Mutations in the β-tubulin binding site for peloruside A confer resistance by targeting a cleft significant in side chain binding.

Peloruside A is a microtubule-stabilizing macrolide that binds to beta tubulin at a site distinct from the taxol site. The site was previously identified by H-D exchange mapping and molecular docking as a region close to the outer surface of the microtubule and confined in a cavity surrounded by a continuous loop of protein folded so as to center on Y340. We have isolated a series of peloruside A-resistant lines of the human ovarian carcinoma cell line A2780(1A9) to better characterize this binding site and the consequences of altering residues in it.

Oligomerization of p53 precedes its association with dynein and nuclear accumulation.

Previous studies have identified several proteins that associate with microtubules and the dynein motor complex including p53, the glucocorticoid and the vitamin D receptors, and the APC (adenomatous polyposis coli) protein; but neither the residues important for this interaction nor the physical state of the proteins involved have been clarified. We observed in SN12C cells harboring a mutant p53 truncated at amino acid 336, impaired nuclear localization and impaired association with dynein. This finding was confirmed and extended by examining a series of truncated p53 proteins that identified residues 336 to 348 as crucial for association with dynein and nuclear transport.

Depletion of mutant p53 and cytotoxicity of histone deacetylase inhibitors.

Mutant p53 is a cancer-specific target for pharmacologic intervention. We show that histone deacetylase inhibitors such as FR901228 and trichostatin A completely depleted mutant p53 in cancer cell lines. This depletion was preceded by induction of p53-regulated transcription.