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Two Steps Forward and One Step Back for Precision in Prostate Cancer Treatment

J Clin Oncol

2020 Robert Montgomery; Peter Nelson; Heather Cheng; Michael Schweizer

N/A

Humoral response to HPV16 proteins in persons with anal high-grade squamous intraepithelial lesion or anal cancer

Cancer Epidemiol Biomarkers Prev

2020 Anna Wald; Margaret Madeleine; Denise Galloway; David Doody

BACKGROUND: This study was launched to evalute the association of early and late antibodies to human papillomavirus (HPV)16 detection and risk of anal high-grade intraepithelial lesions (HSIL) or cancer. METHODS: We analyzed data from persons with anal HSIL or cancer and controls from a case-control study in Seattle, Washington. Sera were evaluated for HPV16 early (E1, E2, E4, E6, E7) and late (L1) antibodies by multiplex serology. Logistic regression models were used to assess serologic associations with risk of anal HSIL or cancer. RESULTS: The study included 67 participants with anal HSIL, 116 with anal cancer, and 830 population-based controls. HPV16 seropositivity to L1 (aOR 13.8, 95% CI 7.4-25.8), E4 (aOR 2.3, 95% CI 1.1-4.5) and E6 (aOR 4.9, 95% CI 1.1-21.2) was associated with HSIL; and detection of all antibodies to HPV16 late and early proteins was associated with increased risk of anal cancer ranging from aOR 1.7 to 32.5 (L1 aOR 12.5 [95% CI 7.3-21.7], E1 aOR 24.9 [95% CI 10.3-59.9], E2 aOR 6.3 [95% CI 3.4-11.7], E4 aOR 2.8 [95% CI 1.6-4.8], E6 aOR 32.5 [95% CI 14.2-74.4] and E7 aOR 1.7 [95% CI 1.0-3.0]). CONCLUSIONS: HPV serologic markers proved to be specific for identifying anal cancer. HPV16 E6 seropositivity is relatively uncommon in persons without anal cancer. IMPACT: This large study comprehensively describes the distinct antibody responses to the HPV16 proteins in persons with anal HSIL or anal cancer. Antibodies to HPV16 E6 should be further evaluated as a potential biomarker for anal cancer prevention.

Tailoring Intensity of Active Surveillance for Low-Risk Prostate Cancer Based on Individualized Prediction of Risk Stability

JAMA Oncol

2020 Lisa Newcomb; Peter Nelson; Kehao Zhu; Anna Faino; Daniel Lin; Yingye Zheng

Importance: Active surveillance is increasingly recognized as the preferred standard of care for men with low-risk prostate cancer. However, active surveillance requires repeated assessments, including prostate-specific antigen tests and biopsies that may increase anxiety, risk of complications, and cost. Objective: To identify and validate clinical parameters that can identify men who can safely defer follow-up prostate cancer assessments. Design, Setting, and Participants: The Canary Prostate Active Surveillance Study (PASS) is a multicenter, prospective active surveillance cohort study initiated in July 2008, with ongoing accrual and a median follow-up period of 4.1 years. Men with prostate cancer managed with active surveillance from 9 North American academic medical centers were enrolled. Blood tests and biopsies were conducted on a defined schedule for least 5 years after enrollment. Model validation was performed among men at the University of California, San Francisco (UCSF) who did not enroll in PASS. Men with Gleason grade group 1 prostate cancer diagnosed since 2003 and enrolled in PASS before 2017 with at least 1 confirmatory biopsy after diagnosis were included. A total of 850 men met these criteria and had adequate follow-up. For the UCSF validation study, 533 active surveillance patients meeting the same criteria were identified. Exclusion criteria were treatment within 6 months of diagnosis, diagnosis before 2003, Gleason grade score of at least 2 at diagnosis or first surveillance biopsy, no surveillance biopsy, or missing data. Exposures: Active surveillance for prostate cancer. Main Outcomes and Measures: Time from confirmatory biopsy to reclassification, defined as Gleason grade group 2 or higher on subsequent biopsy. Results: A total of 850 men (median [interquartile range] age, 64 [58-68] years; 774 [91%] White) were included in the PASS cohort. A total of 533 men (median [interquartile range] age, 61 [57-65] years; 422 [79%] White) were included in the UCSF cohort. Parameters predictive of reclassification on multivariable analysis included maximum percent positive cores (hazard ratio [HR], 1.30 [95% CI, 1.09-1.56]; P=.004), history of any negative biopsy after diagnosis (1 vs 0: HR, 0.52 [95% CI, 0.38-0.71]; P<.001 and 2 vs 0: HR, 0.18 [95% CI, 0.08-0.4]; P<.001), time since diagnosis (HR, 1.62 [95% CI, 1.28-2.05]; P<.001), body mass index (HR, 1.08 [95% CI, 1.05-1.12]; P<.001), prostate size (HR, 0.40 [95% CI, 0.25-0.62]; P<.001), prostate-specific antigen at diagnosis (HR, 1.51 [95% CI, 1.15-1.98]; P=.003), and prostate-specific antigen kinetics (HR, 1.46 [95% CI, 1.23-1.73]; P<.001). For prediction of nonreclassification at 4 years, the area under the receiver operating curve was 0.70 for the PASS cohort and 0.70 for the UCSF validation cohort. This model achieved a negative predictive value of 0.88 (95% CI, 0.83-0.94) for those in the bottom 25th percentile of risk and of 0.95 (95% CI, 0.89-1.00) for those in the bottom 10th percentile. Conclusions and Relevance: In this study, among men with low-risk prostate cancer, heterogeneity prevailed in risk of subsequent disease reclassification. These findings suggest that active surveillance intensity can be modulated based on an individual's risk parameters and that many men may be safely monitored with a substantially less intensive surveillance regimen.

MYCN drives chemoresistance in small cell lung cancer while USP7 inhibition can restore chemosensitivity

Genes Dev

2020 Nan Wu; Emily Eastwood; Deshui Jia; Ryan Basom; Eli Grunblatt; Keith Eaton; A. McGarry Houghton; Ali Ibrahim; David MacPherson; Renato Martins; Justin Norton; Huajia Zhang; Joseph Hiatt

Small cell lung cancer (SCLC) is an aggressive neuroendocrine cancer characterized by initial chemosensitivity followed by emergence of chemoresistant disease. To study roles for MYCN amplification in SCLC progression and chemoresistance, we developed a genetically engineered mouse model of MYCN-overexpressing SCLC. In treatment-naïve mice, MYCN overexpression promoted cell cycle progression, suppressed infiltration of cytotoxic T cells, and accelerated SCLC. MYCN overexpression also suppressed response to cisplatin-etoposide chemotherapy, with similar findings made upon MYCL overexpression. We extended these data to genetically perturb chemosensitive patient-derived xenograft (PDX) models of SCLC. In chemosensitive PDX models, overexpression of either MYCN or MYCL also conferred a switch to chemoresistance. To identify therapeutic strategies for MYCN-overexpressing SCLC, we performed a genome-scale CRISPR-Cas9 sgRNA screen. We identified the deubiquitinase USP7 as a MYCN-associated synthetic vulnerability. Pharmacological inhibition of USP7 resensitized chemoresistant MYCN-overexpressing PDX models to chemotherapy in vivo. Our findings show that MYCN overexpression drives SCLC chemoresistance and provide a therapeutic strategy to restore chemosensitivity.

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

Cell

2020 Cyrus Ghajar

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.

Elevation of Cervical CXCL10 Levels is Associated with HIV-1 Acquisition in Pregnant and Postpartum Women

AIDS

2020 Dara Lehman; Bingjie Wang; Barbra Richardson; Julie Overbaugh

OBJECTIVE: To evaluate the relationship between cervical cytokine/chemokine concentrations and HIV-1 acquisition in peripartum Kenyan women. DESIGN: Nested case-control study METHODS:: Women participating in a prospective study of peripartum HIV acquisition in Kenya (the Mama Salama Study), were tested for HIV-1 at 1-3 month intervals during pregnancy and through 9 months postpartum. Cases positive for HIV-1 RNA during follow-up (N=14), were matched 3:1 with HIV-negative controls (N=42) based on age, marital status, partner HIV-1 status, transactional sex, and timing of cervical swab collection. Concentrations of 5 cytokines (interleukin (IL)-1, IL-6, IL-10, interferon gamma (IFN), and tumor necrosis factor alpha (TNF)) and 4 chemokines (IL-8, C-X-C motif chemokine ligand 10 (CXCL10), macrophage inflammatory protein (MIP)-1 alpha, and MIP-1 beta) were measured from cervical swabs collected at the visit prior to HIV-1 diagnosis (cases) or matched gestational/postpartum time (controls). Cytokine/chemokine concentrations were compared between cases and controls using Wilcoxon rank-sum tests. Principal component analysis was used to create a summary score for closely correlated cytokines/chemokines. Associations with HIV-1 acquisition were analyzed using conditional logistic regression. Path analysis was used to evaluate hypothesized relationships between CXCL10, vaginal washing, Nugent score, and HIV-1 acquisition. RESULTS: Conditional logistic regression analysis demonstrated an association between increased concentrations of CXCL10 and HIV-1 acquisition (OR=1.74, 95% CI 1.04, 2.93; p=0.034). Path analysis confirmed a positive independent association between higher concentrations of CXCL10 and HIV-1 acquisition (path coefficient=0.37, 95% CI 0.15, 0.59; p<0.001). CONCLUSIONS: HIV-1 acquisition was associated with increased cervical concentrations of CXCL10 in pregnant and postpartum women.

Nuclear Membrane Rupture and Its Consequences

Annu Rev Cell Dev Biol

2020 Emily Hatch

The nuclear envelope is often depicted as a static barrier that regulates access between the nucleus and the cytosol. However, recent research has identified many conditions in cultured cells and in vivo in which nuclear membrane ruptures cause the loss of nuclear compartmentalization. These conditions include some that are commonly associated with human disease, such as migration of cancer cells through small spaces and expression of nuclear lamin disease mutations in both cultured cells and tissues undergoing nuclear migration. Nuclear membrane ruptures are rapidly repaired in the nucleus but persist in nuclear compartments that form around missegregated chromosomes called micronuclei. This review summarizes what is known about the mechanisms of nuclear membrane rupture and repair in both the main nucleus and micronuclei, and highlights recent work connecting the loss of nuclear integrity to genome instability and innate immune signaling. These connections link nuclear membrane rupture to complex chromosome alterations, tumorigenesis, and laminopathy etiologies. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 36 is October 6, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Organotypic culture assays for murine and human primary and metastatic-site tumors

Nat Protoc

2020 Kevin Cheung

Cancer invasion and metastasis are challenging to study in vivo since they occur deep inside the body over extended time periods. Organotypic 3D culture of fresh tumor tissue enables convenient real-time imaging, genetic and microenvironmental manipulation and molecular analysis. Here, we provide detailed protocols to isolate and culture heterogenous organoids from murine and human primary and metastatic site tumors. The time required to isolate organoids can vary based on the tissue and organ type but typically takes <7 h. We describe a suite of assays that model specific aspects of metastasis, including proliferation, survival, invasion, dissemination and colony formation. We also specify comprehensive protocols for downstream applications of organotypic cultures that will allow users to (i) test the role of specific genes in regulating various cellular processes, (ii) distinguish the contributions of several microenvironmental factors and (iii) test the effects of novel therapeutics.

Comparison of tumor-associated YAP1 fusions identifies a recurrent set of functions critical for oncogenesis

Genes Dev

2020 Pia Hoellerbauer; Valeri Vasioukhin; Sonali Arora; Patrick Cimino; Frank Szulzewsky; Marina Chan; Patrick Paddison; Taranjit Gujral; Eric Holland

YAP1 is a transcriptional coactivator and the principal effector of the Hippo signaling pathway, which is causally implicated in human cancer. Several YAP1 gene fusions have been identified in various human cancers and identifying the essential components of this family of gene fusions has significant therapeutic value. Here, we show that the YAP1 gene fusions YAP1-MAMLD1, YAP1-FAM118B, YAP1-TFE3, and YAP1-SS18 are oncogenic in mice. Using reporter assays, RNA-seq, ChIP-seq, and loss-of-function mutations, we can show that all of these YAP1 fusion proteins exert TEAD-dependent YAP activity, while some also exert activity of the C'-terminal fusion partner. The YAP activity of the different YAP1 fusions is resistant to negative Hippo pathway regulation due to constitutive nuclear localization and resistance to degradation of the YAP1 fusion proteins. Genetic disruption of the TEAD-binding domain of these oncogenic YAP1 fusions is sufficient to inhibit tumor formation in vivo, while pharmacological inhibition of the YAP1-TEAD interaction inhibits the growth of YAP1 fusion-expressing cell lines in vitro. These results highlight TEAD-dependent YAP activity found in these gene fusions as critical for oncogenesis and implicate these YAP functions as potential therapeutic targets in YAP1 fusion-positive tumors.

Rearranged ERG confers robustness to prostate cancer cells by subverting the function of p53

Urol Oncol

2020 Valeri Vasioukhin

OBJECTIVE: ERG rearrangements are frequent and early events in prostate cancer. The functional role of rearranged ERG, however, is still incompletely understood. ERG rearrangements are maintained during prostate cancer progression suggesting that they may confer a selective advantage. The molecular basis of this notion is the subject of this study. METHODS: A variety of immunological methods were used to characterize the effects of rearranged ERG on p53. Consequences of an overexpression of N-terminally deleted ERG on p53 function were interrogated by measuring apoptosis and cellular senescence in the presence or absence of exogenous DNA damage. Effects of N-terminally deleted ERGon the transactivation function of p53 were analyzed by qRT-PCR. RESULTS: We show that overexpression of ERG leads to an increased basal level of DNA damage and a stabilization of p53 that involves a sequestration of its E3 ubiquitin ligase, MDM2, into nucleoli. A higher p53 expression was also observed in vivo in an ERG-overexpressing prostatic intraepithelial neoplasia mouse model. The correlation between ERG and p53 expression was corroborated in 163 patients with prostate cancer. ERG overexpression was found to inhibit both apoptosis and cellular senescence induced by exogenous DNA damage. Mechanistically, this protective effect of ERG involved an abrogation of the DNA damage-induced expression of p53 target genes. CONCLUSIONS: By protecting tumor cells from the antiproliferative consequences of genotoxic stress, ERG may allow the survival and proliferation of genomically unstable tumor cells. Targeting ERG may therefore represent a promising strategy to suppress such adverse features during prostate cancer progression.