Publications by authors named "Jason A Somarelli"

52 Publications

Extent of tumor fibrosis/hyalinization and infarction following neoadjuvant radiation therapy is associated with improved survival in patients with soft-tissue sarcoma.

Cancer Med 2021 Nov 27. Epub 2021 Nov 27.

Department of Orthopaedics, Duke University, Durham, North Carolina, USA.

Introduction: Current standard of care for most intermediate and high-grade soft-tissue sarcomas (STS) includes limb-preserving surgical resection with either neoadjuvant radiation therapy (NRT) or adjuvant radiation therapy. To date, there have been a few studies that attempt to correlate histopathologic response to NRT with oncologic outcomes in patients with STS.

Methods: Using our institutional database, we identified 58 patients who received NRT followed by surgical resection for primary intermediate or high-grade STS and 34 patients who received surgical resection without NRT but did receive adjuvant radiation therapy or did not receive any radiation therapy. We analyzed four histologic parameters of response to therapy: residual viable tumor, fibrosis/hyalinization, necrosis, and infarction (each ratiometrically determined). Data were stratified into two binary groups. Unadjusted, 5- and 10-year overall survival, and relapsed-free survival (RFS) were calculated using the Kaplan-Meier method.

Results: Analysis of pathologic characteristics showed that patients treated with NRT demonstrate significantly higher tumor infarction, higher tumor fibrosis/hyalinization, and a lower percent viable tumor compared with patients not treated with NRT (p < 0.0001). Based on Kaplan-Meier curve analysis and multivariate cox proportional hazard model for OS and RFS, patients treated with NRT and showing >12.5% tumor fibrosis/hyalinization have significantly higher overall survival and recurrence-free survival at 5 and 10 years.

Discussion And Conclusion: We have identified three histopathologic characteristics-fibrosis, hyalinization, and infarction-that may serve as predictive biomarkers of response to NRT for STS patients. Future prospective studies will be needed to confirm this association.
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http://dx.doi.org/10.1002/cam4.4428DOI Listing
November 2021

The Hallmarks of Cancer as Ecologically Driven Phenotypes.

Front Ecol Evol 2021 Apr 28;9. Epub 2021 Apr 28.

Department of Medicine, Duke Cancer institute, Duke University Medical Center, Durham, NC, United States.

Ecological fitness is the ability of individuals in a population to survive and reproduce. Individuals with increased fitness are better equipped to withstand the selective pressures of their environments. This paradigm pertains to all organismal life as we know it; however, it is also becoming increasingly clear that within multicellular organisms exist highly complex, competitive, and cooperative populations of cells under many of the same ecological and evolutionary constraints as populations of individuals in nature. In this review I discuss the parallels between populations of cancer cells and populations of individuals in the wild, highlighting how individuals in either context are constrained by their environments to converge on a small number of critical phenotypes to ensure survival and future reproductive success. I argue that the hallmarks of cancer can be distilled into key phenotypes necessary for cancer cell fitness: survival and reproduction. I posit that for therapeutic strategies to be maximally beneficial, they should seek to subvert these ecologically driven phenotypic responses.
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http://dx.doi.org/10.3389/fevo.2021.661583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8544241PMC
April 2021

KLF4 Induces Mesenchymal-Epithelial Transition (MET) by Suppressing Multiple EMT-Inducing Transcription Factors.

Cancers (Basel) 2021 Oct 13;13(20). Epub 2021 Oct 13.

Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India.

Epithelial-Mesenchymal Plasticity (EMP) refers to reversible dynamic processes where cells can transition from epithelial to mesenchymal (EMT) or from mesenchymal to epithelial (MET) phenotypes. Both these processes are modulated by multiple transcription factors acting in concert. While EMT-inducing transcription factors (TFs)-TWIST1/2, ZEB1/2, SNAIL1/2/3, GSC, and FOXC2-are well-characterized, the MET-inducing TFs are relatively poorly understood (OVOL1/2 and GRHL1/2). Here, using mechanism-based mathematical modeling, we show that transcription factor KLF4 can delay the onset of EMT by suppressing multiple EMT-TFs. Our simulations suggest that KLF4 overexpression can promote a phenotypic shift toward a more epithelial state, an observation suggested by the negative correlation of KLF4 with EMT-TFs and with transcriptomic-based EMT scoring metrics in cancer cell lines. We also show that the influence of KLF4 in modulating the EMT dynamics can be strengthened by its ability to inhibit cell-state transitions at the epigenetic level. Thus, KLF4 can inhibit EMT through multiple parallel paths and can act as a putative MET-TF. KLF4 associates with the patient survival metrics across multiple cancers in a context-specific manner, highlighting the complex association of EMP with patient survival.
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http://dx.doi.org/10.3390/cancers13205135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533753PMC
October 2021

Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.

Prostate Cancer Prostatic Dis 2021 Oct 13. Epub 2021 Oct 13.

Department of Medicine, Division of Medical Oncology, Duke University School of Medicine, Durham, NC, 27710, USA.

Background: Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available.

Methods: In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis.

Results: This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice.

Conclusion: This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.
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http://dx.doi.org/10.1038/s41391-021-00460-yDOI Listing
October 2021

A Zebrafish Model of Metastatic Colonization Pinpoints Cellular Mechanisms of Circulating Tumor Cell Extravasation.

Front Oncol 2021 23;11:641187. Epub 2021 Sep 23.

Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States.

Metastasis is a multistep process in which cells must detach, migrate/invade local structures, intravasate, circulate, extravasate, and colonize. A full understanding of the complexity of this process has been limited by the lack of ability to study these steps in isolation with detailed molecular analyses. Leveraging a comparative oncology approach, we injected canine osteosarcoma cells into the circulation of transgenic zebrafish with fluorescent blood vessels in a biologically dynamic metastasis extravasation model. Circulating tumor cell clusters that successfully extravasated the vasculature as multicellular units were isolated under imaging (n = 6). These extravasation-positive tumor cell clusters sublines were then molecularly profiled by RNA-Seq. Using a systems-level analysis, we pinpointed the downregulation of KRAS signaling, immune pathways, and extracellular matrix (ECM) organization as enriched in extravasated cells (p < 0.05). Within the extracellular matrix remodeling pathway, we identified versican () as consistently upregulated and central to the ECM gene regulatory network (p < 0.05). Versican expression is prognostic for a poorer metastasis-free and overall survival in patients with osteosarcoma. Together, our results provide a novel experimental framework to study discrete steps in the metastatic process. Using this system, we identify the versican/ECM network dysregulation as a potential contributor to osteosarcoma circulating tumor cell metastasis.
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http://dx.doi.org/10.3389/fonc.2021.641187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495265PMC
September 2021

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Chondrosarcoma: A National Cancer Database Study.

Ann Surg Oncol 2021 Sep 27. Epub 2021 Sep 27.

Department of Orthopaedic Surgery, Duke University Hospital, Durham, NC, USA.

Background: Limited data are available to inform the risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of chondrosarcoma.

Methods: We retrospectively reviewed 6653 patients following surgical resection of primary chondrosarcoma in the National Cancer Database (2004-2017). Both demographic and clinicopathologic variables were assessed for correlation with readmission and short-term mortality utilizing univariate and multivariate logistic regression modeling.

Results: Of 220 readmissions (3.26%), risk factors independently associated with an increased risk of unplanned 30-day readmission included Charlson-Deyo Comorbidity Index (CDCC) (odds ratio [OR] 1.31; p = 0.027), increasing American Joint Committee on Cancer (AJCC) stage (OR 1.31; p = 0.004), undergoing major amputation (OR 2.38; p = 0.001), and axial skeletal location (OR 1.51; p = 0.028). A total of 137 patients died within 90 days of surgery (2.25%). Risk factors associated with increased mortality included the CDCC (OR 1.60; p = 0.001), increasing age (OR 1.06; p < 0.001), having Medicaid insurance status (OR 3.453; p = 0.005), living in a zip code with a higher educational attainment (OR 1.59; p = 0.003), increasing AJCC stage (OR 2.32; p < 0.001), longer postoperative length of stay (OR 1.015; p = 0.033), and positive surgical margins (OR 2.75; p = 0.001). Although a majority of the cohort did not receive radiation therapy (88.8%), receiving radiotherapy (OR 0.132; p = 0.010) was associated with a decreased risk of short-term mortality.

Conclusions: Several tumor, treatment, and patient factors can help inform the risk of readmission and short-term mortality in patients with surgically treated chondrosarcoma.
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http://dx.doi.org/10.1245/s10434-021-10802-8DOI Listing
September 2021

The somatic molecular evolution of cancer: Mutation, selection, and epistasis.

Prog Biophys Mol Biol 2021 10 6;165:56-65. Epub 2021 Aug 6.

Yale College, New Haven, CT, USA; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; Yale Cancer Center, Yale University, New Haven, CT, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA. Electronic address:

Cancer progression has been attributed to somatic changes in single-nucleotide variants, copy-number aberrations, loss of heterozygosity, chromosomal instability, epistatic interactions, and the tumor microenvironment. It is not entirely clear which of these changes are essential and which are ancillary to cancer. The dynamic nature of cancer evolution in a patient can be illuminated using several concepts and tools from classical evolutionary biology. Neutral mutation rates in cancer cells are calculable from genomic data such as synonymous mutations, and selective pressures are calculable from rates of fixation occurring beyond the expectation by neutral mutation and drift. However, these cancer effect sizes of mutations are complicated by epistatic interactions that can determine the likely sequence of gene mutations. In turn, longitudinal phylogenetic analyses of somatic cancer progression offer an opportunity to identify key moments in cancer evolution, relating the timing of driver mutations to corresponding landmarks in the clinical timeline. These analyses reveal temporal aspects of genetic and phenotypic change during tumorigenesis and across clinical timescales. Using a related framework, clonal deconvolution, physical locations of clones, and their phylogenetic relations can be used to infer tumor migration histories. Additionally, genetic interactions with the tumor microenvironment can be analyzed with longstanding approaches applied to organismal genotype-by-environment interactions. Fitness landscapes for cancer evolution relating to genotype, phenotype, and environment could enable more accurate, personalized therapeutic strategies. An understanding of the trajectories underlying the evolution of neoplasms, primary, and metastatic tumors promises fundamental advances toward accurate and personalized predictions of therapeutic response.
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http://dx.doi.org/10.1016/j.pbiomolbio.2021.08.003DOI Listing
October 2021

Analysis of immune subtypes across the epithelial-mesenchymal plasticity spectrum.

Comput Struct Biotechnol J 2021 17;19:3842-3851. Epub 2021 Jun 17.

Department of Medicine, Durham, NC, United Kingdom.

Epithelial-mesenchymal plasticity plays a critical role in many solid tumor types as a mediator of metastatic dissemination and treatment resistance. In addition, there is also a growing appreciation that the epithelial/mesenchymal status of a tumor plays a role in immune evasion and immune suppression. A deeper understanding of the immunological features of different tumor types has been facilitated by the availability of large gene expression datasets and the development of methods to deconvolute bulk RNA-Seq data. These resources have generated powerful new ways of characterizing tumors, including classification of immune subtypes based on differential expression of immunological genes. In the present work, we combine scoring algorithms to quantify epithelial-mesenchymal plasticity with immune subtype analysis to understand the relationship between epithelial plasticity and immune subtype across cancers. We find heterogeneity of epithelial-mesenchymal transition (EMT) status both within and between cancer types, with greater heterogeneity in the expression of EMT-related factors than of MET-related factors. We also find that specific immune subtypes have associated EMT scores and differential expression of immune checkpoint markers.
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http://dx.doi.org/10.1016/j.csbj.2021.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283019PMC
June 2021

Identifying Modifiable and Non-modifiable Risk Factors of Readmission and Short-Term Mortality in Osteosarcoma: A National Cancer Database Study.

Ann Surg Oncol 2021 Nov 20;28(12):7961-7972. Epub 2021 May 20.

Department of Orthopaedic Surgery, Duke University Hospital, Durham, NC, USA.

Background: There are limited data to inform risk of readmission and short-term mortality in musculoskeletal oncology. The goal of this study was to identify factors independently associated with 30-day readmission and 90-day mortality following surgical resection of osteosarcoma.

Methods: We retrospectively reviewed patients (n = 5293) following surgical resection of primary osteosarcoma in the National Cancer Database (2004-2015). Univariate and multivariate methods were used to correlate variables with readmission and short-term mortality.

Results: Of 210 readmissions (3.97%), risk factors independently associated with unplanned 30-day readmission included comorbidity burden (odds ratio [OR] 2.4, p = 0.042), Medicare insurance (OR 1.9, p = 0.021), and axial skeleton location (OR 1.5, p = 0.029). A total of 91 patients died within 90 days of their surgery (1.84%). Risk factors independently associated with mortality included age (hazard ratio 1.1, p < 0.001), increasing comorbidity burden (OR 6.6, p = 0.001), higher grade (OR 1.7, p = 0.007), increasing tumor size (OR 2.2, p = 0.03), metastatic disease at presentation (OR 8.5, p < 0.001), and amputation (OR 2.0, p = 0.04). Chemotherapy was associated with a decreased risk of short-term mortality (p < 0.001).

Conclusions: Several trends were clear: insurance status, tumor location and comorbidity burden were independently associated with readmission rates, while age, amputation, grade, tumor size, metastatic disease, and comorbidity burden were independently associated with short-term mortality.
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http://dx.doi.org/10.1245/s10434-021-10099-7DOI Listing
November 2021

Treatment of Chondroblastoma with Denosumab: A Case Report with a Correlative Analysis of Effect on the RANK Signaling Pathway.

JBJS Case Connect 2021 05 17;11(2). Epub 2021 May 17.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina.

Case: A 15-year-old boy with chondroblastoma of the right hemipelvis presented with significant periacetabular bone destruction. Neoadjuvant denosumab treatment facilitated initial joint preserving surgery. Unfortunately, he experienced 2 local recurrences and underwent wide surgical resection 2 years after his initial diagnosis.

Conclusion: Inhibition of the receptor activator of NF-κB (RANK)/RANK ligand (RANK-L) pathway with denosumab has been used neoadjuvantly for the treatment of giant cell tumor of bone, but its role in the treatment of chondroblastoma is less understood. This patient's clinical response and effect on cellular RANK/RANK-L activity support the consideration of denosumab in the treatment algorithm for other osteolytic bone tumors such as chondroblastoma.
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http://dx.doi.org/10.2106/JBJS.CC.20.00178DOI Listing
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer.

Biomark Res 2021 Feb 18;9(1):14. Epub 2021 Feb 18.

Division of Medical Oncology, Department of Medicine, Duke Cancer Institute, Duke University, DUMC 103861, Durham, NC, 27710, UK.

Background: A subset of men with metastatic prostate cancer (mPC) responds to immune checkpoint inhibitors, and there is an unmet need to predict those most likely to benefit. We characterized circulating tumor cells (CTCs) for expression of immune checkpoint ligands in men with mPC as a non-invasive biomarker of immune evasion and immunotherapy benefit.

Methods: Three cohorts of patients were enrolled: 1) men with mCRPC starting abiraterone acetate/prednisone or enzalutamide (pre-ARSI), 2) men with mCRPC who were progressing on enzalutamide or abiraterone acetate/prednisone (post-ARSI), and 3) men with newly diagnosed metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy. CTCs were captured using the CellSearch® system and stained for PD-L1, PD-L2, B7-H3, and CTLA-4 at baseline, on treatment, and disease progression. Summary statistics on mean CTCs per cohort, as well as rates of ligand positivity were used to analyze CTCs by cohort and by timepoint.

Results: Men in all cohorts and timepoints had prevalent CTC B7-H3 expression (> 80%). We found evidence for CTC PD-L1 expression across disease states, in which > 1 positive CTC or > 50% of CTCs were positive for PD-L1 in 40 and 30% of men with mHSPC, respectively, 60 and 20% of men with mCRPC pre-ARSI, and 70 and 30% of men with mCRPC post-ARSI. CTC PD-L2 expression was present in 20-40% of men in each disease state, while CTC CTLA-4 expression was rare, present in 20% of men with mCRPC pre-ARSI and 10% of men with mCRPC post-ARSI or with mHSPC. CTC immune checkpoint expression was heterogeneous within/between men and across disease states.

Conclusions: We have identified that CTCs from men with mPC heterogeneously express immune checkpoints B7-H3, PD-L1, PD-L2, and CTLA-4, and the detection of these immune checkpoints may enable monitoring on immunotherapy.
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http://dx.doi.org/10.1186/s40364-021-00267-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890610PMC
February 2021

Manganese Porphyrin and Radiotherapy Improves Local Tumor Response and Overall Survival in Orthotopic Murine Mammary Carcinoma Models.

Radiat Res 2021 02;195(2):128-139

Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710.

Novel synthetic compounds, known as manganese porphyrins (MnPs), have been designed to shift the redox status of both normal cells and cancer cells. When MnPs are coupled with cancer therapies, such as radiation, they have been shown to sensitize tumor cells to treatment and protect normal tissues from damage through the modulation of the redox status of various tissue types. Until now, our preclinical studies have focused on local effects of MnPs and radiation; however, we recognize that successful outcomes for cancer patients involve control of tumor cells throughout the body. In this study, using murine orthotopic mammary tumor models, we investigated how MnPs and radiation influence the development of distant metastasis. We hypothesized that the combination of MnP (MnP/RT), such as MnTnBuOE-2-PyP5+ and radiation treatment (RT) would increase local tumor control via a shift in the intratumoral redox environment, leading to subsequent downregulation of HIF-1 in the primary tumor. Secondarily, we hypothesized that these primary tumor treatment effects would result in a reduction in pulmonary metastatic burden. Balb/c mice with orthotopic 4T1 mammary carcinomas were treated with saline, MnP, RT or MnP/RT. We found MnP/RT did extend local tumor growth delay and overall survival compared to controls and was associated with increased intratumoral oxidative stress. However, the primary tumor growth delay observed with MnP/RT was not associated with a reduced pulmonary metastatic burden. Future directions to investigate the effects of MnP/RT on the development of distant metastasis may include modifications to the radiation dose, the experimental timeline or using a murine mammary carcinoma cell line with a less aggressive metastatic behavior. Clinical trials are underway to investigate the clinical utility of MnTnBuOE-2-PyP5+ for patients undergoing radiotherapy for various tumor types. The promising preclinical data from this study, as well as others, provides support that MnP/RT has the potential to improve local tumor control for these patients.
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http://dx.doi.org/10.1667/RADE-20-00109.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962472PMC
February 2021

A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma.

Cancers (Basel) 2020 Nov 11;12(11). Epub 2020 Nov 11.

Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.

Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.

Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.

Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity.

Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.
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http://dx.doi.org/10.3390/cancers12113335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696249PMC
November 2020

A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer.

Mol Cancer Ther 2020 12 6;19(12):2516-2527. Epub 2020 Nov 6.

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.

Colorectal cancer is the third most common cancer in the United States and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDX) to identify new treatments for colorectal cancer. High-throughput screens of 2,100 compounds were performed across six low-passage, patient-derived colorectal cancer cell lines. These screens identified the CDK inhibitor drug class among the most effective cytotoxic compounds across six colorectal cancer lines. Among this class, combined targeting of CDK1, 2, and 9 was the most effective, with ICs ranging from 110 nmol/L to 1.2 μmol/L. Knockdown of CDK9 in the presence of a CDK2 inhibitor (CVT-313) showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Mechanistically, dual CDK2/9 inhibition induced significant G-M arrest and anaphase catastrophe. Combined CDK2/9 inhibition synergistically reduced PDX tumor growth. Our precision medicine pipeline provides a robust screening and validation platform to identify promising new cancer therapies. Application of this platform to colorectal cancer pinpointed CDK2/9 dual inhibition as a novel combinatorial therapy to treat colorectal cancer.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718319PMC
December 2020

Limb salvage versus amputation in patients with osteosarcoma of the extremities: an update in the modern era using the National Cancer Database.

BMC Cancer 2020 Oct 14;20(1):995. Epub 2020 Oct 14.

Department of Orthopaedic Surgery, Duke University Hospital, 311 Trent Drive, Durham, NC, 27710, USA.

Background: Historically, amputation was the primary surgical treatment for osteosarcoma of the extremities; however, with advancements in surgical techniques and chemotherapies limb salvage has replaced amputation as the dominant treatment paradigm. This study assessed the type of surgical resection chosen for osteosarcoma patients in the twenty-first century.

Methods: Utilizing the largest registry of primary osteosarcoma, the National Cancer Database (NCDB), we retrospectively analyzed patients with high grade osteosarcoma of the extremities from 2004 through 2015. Differences between patients undergoing amputation and patients undergoing limb salvage are described. Unadjusted five-year overall survival between patients who received limb salvage and amputation was assessed utilizing Kaplan Meier curves. A multivariate Cox proportional hazard model and propensity matched analysis was used to determine the variables independently correlated with survival.

Results: From a total of 2442 patients, 1855 underwent limb salvage and 587 underwent amputation. Patients undergoing amputation were more likely to be older, male, uninsured, and live in zip codes associated with lower income. Patients undergoing amputation were also more likely to have larger tumors, more comorbid conditions, and metastatic disease at presentation. After controlling for confounders, limb salvage was associated with a significant survival benefit over amputation (HR: 0.70; p < 0.001). Although this may well reflect underlying biases impacting choice of treatment, this survival benefit remained significant after propensity matched analysis of all significantly different independent variables (HR: 0.71; p < 0.01).

Conclusion: Among patients in the NCDB, amputation for osteosarcoma is associated with advanced age, advanced stage, larger tumors, greater comorbidities, and lower income. Limb salvage is associated with a significant survival benefit, even when controlling for significant confounding variables and differences between cohorts.
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http://dx.doi.org/10.1186/s12885-020-07502-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7557006PMC
October 2020

Plastic pollution solutions: emerging technologies to prevent and collectmarineplastic pollution.

Environ Int 2020 11 2;144:106067. Epub 2020 Sep 2.

Nicholas School of the Environment, Duke University Marine Lab, 135 Duke Marine Lab Road, Beaufort, NC 28516, USA. Electronic address:

As plastic waste accumulates in the ocean at alarming rates, the need for efficient and sustainable remediation solutions is urgent. One solution is the development and mobilization of technologies that either 1)prevent plastics from entering waterways or2) collect marine and riverineplastic pollution. To date, however, few reports have focused on these technologies, and information on various technological developments is scattered. This leaves policymakers, innovators, and researchers without a central, comprehensive, and reliable source of information on the status of available technology to target this global problem. The goal of this study was to address this gap by creating a comprehensive inventory of technologies currently used or in development to prevent the leakage of plastic pollution or collect existing plastic pollution. Our Plastic Pollution Prevention and Collection Technology Inventory (https://nicholasinstitute.duke.edu/plastics-technology-inventory) can be used as a roadmap for researchers and governments to 1) facilitate comparisons between the scope of solutions and the breadth and severity of the plastic pollution problem and 2) assist in identifying strengths and weaknesses of current technological approaches. We created this inventory from a systematic search and review of resources that identified technologies. Technologies were organized by the type of technology and target plastics (i.e., macroplastics, microplastic, or both). We identified 52 technologies that fall into the two categories of prevention or collection of plastic pollution. Of these, 59% focus specifically on collecting macroplastic waste already in waterways. While these efforts to collect plastic pollution are laudable, their current capacity and widespread implementation are limited in comparison to their potential and the vast extent of the plastic pollution problem. Similarly, few technologies attempt to prevent plastic pollution leakage, and those that do are limited in scope. A comprehensive approach is needed that combines technology, policymaking, and advocacy to prevent further plastic pollution and the subsequent damage to aquatic ecosystems and human health.
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http://dx.doi.org/10.1016/j.envint.2020.106067DOI Listing
November 2020

Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer.

BMC Cancer 2020 Jun 24;20(1):592. Epub 2020 Jun 24.

Department of Medicine, Division of Medical Oncology, Duke University Medical Center, 3008 Snyderman Building, 905 S. LaSalle St., Durham, NC, 27710, USA.

Background: Metastatic colorectal cancer (CRC) continues to be a major health problem, and current treatments are primarily for disease control and palliation of symptoms. In this study, we developed a precision medicine strategy to discover novel therapeutics for patients with CRC.

Methods: Six matched low-passage cell lines and patient-derived xenografts (PDX) were established from CRC patients undergoing resection of their cancer. High-throughput drug screens using a 119 FDA-approved oncology drug library were performed on these cell lines, which were then validated in vivo in matched PDXs. RNA-Seq analysis was then performed to identify predictors of response.

Results: Our study revealed marked differences in response to standard-of-care agents across patients and pinpointed druggable pathways to treat CRC. Among these pathways co-targeting of fibroblast growth factor receptor (FGFR), SRC, platelet derived growth factor receptor (PDGFR), or vascular endothelial growth factor receptor (VEGFR) signaling was found to be an effective strategy. Molecular analyses revealed potential predictors of response to these druggable pathways.

Conclusions: Our data suggests that the use of matched low-passage cell lines and PDXs is a promising strategy to identify new therapies and pathways to treat metastatic CRC.
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http://dx.doi.org/10.1186/s12885-020-07090-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7313200PMC
June 2020

Preclinical Testing of a Novel Niclosamide Stearate Prodrug Therapeutic (NSPT) Shows Efficacy Against Osteosarcoma.

Mol Cancer Ther 2020 07 5;19(7):1448-1461. Epub 2020 May 5.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina.

Therapeutic advances for osteosarcoma have stagnated over the past several decades, leading to an unmet clinical need for patients. The purpose of this study was to develop a novel therapy for osteosarcoma by reformulating and validating niclosamide, an established anthelminthic agent, as a niclosamide stearate prodrug therapeutic (NSPT). We sought to improve the low and inefficient clinical bioavailability of oral dosing, especially for the relatively hydrophobic classes of anticancer drugs. Nanoparticles were fabricated by rapid solvent shifting and verified using dynamic light scattering and UV-vis spectrophotometry. NSPT efficacy was then studied for cell viability, cell proliferation, and intracellular signaling by Western blot analysis; pulmonary metastatic assay model; and pharmacokinetic and lung mouse metastatic model of osteosarcoma. NSPT formulation stabilizes niclosamide stearate against hydrolysis and delays enzymolysis; increases circulation with approximately 5 hours; reduces cell viability and cell proliferation in human and canine osteosarcoma cells at 0.2-2 μmol/L IC; inhibits recognized growth pathways and induces apoptosis at 20 μmol/L; eliminates metastatic lesions in the lung metastatic model; and when injected intravenously at 50 mg/kg weekly, it prevents metastatic spread in the lungs in a mouse model of osteosarcoma over 30 days. In conclusion, niclosamide was optimized for preclinical drug delivery as a unique prodrug nanoparticle injected intravenously at 50 mg/kg (1.9 mmol/L). This increased bioavailability of niclosamide in the blood stream prevented metastatic disease in the mouse. This chemotherapeutic strategy is now ready for canine trials, and if successful, will be targeted for human trials in patients with osteosarcoma.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0689DOI Listing
July 2020

From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine.

Front Oncol 2020 11;10:117. Epub 2020 Feb 11.

Department of Orthopaedic Surgery, Duke University Medical Center, Durham, NC, United States.

Cancer drug discovery is an inefficient process, with more than 90% of newly-discovered therapies failing to gain regulatory approval. Patient-derived models of cancer offer a promising new approach to identify new treatments; however, for rare cancers, such as sarcomas, access to patient samples is limited, which precludes development of patient-derived models. To address the limited access to patient samples, we have turned to pet dogs with naturally-occurring sarcomas. Although sarcomas make up <1% of all human cancers, sarcomas represent 15% of cancers in dogs. Because dogs have similar immune systems, an accelerated pace of cancer progression, and a shared environment with humans, studying pet dogs with cancer is ideal for bridging gaps between mouse models and human cancers. Here, we present our cross-species personalized medicine pipeline to identify new therapies for sarcomas. We explore this process through the focused study of a pet dog, Teddy, who presented with six synchronous leiomyosarcomas. Using our pipeline we identified proteasome inhibitors as a potential therapy for Teddy. Teddy was treated with bortezomib and showed a varied response across tumors. Whole exome sequencing revealed substantial genetic heterogeneity across Teddy's recurrent tumors and metastases, suggesting that intra-patient heterogeneity and tumoral adaptation were responsible for the heterogeneous clinical response. Ubiquitin proteomics coupled with exome sequencing revealed multiple candidate driver mutations in proteins related to the proteasome pathway. Together, our results demonstrate how the comparative study of canine sarcomas offers important insights into the development of personalized medicine approaches that can lead to new treatments for sarcomas in both humans and canines.
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http://dx.doi.org/10.3389/fonc.2020.00117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7026496PMC
February 2020

Baby Genomics: Tracing the Evolutionary Changes That Gave Rise to Placentation.

Genome Biol Evol 2020 03;12(3):35-47

Bioinformatics Research Center, North Carolina State University.

It has long been challenging to uncover the molecular mechanisms behind striking morphological innovations such as mammalian pregnancy. We studied the power of a robust comparative orthology pipeline based on gene synteny to address such problems. We inferred orthology relations between human genes and genes from each of 43 other vertebrate genomes, resulting in ∼18,000 orthologous pairs for each genome comparison. By identifying genes that first appear coincident with origin of the placental mammals, we hypothesized that we would define a subset of the genome enriched for genes that played a role in placental evolution. We thus pinpointed orthologs that appeared before and after the divergence of eutherian mammals from marsupials. Reinforcing previous work, we found instead that much of the genetic toolkit of mammalian pregnancy evolved through the repurposing of preexisting genes to new roles. These genes acquired regulatory controls for their novel roles from a group of regulatory genes, many of which did in fact originate at the appearance of the eutherians. Thus, orthologs appearing at the origin of the eutherians are enriched in functions such as transcriptional regulation by Krüppel-associated box-zinc-finger proteins, innate immune responses, keratinization, and the melanoma-associated antigen protein class. Because the cellular mechanisms of invasive placentae are similar to those of metastatic cancers, we then used our orthology inferences to explore the association between placenta invasion and cancer metastasis. Again echoing previous work, we find that genes that are phylogenetically older are more likely to be implicated in cancer development.
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http://dx.doi.org/10.1093/gbe/evaa026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144826PMC
March 2020

Discordant and heterogeneous clinically relevant genomic alterations in circulating tumor cells vs plasma DNA from men with metastatic castration resistant prostate cancer.

Genes Chromosomes Cancer 2020 04 28;59(4):225-239. Epub 2019 Nov 28.

Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.

Circulating tumor cell (CTC) and cell-free (cf) DNA-based genomic alterations are increasingly being used for clinical decision-making in oncology. However, the concordance and discordance between paired CTC and cfDNA genomic profiles remain largely unknown. We performed comparative genomic hybridization (CGH) on CTCs and cfDNA, and low-pass whole genome sequencing (lpWGS) on cfDNA to characterize genomic alterations (CNA) and tumor content in two independent prospective studies of 93 men with mCRPC treated with enzalutamide/abiraterone, or radium-223. Comprehensive analysis of 69 patient CTCs and 72 cfDNA samples from 93 men with mCRPC, including 64 paired samples, identified common concordant gains in FOXA1, AR, and MYC, and losses in BRCA1, PTEN, and RB1 between CTCs and cfDNA. Concordant PTEN loss and discordant BRCA2 gain were associated with significantly worse outcomes in Epic AR-V7 negative men with mCRPC treated with abiraterone/enzalutamide. We identified and externally validated CTC-specific genomic alternations that were discordant in paired cfDNA, even in samples with high tumor content. These CTC/cfDNA-discordant regions included key genomic regulators of lineage plasticity, osteomimicry, and cellular differentiation, including MYCN gain in CTCs (31%) that was rarely detected in cfDNA. CTC MYCN gain was associated with poor clinical outcomes in AR-V7 negative men and small cell transformation. In conclusion, we demonstrated concordance of multiple genomic alterations across CTC and cfDNA platforms; however, some genomic alterations displayed substantial discordance between CTC DNA and cfDNA despite the use of identical copy number analysis methods, suggesting tumor heterogeneity and divergent evolution associated with poor clinical outcomes.
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http://dx.doi.org/10.1002/gcc.22824DOI Listing
April 2020

Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life.

Mol Biol Evol 2020 Jan;37(1):11-17

Duke Cancer Institute, Durham, NC.

Despite a considerable expenditure of time and resources and significant advances in experimental models of disease, cancer research continues to suffer from extremely low success rates in translating preclinical discoveries into clinical practice. The continued failure of cancer drug development, particularly late in the course of human testing, not only impacts patient outcomes, but also drives up the cost for those therapies that do succeed. It is clear that a paradigm shift is necessary if improvements in this process are to occur. One promising direction for increasing translational success is comparative oncology-the study of cancer across species, often involving veterinary patients that develop naturally-occurring cancers. Comparative oncology leverages the power of cross-species analyses to understand the fundamental drivers of cancer protective mechanisms, as well as factors contributing to cancer initiation and progression. Clinical trials in veterinary patients with cancer provide an opportunity to evaluate novel therapeutics in a setting that recapitulates many of the key features of human cancers, including genomic aberrations that underly tumor development, response and resistance to treatment, and the presence of comorbidities that can affect outcomes. With a concerted effort from basic scientists, human physicians and veterinarians, comparative oncology has the potential to enhance the cost-effectiveness and efficiency of pipelines for cancer drug discovery and other cancer treatments.
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http://dx.doi.org/10.1093/molbev/msz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204703PMC
January 2020

Molecular Biology and Evolution of Cancer: From Discovery to Action.

Mol Biol Evol 2020 02;37(2):320-326

Department of Biostatistics, Yale School of Public Health, New Haven, CT.

Cancer progression is an evolutionary process. During this process, evolving cancer cell populations encounter restrictive ecological niches within the body, such as the primary tumor, circulatory system, and diverse metastatic sites. Efforts to prevent or delay cancer evolution-and progression-require a deep understanding of the underlying molecular evolutionary processes. Herein we discuss a suite of concepts and tools from evolutionary and ecological theory that can inform cancer biology in new and meaningful ways. We also highlight current challenges to applying these concepts, and propose ways in which incorporating these concepts could identify new therapeutic modes and vulnerabilities in cancer.
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http://dx.doi.org/10.1093/molbev/msz242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993850PMC
February 2020

Immune dysregulation and osteosarcoma: Staphylococcus aureus downregulates TGF-β and heightens the inflammatory signature in human and canine macrophages suppressed by osteosarcoma.

Vet Comp Oncol 2020 Mar 15;18(1):64-75. Epub 2019 Oct 15.

Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina.

Since William Coley utilized bacterial immunotherapy to treat sarcomas in the late 19th century, an association between infection and improved survival has been reported for human and canine osteosarcoma patients. One of the reasons for this improved survival is likely a reactivation of the host immune system towards an inflammatory anti-tumour response, and one of the key players is the macrophage. Yet, despite their importance, the response of macrophages to infectious agents in the context of osteosarcoma has not been thoroughly evaluated. The aim of this study was to evaluate how in vitro exposure to a bacterial agent (Staphylococcus aureus) influenced canine and human macrophage differentiation in the presence of osteosarcoma. Our hypothesis was that S. aureus would, in the presence of osteosarcoma, induce a macrophage phenotype with significantly increased inflammatory signatures. Consistent with our hypothesis, human macrophages co-cultured with osteosarcoma and S. aureus exhibited increased IFN-γ, TNF-α and IL-12p70 cytokine secretion, decreased TGF-β cytokine secretion and increased mRNA expression of TNF-α when compared with macrophages co-cultured with osteosarcoma and to macrophages cultured alone. Canine macrophages similarly exhibited increased IFN-γ and TNF-α cytokine secretion, decreased TGF-β cytokine secretion, increased mRNA expression of TNF-α and increased surface receptor expression of CD80 when co-cultured with osteosarcoma and S. aureus. Collectively, the findings of this study suggest that infection upregulates the inflammatory immune response to counteract osteosarcoma-induced immune suppression. This work informs a potential therapeutic strategy to optimize inflammatory stimuli for triggering an anti-osteosarcoma macrophage response.
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http://dx.doi.org/10.1111/vco.12529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7384208PMC
March 2020

Pharmacodynamic study of radium-223 in men with bone metastatic castration resistant prostate cancer.

PLoS One 2019 28;14(5):e0216934. Epub 2019 May 28.

Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC, United States of America.

Background: Radium-223 is a targeted alpha-particle therapy that improves survival in men with metastatic castration resistant prostate cancer (mCRPC), particularly in men with elevated serum levels of bone alkaline phosphatase (B-ALP). We hypothesized that osteomimicry, a form of epithelial plasticity leading to an osteoblastic phenotype, may contribute to intralesional deposition of radium-223 and subsequent irradiation of the tumor microenvironment.

Methods: We conducted a pharmacodynamic study (NCT02204943) of radium-223 in men with bone mCRPC. Prior to and three and six months after radium-223 treatment initiation, we collected CTCs and metastatic biopsies for phenotypic characterization and CTC genomic analysis. The primary objective was to describe the impact of radium-223 on the prevalence of CTC B-ALP over time. We measured radium-223 decay products in tumor and surrounding normal bone during treatment. We validated genomic findings in a separate independent study of men with bone metastatic mCRPC (n = 45) and publicly accessible data of metastatic CRPC tissues.

Results: We enrolled 20 men with symptomatic bone predominant mCRPC and treated with radium-223. We observed greater radium-223 radioactivity levels in metastatic bone tumor containing biopsies compared with adjacent normal bone. We found evidence of persistent Cellsearch CTCs and B-ALP (+) CTCs in the majority of men over time during radium-223 therapy despite serum B-ALP normalization. We identified genomic gains in osteoblast mimicry genes including gains of ALPL, osteopontin, SPARC, OB-cadherin and loss of RUNX2, and validated genomic alterations or increased expression at the DNA and RNA level in an independent cohort of 45 men with bone-metastatic CRPC and in 150 metastatic biopsies from men with mCRPC.

Conclusions: Osteomimicry may contribute in part to the uptake of radium-223 within bone metastases and may thereby enhance the therapeutic benefit of this bone targeting radiotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216934PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538141PMC
January 2020

Prospective Multicenter Validation of Androgen Receptor Splice Variant 7 and Hormone Therapy Resistance in High-Risk Castration-Resistant Prostate Cancer: The PROPHECY Study.

J Clin Oncol 2019 05 13;37(13):1120-1129. Epub 2019 Mar 13.

1 Duke University, Durham, NC.

Purpose: Androgen receptor splice variant 7 (AR-V7) results in a truncated receptor, which leads to ligand-independent constitutive activation that is not inhibited by anti-androgen therapies, including abiraterone or enzalutamide. Given that previous reports suggested that circulating tumor cell (CTC) AR-V7 detection is a poor prognostic indicator for the clinical efficacy of secondary hormone therapies, we conducted a prospective multicenter validation study.

Patients And Methods: PROPHECY ( ClinicalTrials.gov identifier: NCT02269982) is a multicenter, prospective-blinded study of men with high-risk mCRPC starting abiraterone acetate or enzalutamide treatment. The primary objective was to validate the prognostic significance of baseline CTC AR-V7 on the basis of radiographic or clinical progression free-survival (PFS) by using the Johns Hopkins University modified-AdnaTest CTC AR-V7 mRNA assay and the Epic Sciences CTC nuclear-specific AR-V7 protein assay. Overall survival (OS) and prostate-specific antigen responses were secondary end points.

Results: We enrolled 118 men with mCRPC who were starting abiraterone or enzalutamide treatment. AR-V7 detection by both the Johns Hopkins and Epic AR-V7 assays was independently associated with shorter PFS (hazard ratio, 1.9 [95% CI, 1.1 to 3.3; = .032] and 2.4 [95% CI, 1.1 to 5.1; = .020], respectively) and OS (hazard ratio, 4.2 [95% CI, 2.1 to 8.5] and 3.5 [95% CI, 1.6 to 8.1], respectively) after adjusting for CTC number and clinical prognostic factors. Men with AR-V7-positive mCRPC had fewer confirmed prostate-specific antigen responses (0% to 11%) or soft tissue responses (0% to 6%). The observed percentage agreement between the two AR-V7 assays was 82%.

Conclusion: Detection of AR-V7 in CTCs by two blood-based assays is independently associated with shorter PFS and OS with abiraterone or enzalutamide, and such men with mCRPC should be offered alternative treatments.
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http://dx.doi.org/10.1200/JCO.18.01731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494355PMC
May 2019
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