Publications by authors named "David Nanus"

Article Synopsis
  • Advanced urothelial cancer displays significant genetic diversity and involves complex interactions between internal and external mutagens, which contributes to its deadly nature.
  • The study revealed that APOBEC3-induced mutations occur early during tumor development, while chemotherapy leads to a surge of later mutations, with both processes affecting the structure of extrachromosomal DNA.
  • Findings emphasized the role of circular ecDNA in the development of treatment resistance, specifically through CCND1 amplifications, highlighting key mechanisms that can inform future cancer therapies.
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Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, for the immunostaining experiments shown in Fig. 3C on p. 1195, the 'NEP' and 'PTX' panels contained overlapping data, such that data which were intended to show the results of differently performed experiments had apparently been derived from the same original source.

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Unlabelled: Circulating tumor cells (CTCs) captured from the bloodstream of patients with solid tumors have the potential to accelerate precision oncology by providing insight into tumor biology, disease progression and response to treatment. However, their potential is hampered by the lack of standardized CTC enrichment platforms across tumor types. EpCAM-based CTC enrichment, the most commonly used platform, is limited by EpCAM downregulation during metastasis and the low EpCAM expression in certain tumor types, including the highly prevalent and lethal NSCLC.

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Article Synopsis
  • Cancer of unknown primary (CUP) poses a major challenge, being a leading cause of cancer death despite better diagnostic methods.
  • A novel genomic analysis using whole-exome sequencing (WES) and RNA sequencing (RNA-seq) helped tailor treatment for a patient with a history of multiple tumors and fast progression on chemotherapy.
  • The approach resulted in significant improvements across all metastatic sites and underscores the need for personalized genomic profiling to effectively manage CUP and identify tumor origins.
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Purpose: HOXB13 is an androgen receptor (AR) coregulator specifically expressed in cells of prostatic lineage. We sought to associate circulating tumor cell (CTC) HOXB13 expression with outcomes in men with mCRPC treated with abiraterone or enzalutamide.

Experimental Design: We conducted a retrospective analysis of the multicenter prospective PROPHECY trial of mCRPC men (NCT02269982, n = 118) treated with abiraterone/enzalutamide.

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Background: Androgen deprivation therapy (ADT) is a common treatment modality for men with prostate cancer. Increases in adipose tissue mass and decreases in skeletal muscle mass are known on-target adverse effects of standard ADT. The effects of newer agents such as abiraterone acetate (ABI) and enzalutamide (ENZA) on body composition and how these compare with standard luteinizing hormone-releasing hormone agonists (aLHRHs) are unclear.

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Purpose: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225.

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Background: Early detection of prostate cancer using prostate-specific antigen (PSA) remains controversial and disparities in the receipt of prostate cancer screening persist in the US. We sought to examine disparities in PSA testing rates among groups with higher prostate cancer risk and differential access to healthcare.

Methods: We identified a cohort of 37,706 males within the All of Us Research Program without a history of prostate cancer between the ages of 40 and 85 at time of enrollment (2017-2021).

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Background: Ultra-hypofractionated image-guided stereotactic body radiotherapy (SBRT) is increasingly used for definitive treatment of localized prostate cancer. Magnetic resonance imaging-guided radiotherapy (MRgRT) facilitates improved visualization, real-time tracking of targets and/or organs-at-risk (OAR), and capacity for adaptive planning which may translate to improved targeting and reduced toxicity to surrounding tissues. Given promising results from NRG-GU003 comparing conventional and moderate hypofractionation in the post-operative setting, there is growing interest in exploring ultra-hypofractionated post-operative regimens.

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Background: Neutrophil count:lymphocyte count ratio (NLR) may be a prognostic factor for men with advanced prostate cancer. We hypothesized that it is associated with prostate-specific antigen (PSA) response and survival in men treated with prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy (TRT).

Methods: Data of 180 men with metastatic castration-resistant prostate cancer (mCRPC) who were treated in sequential prospective radionuclide clinical trials from 2002 to 2021 (utilizing 177Lu-J591, 90Y-J591, 177Lu-PSMA-617, or 225Ac-J591) were retrospectively analyzed.

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Genetically engineered mouse models (GEMMs) are important immunocompetent models for research into the roles of individual genes in cancer and the development of novel therapies. Here we use inducible CRISPR-Cas9 systems to develop two GEMMs which aim to model the extensive chromosome p3 deletion frequently observed in clear cell renal cell carcinoma (ccRCC). We cloned paired guide RNAs targeting early exons of Bap1, Pbrm1, and Setd2 in a construct containing a Cas9 (nickase, hSpCsn1n) driven by tetracycline (tet)-responsive elements (TRE3G) to develop our first GEMM.

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Purpose: In men with metastatic castration-resistant prostate cancer (mCRPC), prostate-specific membrane antigen (PSMA)-targeted radioligand therapy has drastically improved clinical outcomes. A liquid biopsy characterizing PSMA expression could be useful in guiding optimal therapy.

Experimental Design: We conducted a retrospective analysis of the prospective multicenter PROPHECY (Prospective CiRculating PrOstate Cancer Predictors in HighEr Risk mCRPC StudY) trial of men with mCRPC (n = 118) treated with abiraterone (abi) or enzalutamide (enza).

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In clear cell renal cell carcinoma (ccRCC), activation of hypoxic signaling induces NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) expression. Over 90% of ccRCCs exhibit overexpression of NDUFA4L2, which we previously showed contributes to ccRCC proliferation and survival. The function of NDUFA4L2 in ccRCC has not been fully elucidated.

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Cancer fatalism-the belief that death is inevitable when cancer is present-has been identified as a barrier to cancer screening, detection, and treatment. Our study examined the relationship between self-reported cancer fatalism and adherence to cancer screening guidelines of the breasts, cervix, colon, and prostate among a diverse sample of urban-dwelling adults in Brooklyn, New York. Between May 2019 and August 2020, we conducted a cross-sectional survey of adults 40 + years of age (n = 2,341) residing in Brooklyn neighborhoods with high cancer mortality.

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Background: During cancer treatments, patients often defer primary care and comorbidity management, which may not be optimal for overall health when patients transition into survivorship. We sought to quantify primary care utilization among cancer survivors who are ≥2 years post cancer treatments.

Methods: 951 cancer survivors were included in this national, prospective cohort study using the Regional Geographic and Racial Differences in Stroke (REGARDS) data.

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Expression of the AR splice variant, androgen receptor variant 7 (AR-V7), in prostate cancer is correlated with poor patient survival and resistance to AR targeted therapies and taxanes. Currently, there is no specific inhibitor of AR-V7, while the molecular mechanisms regulating its biological function are not well elucidated. Here, we report that AR-V7 has unique biological features that functionally differentiate it from canonical AR-fl or from the second most prevalent variant, AR-v567.

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Research has shown extensive metabolic remodeling in clear cell renal cell carcinoma (ccRCC), with increased glutathione (GSH) levels. We hypothesized that activating transcription factor-4 (ATF4) and the integrated stress response (ISR) induce a metabolic shift, including increased GSH accumulation, and that Vitamin A deficiency (VAD), found in ccRCCs, can also activate ATF4 signaling in the kidney. To determine the role of ATF4, we used publicly available RNA sequencing (RNA-seq) data sets from The Cancer Genomics Atlas.

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Purpose: Despite cancer and cardiovascular disease (CVD) sharing several modifiable risk factors, few unified prevention efforts exist. We sought to determine the association between risk perception for cancer and CVD and engagement in healthy behaviors.

Methods: Between May 2019 and August 2020, we conducted a cross-sectional survey of adults ≥ 40 years residing in Brooklyn neighborhoods with high cancer mortality.

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Primary clear cell renal cell carcinoma (ccRCC) has been previously characterized, but the genomic landscape of metastatic ccRCC is largely unexplored. Here, we performed whole exome sequencing (WES) in 68 samples from 44 patients with ccRCC, including 52 samples from a metastatic site. SETD2, PBRM1, APC and VHL were the most frequently mutated genes in the metastatic ccRCC cohort.

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Prostate cancer (PCa) is the second most diagnosed cancer among men. Targeted PCa screening may decrease PCa-specific mortality. Prostate-specific antigen (PSA) is the most reliable and widely accepted tumor biomarker for screening and monitoring PCa status.

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Background: Targeted sequencing of circulating tumour DNA (ctDNA) is a promising tool to monitor dynamic changes in the variant allele frequencies (VAF) of genomic alterations and predict clinical outcomes in patients with advanced urothelial carcinoma (UC).

Methods: We performed targeted sequencing of 182 serial ctDNA samples from 53 patients with advanced UC.

Results: Serial ctDNA-derived metrics predicted the clinical outcomes in patients with advanced UC.

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Mitochondrial dysfunction and aberrant glycolysis are hallmarks of human clear cell renal cell carcinoma (ccRCC). Whereas glycolysis is thoroughly studied, little is known about the mitochondrial contribution to the pathology of ccRCC. Mitochondrial Ndufa4l2 is predictive of poor survival of ccRCC patients, and in kidney cancer cell lines the protein supports proliferation and colony formation.

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In this case report, we present a patient with the rare plasmacytoid variant of urothelial cancer. Notable elements of his course include: complete response to neoadjuvant paclitaxel, gemcitabine, cisplatin, development of metastatic disease to the rectum, sustained disease control with dual HER2 targeting therapy, and subsequent complete response to enfortumab vedotin. Plasmacytoid urothelial cancer accounts for just 1-3% of all urothelial cancer cases and is associated with more aggressive disease, with a propensity for intra-abdominal spread and poor response to neoadjuvant therapy.

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Article Synopsis
  • The study evaluates the effectiveness of on-site plasma-based next-generation sequencing (NGS) for analyzing circulating tumor DNA (ctDNA) in cancer patients, particularly those with metastatic disease.
  • Results show that the NGS test has a higher success rate in detecting genetic alterations from plasma samples compared to primary tumor samples, demonstrating its potential utility in clinical practice.
  • The findings support the integration of plasma tests into routine oncology management, as they provide valuable information to guide precision therapy while reducing the need for invasive tissue biopsies.
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