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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. A patient was diagnosed with a large semi-contiguous tumor by imaging, histologically composed of a large Gleason score 9 tumor with an adjacent Gleason score 7 nodule. DNA sequencing demonstrates these are two independent tumors, as only the Gleason 9 tumor harbors single-copy losses of PTEN and TP53 . The PTEN / TP53 -deficient tumor demonstrates treatment resistance, selecting for subclones with mutations to the remaining copies of PTEN and TP53 , while the Gleason 7 PTEN -intact tumor is almost entirely ablated. These findings indicate that spatiogenetic variability is a major confounder for personalized treatment of patients with prostate cancer. Prostate cancer is often a multifocal disease but how best to manage this clinically remains unclear. Here, the authors report a single case study of a patient with two genetically diverse tumours which showed differential response to therapy.

Understanding the developmental relationship between indolent and aggressive tumors is central to understanding disease progression and making treatment decisions. For example, most men diagnosed with prostate cancer have clinically indolent disease and die from other causes. Overtreatment of prostate cancer remains a concern. Here we use laser microdissection followed by exome sequencing of low‐ and high‐grade prostate cancer foci from four subjects, and metastatic disease from two of those subjects, to evaluate the molecular relationship of coincident cancer foci. Seventy of 79 (87%) high‐confidence somatic mutations in low‐grade disease were private to low‐grade foci. In contrast, high‐grade foci and metastases harbored many of the same mutations. In cases in which there was a metastatic focus, 15 of 80 (19%) high‐confidence somatic mutations in high‐grade foci were private. Seven of the 80 (9%) were shared with low‐grade foci and 65 (82%) were shared with metastatic foci. Notably, mutations in cancer‐associated genes and the p53 signaling pathway were found exclusively in high‐grade foci and metastases. The pattern of mutations is consistent with early divergence between low‐ and high‐grade foci and late divergence between high‐grade foci and metastases. These data provide insights into the development of high‐grade and metastatic prostate cancer. The overwhelming majority of somatic mutations in coincident low and high grade prostate cancer foci are private, suggesting these foci diverge early from a common progenitor. In contrast, synchronous metastatic disease contains few mutations not already present in high grade prostate cancer foci.

Checkpoint inhibitors targeting PD-1/PD-L1, such as pembrolizumab, can be effective in a small population of biomarker-selected patients with metastatic prostate cancer (mPC), as has been demonstrated by small case series. The objective of this study is to help identify which biomarker-selected patients are most likely to benefit from pembrolizumab and estimate their likelihood of response. This is a single-center study in which we analyzed clinical data of 18 patients with mPC who were treated with pembrolizumab for a biomarker-driven indication. We found that 38.9% of patients showed a 50% or greater decline in PSA, all of whom had high microsatellite instability (MSI-H). One patient with MSI-H and high tumor mutation burden (TMB-H) had 100% decline in PSA and remained on pembrolizumab after 47 months. Neither MSI-H nor TMB-H, however, was sufficient for response. These results support biomarker testing for all patients with mPC and use of immunotherapy in select populations.

Neuroendocrine prostate cancer is complex, comprising a wide spectrum of phenotypes, which has led to very different entities being inappropriately lumped together or assumed to behave like more common entities. Elucidating subtle differences is critical for treatment decision making, as this commentary describes.

Background Genetic analysis of advanced cancer is limited by availability of representative tissue. Biopsies of prostate cancer metastasized to bone are invasive with low quantity of tumor tissue. The prostate cancer genome is dynamic, however, with temporal heterogeneity requiring repeated evaluation as the disease evolves. Circulating tumor cells (CTCs) offer an alternative, “liquid biopsy”, though single CTC sequencing efforts are laborious with high failure rates. Methods We performed exome sequencing of matched treatment-naïve tumor tissue, castrate resistant tumor tissue, and pooled CTC samples, and compared mutations identified in each. Results Thirty-seven percent of CTC mutations were private to CTCs, one mutation was shared with treatment-naïve disease alone, and 62% of mutations were shared with castrate-resistant disease, either alone or with treatment-naïve disease. An acquired nonsense mutation in the Retinoblastoma gene, which is associated with progression to small cell cancer, was identified in castrate resistant and CTC samples, but not treatment-naïve disease. This timecourse correlated with the tumor acquiring neuroendocrine features and a change to neuroendocrine-specific therapy. Conclusions These data support the use of pooled CTCs to facilitate the genetic analysis of late stage prostate cancer.

Background Many current therapies for metastatic castration-resistant prostate cancer (mCRPC) are aimed at AR signaling; however, resistance to these therapies is inevitable. To personalize CRPC therapy in an individual with clinical progression despite maximal AR signaling blockade, it is important to characterize the status of AR activity within their cancer. Biopsies of bone metastases are invasive and frequently fail to yield sufficient tissue for further study. Evaluation of circulating tumor cells (CTCs) offers an alternative, minimally invasive mechanism to characterize and study late-stage disease. The goal of this study was to evaluate the utility of CTC interrogation with respect to the AR as a potential novel therapeutic biomarker in patients with mCRPC. Methods Fifteen mL of whole blood was collected from patients with progressive, metastatic mCRPC, the mononuclear cell portion was isolated, and fluorescence-activated cell sorting (FACS) was used to isolate and evaluate CTCs. A novel protocol was optimized to use ImageStreamX to quantitatively analyze AR expression and subcellular localization within CTCs. Co-expression of AR and the proliferation marker Ki67 was also determined using ImageStreamX. Results We found inter-patient and intra-patient heterogeneity in expression and localization of AR. Increased AR expression and nuclear localization are associated with elevated co-expression of Ki-67, consistent with the continued role for AR in castration-resistant disease. Despite intra-patient heterogeneity, CTCs from patients with prior exposure to abiraterone had increased AR expression compared to CTCs from patients who were abiraterone-naïve. Conclusions As our toolbox for targeting AR function expands, our ability to evaluate AR expression and function within tumor samples from patients with late-stage disease will likely be a critical component of the personalized management of advanced prostate cancer. AR expression and nuclear localization varies within patients and between patients; however it remains associated with markers of proliferation. This supports a molecularly diverse AR-centric pathobiology imparting castration-resistance.

Abstract Background Despite advances in the treatment of metastatic ccRCC, few patients are cured. Therapies exploiting novel targets are needed. Antigen screening identified ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase family member 3) as having consistent high expression in ccRCC and low expression in normal tissue. ENPP3 is a transmembrane ectoenzyme involved in hydrolysis of extracellular nucleotides. XmAb819 is a 2 + 1 bispecific antibody with high-avidity bivalent ENPP3 binding and mid-affinity monovalent CD3 binding. XmAb819 is engineered for preferential engagement and T cell-mediated cytolysis of high ENPP3-expressing cancer cells. Methods This is a multicenter, open-label, dose-escalation/expansion study enrolling up to 190 participants with advanced ccRCC. The primary objective is safety and tolerability; the secondary objective is preliminary anti-tumor activity. Part A, dose escalation, establishes a priming dose, step-up dose(s), a cohort-limit dose, and the dosing schedule for both intravenous (IV) and subcutaneous (SC) administration. Part B, dose expansion, evaluates the safety and efficacy of the recommended dose established in Part A. All subjects will have disease progression on standard-of-care therapies. XmAb819 will be administered weekly; cohort-limit doses will be administered in 21-day cycles until disease progression or unacceptable toxicity. Adverse events are graded using CTCAE v5.0; CRS using ASTCT Consensus Grading (Lee, 2019). Efficacy is assessed per investigator using RECIST v1.1. Enrollment and dose escalation continues in both the IV and SC cohorts. Significance & Vision XmAb819 is an investigational, novel bispecific T-cell engager engineered to bind and kill high ENPP3-expressing cells. The XmAb819-01 study is a trial designed to enroll patients with ccRCC, a solid tumor that overexpresses ENPP3. Initial evidence of anti-tumor activity in ccRCC has been observed, and tolerability supports continued dose escalation. Trial Schema The dosing period consists of priming, step-up, and target doses.

ABSTRACT The PI3K-AKT pathway has pleiotropic effects, and its inhibition has long been of interest in the management of prostate cancer, where a compensatory increase in PI3K signaling has been reported following Androgen Receptor (AR) blockade. Prostate cancer cells can also bypass AR blockade through induction of other hormone receptors, in particular the glucocorticoid receptor (GR). Here we demonstrate that AKT inhibition significantly decreases cell proliferation through both cytostatic and cytotoxic effects. The cytotoxic effect is enhanced by AR inhibition and is most pronounced in models that induce compensatory GR expression. AKT inhibition increases canonical AR activity and remodels the chromatin landscape, decreasing enhancer interaction at the GR gene (NR3C1) locus. Importantly, it blocks induction of GR expression and activity following AR blockade. This is confirmed in multiple in vivo models, where AKT inhibition of established xenografts leads to increased canonical AR activity, decreased GR expression, and marked anti-tumor activity. Overall, our results demonstrate that inhibition of the PI3K/AKT pathway can block GR activity and overcome GR-mediated resistance to AR-targeted therapy. Ipatasertib is currently in clinical development, and GR induction may be a biomarker to identify responsive patients or a responsive disease state. SIGNIFICANCE Induced GR expression is compensatory for AR blockade and confers resistance to AR-targeted therapy. Here we show that inhibition of the PI3K/AKT pathway remodels the chromatin landscape, blocks the induction of GR expression and overrides enzalutamide resistance.

Deregulated growth factor activation is a common event in the generation and maintenance of human tumors. The serine/threonine kinase Akt is a major target downstream of many growth factor signaling pathways. It has been found to be overexpressed in a number of cancer types and undergoes deregulated activation in many more. Its activity has been shown to contribute to both cellular transformation and therapeutic resistance. Further understanding of the contribution of Akt activity to tumor growth and persistence will contribute to better targeting of the Akt signaling pathway and enhanced therapeutic options. We have used the non-transformed cell line FL5.12 with inducible Akt activation to precisely address the contribution of Akt to malignant growth and therapeutic resistance. Previous work from our lab demonstrated that Akt contributes directly to the malignant transformation of FL5.12 cells. This thesis focused primarily on its role in chemotherapeutic resistance. The emerging role of mTOR activity in mediating Akt function has prompted our investigation into the relationship between the activities of Akt and mTOR. We have used multiple mechanisms to investigate the effects of mTOR inhibition and activation, both chemical and genetic. Our results indicate that Akt mediates resistance to multiple antimicrotubule chemotherapeutic agents, and this resistance is dependent on mTOR. Despite previous reports which link the ability of Akt and mTOR to promote survival following growth factor withdrawal with their enhancement of glycolytic metabolism, these factors are shown to promote resistance even when hexokinase activity and glycolytic rate are significantly inhibited. Our work also demonstrates a rapamycin-sensitive, positive feedback mechanism between mTOR and Akt, including a membrane-targeted, “constitutively active” mutant Akt. Constitutively active mTOR also contributes to resistance to antimicrotubule agents, though it is not sufficient to enhance Akt phosphorylation. These data suggest a model where mTOR contributes to therapy resistance through multiple mechanisms, independent of glycolytic metabolism maintenance. These results may be an important contribution to the rational design of therapies incorporating mTOR inhibitors, which are currently being evaluated in phase II and III clinical trials.

Little research has examined associations between disaster-related home loss and multiple domains of health and well-being, with extended long-term follow-up and comprehensive adjustment for pre-disaster characteristics of survivors. We examined the longitudinal associations between disaster-induced home loss and 34 indicators of health and well-being, assessed post-disaster. We used data from a preexisting cohort study of Japanese older adults in an area directly impacted by the 2011 Japan Earthquake ( and , depending on the outcomes). The study was initiated in 2010, and disaster-related home loss status was measured in 2013 retrospectively. The 34 outcomes were assessed in 2020 and covered dimensions of physical health, mental health, health behaviors/sleep, social well-being, cognitive social capital, subjective well-being, and prosocial/altruistic behaviors. We estimated the associations between disaster-related home loss and the outcomes, using targeted maximum likelihood estimation and SuperLearner. We adjusted for pre-disaster characteristics from the wave conducted 7 months before the disaster (i.e., 2010), including prior outcome values that were available. After Bonferroni correction for multiple testing, we found that home loss (vs. no home loss) was associated with increased posttraumatic stress symptoms ( ; 95% CI: 0.35, 0.65), increased daily sleepiness (0.38; 95% CI: 0.21, 0.54), lower trust in the community ( ; 95% CI: , ), lower community attachment ( ; 95% CI: , ), and lower prosociality ( ; 95% CI: , ). We found modest evidence for the associations with increased depressive symptoms, increased hopelessness, more chronic conditions, higher body mass index, lower perceived mutual help in the community, and decreased happiness. There was little evidence for associations with the remaining 23 outcomes. Home loss due to a disaster may have long-lasting adverse impacts on the cognitive social capital, mental health, and prosociality of older adult survivors. https://doi.org/10.1289/EHP10903.