Publications by authors named "Samir Hanash"

272 Publications

A MYC-Driven Plasma Polyamine Signature for Early Detection of Ovarian Cancer.

Cancers (Basel) 2021 Feb 22;13(4). Epub 2021 Feb 22.

Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

MYC is an oncogenic driver in the pathogenesis of ovarian cancer. We previously demonstrated that MYC regulates polyamine metabolism in triple-negative breast cancer (TNBC) and that a plasma polyamine signature is associated with TNBC development and progression. We hypothesized that a similar plasma polyamine signature may associate with ovarian cancer (OvCa) development. Using mass spectrometry, four polyamines were quantified in plasma from 116 OvCa cases and 143 controls (71 healthy controls + 72 subjects with benign pelvic masses) (Test Set). Findings were validated in an independent plasma set from 61 early-stage OvCa cases and 71 healthy controls (Validation Set). Complementarity of polyamines with CA125 was also evaluated. Receiver operating characteristic area under the curve (AUC) of individual polyamines for distinguishing cases from healthy controls ranged from 0.74-0.88. A polyamine signature consisting of diacetylspermine + N-(3-acetamidopropyl)pyrrolidin-2-one in combination with CA125 developed in the Test Set yielded improvement in sensitivity at >99% specificity relative to CA125 alone (73.7% vs 62.2%; McNemar exact test 2-sided P: 0.019) in the validation set and captured 30.4% of cases that were missed with CA125 alone. Our findings reveal a MYC-driven plasma polyamine signature associated with OvCa that complemented CA125 in detecting early-stage ovarian cancer.
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http://dx.doi.org/10.3390/cancers13040913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7927060PMC
February 2021

The length of the receiver operating characteristic curve and the two cutoff Youden index within a robust framework for discovery, evaluation, and cutoff estimation in biomarker studies involving improper receiver operating characteristic curves.

Stat Med 2021 Mar 2;40(7):1767-1789. Epub 2021 Feb 2.

Department of Biostatistics, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

During the early stage of biomarker discovery, high throughput technologies allow for simultaneous input of thousands of biomarkers that attempt to discriminate between healthy and diseased subjects. In such cases, proper ranking of biomarkers is highly important. Common measures, such as the area under the receiver operating characteristic (ROC) curve (AUC), as well as affordable sensitivity and specificity levels, are often taken into consideration. Strictly speaking, such measures are appropriate under a stochastic ordering assumption, which implies, without loss of generality, that higher measurements are more indicative for the disease. Such an assumption is not always plausible and may lead to rejection of extremely useful biomarkers at this early discovery stage. We explore the length of a smooth ROC curve as a measure for biomarker ranking, which is not subject to directionality. We show that the length corresponds to a divergence, is identical to the corresponding length of the optimal (likelihood ratio) ROC curve, and is an appropriate measure for ranking biomarkers. We explore the relationship between the length measure and the AUC of the optimal ROC curve. We then provide a complete framework for the evaluation of a biomarker in terms of sensitivity and specificity through a proposed ROC analogue for use in improper settings. In the absence of any clinical insight regarding the appropriate cutoffs, we estimate the sensitivity and specificity under a two-cutoff extension of the Youden index and we further take into account the implied costs. We apply our approaches on two biomarker studies that relate to pancreatic and esophageal cancer.
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http://dx.doi.org/10.1002/sim.8869DOI Listing
March 2021

Single-cell dissection of intratumoral heterogeneity and lineage diversity in metastatic gastric adenocarcinoma.

Nat Med 2021 01 4;27(1):141-151. Epub 2021 Jan 4.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Intratumoral heterogeneity (ITH) is a fundamental property of cancer; however, the origins of ITH remain poorly understood. We performed single-cell transcriptome profiling of peritoneal carcinomatosis (PC) from 15 patients with gastric adenocarcinoma (GAC), constructed a map of 45,048 PC cells, profiled the transcriptome states of tumor cell populations, incisively explored ITH of malignant PC cells and identified significant correlates with patient survival. The links between tumor cell lineage/state compositions and ITH were illustrated at transcriptomic, genotypic, molecular and phenotypic levels. We uncovered the diversity in tumor cell lineage/state compositions in PC specimens and defined it as a key contributor to ITH. Single-cell analysis of ITH classified PC specimens into two subtypes that were prognostically independent of clinical variables, and a 12-gene prognostic signature was derived and validated in multiple large-scale GAC cohorts. The prognostic signature appears fundamental to GAC carcinogenesis and progression and could be practical for patient stratification.
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http://dx.doi.org/10.1038/s41591-020-1125-8DOI Listing
January 2021

Integrated genomic profiling and modelling for risk stratification in patients with advanced oesophagogastric adenocarcinoma.

Gut 2020 Dec 17. Epub 2020 Dec 17.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Prognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.

Design: We profiled 40 untreated mEGACs (20 shorter survivors <13 months and 20 longer survivors >36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.

Results: alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and 'cold' immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets and ). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.

Conclusion: This study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.
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http://dx.doi.org/10.1136/gutjnl-2020-322707DOI Listing
December 2020

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

Gastroenterology 2021 Mar 14;160(4):1373-1383.e6. Epub 2020 Dec 14.

Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address:

Background & Aims: There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established.

Methods: CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined.

Results: In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection.

Conclusion: CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.
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http://dx.doi.org/10.1053/j.gastro.2020.11.052DOI Listing
March 2021

Contribution of a Blood-Based Protein Biomarker Panel to the Classification of Indeterminate Pulmonary Nodules.

J Thorac Oncol 2021 02 31;16(2):228-236. Epub 2020 Oct 31.

McCombs Institute for the Early Detection and Treatment of Cancer, University of Texas MD Anderson Cancer Center, Houston, Texas.

Rationale: The workup and longitudinal monitoring for subjects presenting with pulmonary nodules is a pressing clinical problem. A blood-based biomarker panel potentially has utility for identifying subjects at higher risk for harboring a malignant nodule for whom additional workup would be indicated or subjects at reduced risk for whom imaging-based follow-up would be indicated.

Objectives: To assess whether a previously described four-protein biomarker panel, reported to improve assessment of lung cancer risk compared with a smoking-based lung cancer risk model, can provide discrimination between benign and malignant indeterminate pulmonary nodules.

Methods: A previously validated multiplex enzyme-linked immunoassay was performed on matched case and control samples from each cohort.

Measurements: The biomarker panel was tested in two case-control cohorts of patients presenting with indeterminate pulmonary nodules at the University of Pittsburgh Medical Center and the University of Texas Southwestern.

Main Results: In both cohorts, the biomarker panel resulted in improved prediction of lung cancer risk over a model on the basis of nodule size alone. Of particular note, the addition of the marker panel to nodule size greatly improved sensitivity at a high specificity in both cohorts.

Conclusions: A four-marker biomarker panel, previously validated to improve lung cancer risk prediction, was found to also have utility in distinguishing benign from malignant indeterminate pulmonary nodules. Its performance in improving sensitivity at a high specificity indicates potential utility of the marker panel in assessing likelihood of malignancy in otherwise indeterminate nodules.
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http://dx.doi.org/10.1016/j.jtho.2020.09.024DOI Listing
February 2021

Biomarkers for Lung Cancer Screening and Detection.

Cancer Epidemiol Biomarkers Prev 2020 Dec 22;29(12):2411-2415. Epub 2020 Oct 22.

McCombs Institute for the Prevention and Treatment of Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Lung cancer is the leading worldwide cause of cancer mortality, as it is often detected at an advanced stage. Since 2011, low-dose CT scan-based screening has promised a 20% reduction in lung cancer mortality. However, effectiveness of screening has been limited by eligibility only for a high-risk population of heavy smokers and a large number of false positives generated by CT. Biomarkers have tremendous potential to improve early detection of lung cancer by refining lung cancer risk, stratifying positive CT scans, and categorizing intermediate-risk pulmonary nodules. Three biomarker tests (Early CDT-Lung, Nodify XL2, Percepta) have undergone extensive validation and are available to the clinician. The authors discuss these tests, with their clinical applicability and limitations, current ongoing evaluation, and future directions for biomarkers in lung cancer screening and detection.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710615PMC
December 2020

NFATc Acts as a Non-Canonical Phenotypic Stability Factor for a Hybrid Epithelial/Mesenchymal Phenotype.

Front Oncol 2020 8;10:553342. Epub 2020 Sep 8.

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

Metastasis remains the cause of over 90% of cancer-related deaths. Cells undergoing metastasis use phenotypic plasticity to adapt to their changing environmental conditions and avoid therapy and immune response. Reversible transitions between epithelial and mesenchymal phenotypes - epithelial-mesenchymal transition (EMT) and its reverse mesenchymal-epithelial transition (MET) - form a key axis of phenotypic plasticity during metastasis and therapy resistance. Recent studies have shown that the cells undergoing EMT/MET can attain one or more hybrid epithelial/mesenchymal (E/M) phenotypes, the process of which is termed as partial EMT/MET. Cells in hybrid E/M phenotype(s) can be more aggressive than those in either epithelial or mesenchymal state. Thus, it is crucial to identify the factors and regulatory networks enabling such hybrid E/M phenotypes. Here, employing an integrated computational-experimental approach, we show that the transcription factor nuclear factor of activated T-cell (NFATc) can inhibit the process of complete EMT, thus stabilizing the hybrid E/M phenotype. It increases the range of parameters enabling the existence of a hybrid E/M phenotype, thus behaving as a phenotypic stability factor (PSF). However, unlike previously identified PSFs, it does not increase the mean residence time of the cells in hybrid E/M phenotypes, as shown by stochastic simulations; rather it enables the co-existence of epithelial, mesenchymal and hybrid E/M phenotypes and transitions among them. Clinical data suggests the effect of NFATc on patient survival in a tissue-specific or context-dependent manner. Together, our results indicate that NFATc behaves as a non-canonical PSF for a hybrid E/M phenotype.
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http://dx.doi.org/10.3389/fonc.2020.553342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7506140PMC
September 2020

Novel urinary protein biomarker panel for early diagnosis of gastric cancer.

Br J Cancer 2020 11 16;123(11):1656-1664. Epub 2020 Sep 16.

Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, 467-8601, Japan.

Background: With the goal of discovering non-invasive biomarkers for early diagnosis of GC, we conducted a case-control study utilising urine samples from individuals with predominantly early GC vs. healthy control (HC).

Methods: Among urine samples from 372 patients, age- and sex-matched 282 patients were randomly divided into three groups: 18 patients in a discovery cohort; 176 patients in a training cohort and 88 patients in a validation cohort.

Results: Among urinary proteins identified in the comprehensive quantitative proteomics analysis, urinary levels of TFF1 (uTFF1) and ADAM12 (uADAM12) were significantly independent diagnostic biomarkers for GC, in addition to Helicobacter pylori status. A urinary biomarker panel combining uTFF1, uADAM12 and H. pylori significantly distinguished between HC and GC patients in both training and validation cohorts. On the analysis for sex-specific biomarkers, this combination panel demonstrated a good AUC of 0.858 for male GC, whereas another combination panel of uTFF1, uBARD1 and H. pylori also provided a good AUC of 0.893 for female GC. Notably, each panel could distinguish even stage I GC patients from HC patients (AUC = 0.850 for males; AUC = 0.845 for females).

Conclusions: Novel urinary protein biomarker panels represent promising non-invasive biomarkers for GC, including early-stage disease.
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http://dx.doi.org/10.1038/s41416-020-01063-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686371PMC
November 2020

Caveolin-1-mediated sphingolipid oncometabolism underlies a metabolic vulnerability of prostate cancer.

Nat Commun 2020 08 27;11(1):4279. Epub 2020 Aug 27.

Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.

Plasma and tumor caveolin-1 (Cav-1) are linked with disease progression in prostate cancer. Here we report that metabolomic profiling of longitudinal plasmas from a prospective cohort of 491 active surveillance (AS) participants indicates prominent elevations in plasma sphingolipids in AS progressors that, together with plasma Cav-1, yield a prognostic signature for disease progression. Mechanistic studies of the underlying tumor supportive onco-metabolism reveal coordinated activities through which Cav-1 enables rewiring of cancer cell lipid metabolism towards a program of 1) exogenous sphingolipid scavenging independent of cholesterol, 2) increased cancer cell catabolism of sphingomyelins to ceramide derivatives and 3) altered ceramide metabolism that results in increased glycosphingolipid synthesis and efflux of Cav-1-sphingolipid particles containing mitochondrial proteins and lipids. We also demonstrate, using a prostate cancer syngeneic RM-9 mouse model and established cell lines, that this Cav-1-sphingolipid program evidences a metabolic vulnerability that is targetable to induce lethal mitophagy as an anti-tumor therapy.
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http://dx.doi.org/10.1038/s41467-020-17645-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453025PMC
August 2020

The Long Noncoding RNA CCAT2 Induces Chromosomal Instability Through BOP1-AURKB Signaling.

Gastroenterology 2020 12 15;159(6):2146-2162.e33. Epub 2020 Aug 15.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Background & Aims: Chromosomal instability (CIN) is a carcinogenesis event that promotes metastasis and resistance to therapy by unclear mechanisms. Expression of the colon cancer-associated transcript 2 gene (CCAT2), which encodes a long noncoding RNA (lncRNA), associates with CIN, but little is known about how CCAT2 lncRNA regulates this cancer enabling characteristic.

Methods: We performed cytogenetic analysis of colorectal cancer (CRC) cell lines (HCT116, KM12C/SM, and HT29) overexpressing CCAT2 and colon organoids from C57BL/6N mice with the CCAT2 transgene and without (controls). CRC cells were also analyzed by immunofluorescence microscopy, γ-H2AX, and senescence assays. CCAT2 transgene and control mice were given azoxymethane and dextran sulfate sodium to induce colon tumors. We performed gene expression array and mass spectrometry to detect downstream targets of CCAT2 lncRNA. We characterized interactions between CCAT2 with downstream proteins using MS2 pull-down, RNA immunoprecipitation, and selective 2'-hydroxyl acylation analyzed by primer extension analyses. Downstream proteins were overexpressed in CRC cells and analyzed for CIN. Gene expression levels were measured in CRC and non-tumor tissues from 5 cohorts, comprising more than 900 patients.

Results: High expression of CCAT2 induced CIN in CRC cell lines and increased resistance to 5-fluorouracil and oxaliplatin. Mice that expressed the CCAT2 transgene developed chromosome abnormalities, and colon organoids derived from crypt cells of these mice had a higher percentage of chromosome abnormalities compared with organoids from control mice. The transgenic mice given azoxymethane and dextran sulfate sodium developed more and larger colon polyps than control mice given these agents. Microarray analysis and mass spectrometry indicated that expression of CCAT2 increased expression of genes involved in ribosome biogenesis and protein synthesis. CCAT2 lncRNA interacted directly with and stabilized BOP1 ribosomal biogenesis factor (BOP1). CCAT2 also increased expression of MYC, which activated expression of BOP1. Overexpression of BOP1 in CRC cell lines resulted in chromosomal missegregation errors, and increased colony formation, and invasiveness, whereas BOP1 knockdown reduced viability. BOP1 promoted CIN by increasing the active form of aurora kinase B, which regulates chromosomal segregation. BOP1 was overexpressed in polyp tissues from CCAT2 transgenic mice compared with healthy tissue. CCAT2 lncRNA and BOP1 mRNA or protein were all increased in microsatellite stable tumors (characterized by CIN), but not in tumors with microsatellite instability compared with nontumor tissues. Increased levels of CCAT2 lncRNA and BOP1 mRNA correlated with each other and with shorter survival times of patients.

Conclusions: We found that overexpression of CCAT2 in colon cells promotes CIN and carcinogenesis by stabilizing and inducing expression of BOP1 an activator of aurora kinase B. Strategies to target this pathway might be developed for treatment of patients with microsatellite stable colorectal tumors.
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http://dx.doi.org/10.1053/j.gastro.2020.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7725986PMC
December 2020

Extracellular Vesicles Mediate B Cell Immune Response and Are a Potential Target for Cancer Therapy.

Cells 2020 06 22;9(6). Epub 2020 Jun 22.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Extracellular vesicles (EVs) are increasingly understood to participate directly in many essential aspects of host antitumor immune response. Tumor- and immune-cell-derived EVs function in local and systemic contexts with roles in immune processes including cancer antigen conveyance, immune cell priming and activation, as well as immune escape. Current practice of cancer immunotherapy has de facto focused on eliciting T-cell-mediated cytotoxic responses. Humoral immunity is also known to exert antitumor effects, and B cells have been demonstrated to have functions that extend beyond antibody production to include antigen presentation and activation and modulation of T cells and innate immune effectors. Evidence of B cell response against tumor-associated antigens (TAAs) is observed in early stages of tumorigenesis and in most solid tumor types. It is known that EVs convey diverse TAAs, express antigenic-peptide-loaded MHCs, and complex with circulating plasma antitumoral autoantibodies. In this review, we will consider the relationships between EVs, B cells, and other antigen-presenting cells, especially in relation to TAAs. Understanding the intersection of EVs and the cancer immunome will enable opportunities for developing tumor antigen targets, antitumor vaccines and harnessing the full potential of multiple immune system components for next-generation cancer immunotherapies.
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http://dx.doi.org/10.3390/cells9061518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7349483PMC
June 2020

Biomarkers and Strategy to Detect Preinvasive and Early Pancreatic Cancer: State of the Field and the Impact of the EDRN.

Cancer Epidemiol Biomarkers Prev 2020 Dec 12;29(12):2513-2523. Epub 2020 Jun 12.

Van Andel Institute, Grand Rapids, Michigan.

Patients afflicted with pancreatic ductal adenocarcinoma (PDAC) face a dismal prognosis, but headway could be made if physicians could identify the disease earlier. A compelling strategy to broaden the use of surveillance for PDAC is to incorporate molecular biomarkers in combination with clinical analysis and imaging tools. This article summarizes the components involved in accomplishing biomarker validation and an analysis of the requirements of molecular biomarkers for disease surveillance. We highlight the significance of consortia for this research and highlight resources and infrastructure of the Early Detection Research Network (EDRN). The EDRN brings together the multifaceted expertise and resources needed for biomarker validation, such as study design, clinical care, biospecimen collection and handling, molecular technologies, and biostatistical analysis, and studies coming out of the EDRN have yielded biomarkers that are moving forward in validation. We close the article with an overview of the current investigational biomarkers, an analysis of their performance relative to the established benchmarks, and an outlook on the current needs in the field. The outlook for improving the early detection of PDAC looks promising, and the pace of further research should be quickened through the resources and expertise of the EDRN and other consortia.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710622PMC
December 2020

Dickkopf-related protein 3 is a novel biomarker for chronic GVHD after allogeneic hematopoietic cell transplantation.

Blood Adv 2020 06;4(11):2409-2417

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.

To identify plasma biomarkers associated with fibrotic mechanisms of chronic graft-versus-host disease (GVHD), we used multiplex mass spectrometry with pooled samples for biomarker discovery in comparing proteomic profiles between patients with newly diagnosed sclerotic chronic GVHD (n = 21), those with newly diagnosed nonsclerotic chronic GVHD (n = 33), and those without chronic GVHD (n = 20). Immunoassay was used to measure protein concentrations of individual discovery samples and 186 independent verification samples. The discovery mass spectrometry analysis identified 2 candidate proteins with at least 1.5-fold difference in sclerotic GVHD: Dickkopf-related protein 3 (DKK3) and interleukin-1 receptor accessory protein (IL1RAP). Analysis of individual discovery samples by immunoassay showed that DKK3, a modulator of the Wnt signaling pathway, was a biomarker for both sclerotic and nonsclerotic chronic GVHD. Verification analysis of 186 patients confirmed that elevated plasma DKK3 concentrations were associated with chronic GVHD, regardless of the presence or absence of sclerosis, and that the area under the receiver operating characteristic curve was 0.85 for association of DKK3 concentrations with chronic GVHD. Multiple linear regression analysis showed that chronic GVHD with or without steroid treatment and patient age were independently associated with DKK3 concentrations. Patients with high DKK3 concentrations had a higher nonrelapse mortality than those with low concentrations. The lower IL1RAP concentrations in patients with sclerotic GVHD compared with other conditions in the discovery cohort were not confirmed in the verification cohort. DKK3 is a novel biomarker for chronic GVHD. Further studies are needed to determine the biological functions of DKK3 in the pathogenesis of chronic GVHD.
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http://dx.doi.org/10.1182/bloodadvances.2020001485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284089PMC
June 2020

Dietary inflammatory potential in relation to the gut microbiome: results from a cross-sectional study.

Br J Nutr 2020 11 1;124(9):931-942. Epub 2020 Jun 1.

Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX77030, USA.

Diet has direct and indirect effects on health through inflammation and the gut microbiome. We investigated total dietary inflammatory potential via the literature-derived index (Dietary Inflammatory Index (DII®)) with gut microbiota diversity, composition and function. In cancer-free patient volunteers initially approached at colonoscopy and healthy volunteers recruited from the medical centre community, we assessed 16S ribosomal DNA in all subjects who provided dietary assessments and stool samples (n 101) and the gut metagenome in a subset of patients with residual fasting blood samples (n 34). Associations of energy-adjusted DII scores with microbial diversity and composition were examined using linear regression, permutational multivariate ANOVA and linear discriminant analysis. Spearman correlation was used to evaluate associations of species and pathways with DII and circulating inflammatory markers. Across DII levels, α- and β-diversity did not significantly differ; however, Ruminococcus torques, Eubacterium nodatum, Acidaminococcus intestini and Clostridium leptum were more abundant in the most pro-inflammatory diet group, while Akkermansia muciniphila was enriched in the most anti-inflammatory diet group. With adjustment for age and BMI, R. torques, E. nodatum and A. intestini remained significantly associated with a more pro-inflammatory diet. In the metagenomic and fasting blood subset, A. intestini was correlated with circulating plasminogen activator inhibitor-1, a pro-inflammatory marker (rho = 0·40), but no associations remained significant upon correction for multiple testing. An index reflecting overall inflammatory potential of the diet was associated with specific microbes, but not overall diversity of the gut microbiome in our study. Findings from this preliminary study warrant further research in larger samples and prospective cohorts.
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http://dx.doi.org/10.1017/S0007114520001853DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554089PMC
November 2020

Plasma-Derived Extracellular Vesicles Convey Protein Signatures that Reflect Pathophysiology in Lung and Pancreatic Adenocarcinomas.

Cancers (Basel) 2020 May 2;12(5). Epub 2020 May 2.

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Using a combination of mass-spectrometry and aptamer array-based proteomics, we characterized the protein features of circulating extracellular vesicles (EVs) in the context of lung (LUAD) and pancreatic ductal (PDAC) adenocarcinomas. We profiled EVs isolated from conditioned media of LUAD and PDAC cell lines to identify EV-associated protein cargoes released by these cancer cell types. Analysis of the resulting data identified LUAD and PDAC specific and pan-adenocarcinoma EV protein signatures. Bioinformatic analyses confirmed enrichment of proteins annotated to vesicle-associated processes and intracellular compartments, as well as representation of cancer hallmark functions and processes. Analysis of upstream regulator networks indicated significant enrichment of TP53, MYC, TGFB1 and KRAS-driven network effectors ( = 1.69 × 10-2.93 × 10) manifest in the adenocarcinoma sEV protein cargoes. We extended these findings by profiling the proteome of EVs isolated from lung ( = 15) and pancreatic ductal ( = 6) adenocarcinoma patient plasmas obtained at time of diagnosis, along with EVs derived from matched healthy controls ( = 21). Exploration of these proteomic data revealed abundant protein features in the plasma EVs with capacity to distinguish LUAD and PDAC cases from controls, including features yielding higher performance in the plasma EV isolates relative to unfractionated plasmas.
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http://dx.doi.org/10.3390/cancers12051147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281335PMC
May 2020

YAP1 mediates gastric adenocarcinoma peritoneal metastases that are attenuated by YAP1 inhibition.

Gut 2021 Jan 27;70(1):55-66. Epub 2020 Apr 27.

Department of Gastrointestinal Medical Oncology, UT MD Anderson Cancer Center, Houston, TX, USA

Objective: Peritoneal carcinomatosis (PC; malignant ascites or implants) occurs in approximately 45% of advanced gastric adenocarcinoma (GAC) patients and associated with a poor survival. The molecular events leading to PC are unknown. The yes-associated protein 1 () oncogene has emerged in many tumour types, but its clinical significance in PC is unclear. Here, we investigated the role of YAP1 in PC and its potential as a therapeutic target.

Methods: Patient-derived PC cells, patient-derived xenograft (PDX) and patient-derived orthotopic (PDO) models were used to study the function of YAP1 in vitro and in vivo. Immunofluorescence and immunohistochemical staining, RNA sequencing (RNA-Seq) and single-cell RNA-Seq (sc-RNA-Seq) were used to elucidate the expression of YAP1 and PC cell heterogeneity. LentiCRISPR/Cas9 knockout of YAP1 and a YAP1 inhibitor were used to dissect its role in PC metastases.

Results: YAP1 was highly upregulated in PC tumour cells, conferred cancer stem cell (CSC) properties and appeared to be a metastatic driver. Dual staining of YAP1/EpCAM and sc-RNA-Seq revealed that PC tumour cells were highly heterogeneous, YAP1 PC cells had CSC-like properties and easily formed PDX/PDO tumours but also formed PC in mice, while genetic knockout YAP1 significantly slowed tumour growth and eliminated PC in PDO model. Additionally, pharmacologic inhibition of YAP1 specifically reduced CSC-like properties and suppressed tumour growth in YAP1 PC cells especially in combination with cytotoxics in vivo PDX model.

Conclusions: YAP1 is essential for PC that is attenuated by YAP1 inhibition. Our data provide a strong rationale to target YAP1 in clinic for GAC patients with PC.
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http://dx.doi.org/10.1136/gutjnl-2019-319748DOI Listing
January 2021

Immune-Complexome Analysis Identifies Immunoglobulin-Bound Biomarkers That Predict the Response to Chemotherapy of Pancreatic Cancer Patients.

Cancers (Basel) 2020 Mar 21;12(3). Epub 2020 Mar 21.

Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Torino, Italy.

Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive malignancy with a very poor outcome. Although chemotherapy (CT) treatment has poor efficacy, it can enhance tumor immunogenicity. Tumor-Associated Antigens (TAA) are self-proteins that are overexpressed in tumors that may induce antibody production and can be PDA theranostic targets. However, the prognostic value of TAA-antibody association as Circulating Immune Complexes (CIC) has not yet been elucidated, mainly due to the lack of techniques that lead to their identification. In this study, we show a novel method to separate IgG, IgM, and IgA CIC from sera to use them as prognostic biomarkers of CT response. The PDA Immune-Complexome (IC) was identified using a LTQ-Orbitrap mass spectrometer followed by computational analysis. The analysis of the IC of 37 PDA patients before and after CT revealed differential associated antigens (DAA) for each immunoglobulin class. Our method identified different PDA-specific CIC in patients that were associated with poor prognosis patients. Finally, CIC levels were significantly modified by CT suggesting that they can be used as effective prognostic biomarkers to follow CT response in PDA patients.
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http://dx.doi.org/10.3390/cancers12030746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140049PMC
March 2020

A Promising CPS1 Inhibitor Keeping Ammonia from Fueling Cancer.

Cell Chem Biol 2020 03;27(3):253-254

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Carbamoyl phosphate synthetase 1 (CPS1) drives ammonia conversion to carbamoyl phosphate, and its overexpression supports pyrimidine synthesis and tumor growth, highlighting the potential of CPS1 inhibition as a therapeutic target. In this issue of Cell Chemical Biology, Yao et al. (2020) introduce H3B-120 as a promising novel inhibitor of CPS1.
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http://dx.doi.org/10.1016/j.chembiol.2020.03.002DOI Listing
March 2020

Proteome Profiling Uncovers an Autoimmune Response Signature That Reflects Ovarian Cancer Pathogenesis.

Cancers (Basel) 2020 Feb 19;12(2). Epub 2020 Feb 19.

Department of Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Harnessing the immune response to tumor antigens in the form of autoantibodies, which occurs early during tumor development, has relevance to the detection of cancer at early stages. We conducted an initial screen of antigens associated with an autoantibody response in serous ovarian cancer using recombinant protein arrays. The top 25 recombinants that exhibited increased reactivity with cases compared to controls revealed TP53 and MYC, which are ovarian cancer driver genes, as major network nodes. A mass spectrometry based independent analysis of circulating immunoglobulin (Ig)-bound proteins in ovarian cancer and of ovarian cancer cell surface MHC-II bound peptides also revealed a TP53-MYC related network of antigens. Our findings support the occurrence of a humoral immune response to antigens linked to ovarian cancer driver genes that may have utility for early detection applications.
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http://dx.doi.org/10.3390/cancers12020485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072578PMC
February 2020

Therapeutic potential of FLANC, a novel primate-specific long non-coding RNA in colorectal cancer.

Gut 2020 10 27;69(10):1818-1831. Epub 2020 Jan 27.

Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: To investigate the function of a novel primate-specific long non-coding RNA (lncRNA), named FLANC, based on its genomic location (co-localised with a pyknon motif), and to characterise its potential as a biomarker and therapeutic target.

Design: FLANC expression was analysed in 349 tumours from four cohorts and correlated to clinical data. In a series of multiple in vitro and in vivo models and molecular analyses, we characterised the fundamental biological roles of this lncRNA. We further explored the therapeutic potential of targeting FLANC in a mouse model of colorectal cancer (CRC) metastases.

Results: FLANC, a primate-specific lncRNA feebly expressed in normal colon cells, was significantly upregulated in cancer cells compared with normal colon samples in two independent cohorts. High levels of FLANC were associated with poor survival in two additional independent CRC patient cohorts. Both in vitro and in vivo experiments demonstrated that the modulation of FLANC expression influenced cellular growth, apoptosis, migration, angiogenesis and metastases formation ability of CRC cells. In vivo pharmacological targeting of FLANC by administration of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine nanoparticles loaded with a specific small interfering RNA, induced significant decrease in metastases, without evident tissue toxicity or pro-inflammatory effects. Mechanistically, FLANC upregulated and prolonged the half-life of phosphorylated STAT3, inducing the overexpression of VEGFA, a key regulator of angiogenesis.

Conclusions: Based on our findings, we discovered, FLANC as a novel primate-specific lncRNA that is highly upregulated in CRC cells and regulates metastases formation. Targeting primate-specific transcripts such as FLANC may represent a novel and low toxic therapeutic strategy for the treatment of patients.
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http://dx.doi.org/10.1136/gutjnl-2019-318903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382985PMC
October 2020

Assessment of ST2 for risk of death following graft-versus-host disease in pediatric and adult age groups.

Blood 2020 04;135(17):1428-1437

Indiana University School of Medicine, Indianapolis, IN.

Assessment of prognostic biomarkers of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group is lacking. To address this need, we conducted a prospective cohort study with 415 patients at 6 centers: 170 were children age 10 years or younger and 245 were patients older than age 10 years (both children and adults were accrued from 2013 to 2018). The following 4 plasma biomarkers were assessed pre-HCT and at days +7, +14, and +21 post-HCT: stimulation-2 (ST2), tumor necrosis factor receptor 1 (TNFR1), regenerating islet-derived protein 3α (REG3α), and interleukin-6 (IL-6). We performed landmark analyses for NRM, dichotomizing the cohort at age 10 years or younger and using each biomarker median as a cutoff for high- and low-risk groups. Post-HCT biomarker analysis showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in children age 10 years or younger (ST2: hazard ratio [HR], 9.13; 95% confidence interval [CI], 2.74-30.38; P = .0003; TNFR1: HR, 4.29; 95% CI, 1.48-12.48; P = .0073; REG3α: HR, 7.28; 95% CI, 2.05-25.93; P = .0022); and in children and adults older than age 10 years (ST2: HR, 2.60; 95% CI, 1.15-5.86; P = .021; TNFR1: HR, 2.09; 95% CI, 0.96-4.58; P = .06; and REG3α: HR, 2.57; 95% CI, 1.19-5.55; P = .016). When pre-HCT biomarkers were included, only ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, and graft-versus-host-disease prophylaxis), ST2 remained associated with NRM only in recipients age 10 years or younger (HR, 4.82; 95% CI, 1.89-14.66; P = .0056). Assays of ST2, TNFR1, and REG3α in the first 3 weeks after HCT have prognostic value for NRM in both children and adults. The presence of ST2 before HCT is a prognostic biomarker for NRM in children age 10 years or younger allowing for additional stratification. This trial was registered at www.clinicaltrials.gov as #NCT02194439.
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http://dx.doi.org/10.1182/blood.2019002334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180084PMC
April 2020

Development of autoantibody signatures for common cancers.

Semin Immunol 2020 02 8;47:101388. Epub 2020 Jan 8.

Department of Clinical Cancer Prevention, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. Electronic address:

A humoral immune response in the form of autoantibodies to tumor antigens occurs early during tumor development. Identification of antigens that induce an autoantibody response restricted to a cancer type has the potential to yield markers useful for early detection. A multitude of strategies are currently available for the discovery of tumor antigens directed autoantibodies in circulation. Each approach has advantages and limitations for comprehensive discovery of antigenic epitopes. Herein, we review established and novel strategies and methodologies and highlight potential cancer applications.
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http://dx.doi.org/10.1016/j.smim.2020.101388DOI Listing
February 2020

The BE GONE trial study protocol: a randomized crossover dietary intervention of dry beans targeting the gut microbiome of overweight and obese patients with a history of colorectal polyps or cancer.

BMC Cancer 2019 Dec 18;19(1):1233. Epub 2019 Dec 18.

Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1340, Houston, TX, TX 77030, USA.

Background: Mouse and human studies support the promise of dry beans to improve metabolic health and to lower cancer risk. In overweight/obese patients with a history of colorectal polyps or cancer, the Beans to Enrich the Gut microbiome vs. Obesity's Negative Effects (BE GONE) trial will test whether and how an increase in the consumption of pre-cooked, canned dry beans within the context of usual diet and lifestyle can enhance the gut landscape to improve metabolic health and reduce cancer risk.

Methods/design: This randomized crossover trial is designed to characterize changes in (1) host markers spanning lipid metabolism, inflammation, and obesity-related cancer risk; (2) compositional and functional profiles of the fecal microbiome; and (3) host and microbial metabolites. With each subject serving as their own control, the trial will compare the participant's usual diet with (intervention) and without (control) dry beans. Canned, pre-cooked dry beans are provided to participants and the usual diet continually assessed and monitored. Following a 4-week run-in and equilibration period, each participant provides a total of 5 fasting blood and 6 stool samples over a total period of 16 weeks. The intervention consists of a 2-week ramp-up of dry bean intake to 1 cup/d, which is then continued for an additional 6 weeks. Intra- and inter-individual outcomes are assessed across each crossover period with consideration of the joint or modifying effects of the usual diet and baseline microbiome.

Discussion: The BE GONE trial is evaluating a scalable dietary prevention strategy targeting the gut microbiome of high-risk patients to mitigate the metabolic and inflammatory effects of adiposity that influence colorectal cancer risk, recurrence, and survival. The overarching scientific goal is to further elucidate interactions between diet, the gut microbiome, and host metabolism. Improved understanding of the diet-microbiota interplay and effective means to target these relationships will be key to the future of clinical and public health approaches to cancer and other major diet- and obesity-related diseases.

Trial Registration: This protocol is registered with the U.S. National Institutes of Health trial registry, ClinicalTrials.gov, under the identifier NCT02843425. First posted July 25, 2016; last verified January 25, 2019.
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http://dx.doi.org/10.1186/s12885-019-6400-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921460PMC
December 2019

Measuring human carboxylesterase 2 activity in pancreatic cancer patient-derived xenografts using a ratiometric fluorescent chemosensor.

Chem Sci 2019 Sep 29;10(36):8428-8437. Epub 2019 Jul 29.

Department of Chemical and Physical Sciences , University of Toronto Mississauga , Mississauga , ON L5L 1C6 , Canada . Email:

Irinotecan-based therapy is a common treatment for pancreatic cancer. To elicit its anticancer activity, the drug requires first the hydrolysis action of the enzyme human carboxylesterase 2 (hCES2). It has been established that pancreatic cancer patients have various levels of hCES2, whereby patients having low levels respond poorer to Irinotecan than patients with higher levels, suggesting that hCES2 can be used to predict response. However, current methods that measure hCES2 activity are inaccurate, complex or lengthy, thus being incompatible for use in a clinical setting. Here, we developed a small molecule ratiometric fluorescent chemosensor that accurately measures hCES2 activity in a single-step within complex mixtures. Our chemosensor is highly selective for hCES2 over hCES1, cell permeable and can measure hCES2 activity in pancreatic cancer patient-derived xenografts. Given the simplicity, accuracy and tissue compatibility of our assay, we anticipate our chemosensor can be used to predict patient response to Irinotecan-based therapy.
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http://dx.doi.org/10.1039/c9sc00283aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844279PMC
September 2019

Failure to Disclose Potential Conflict of Interest-Letter of Explanation.

JAMA Oncol 2019 Nov 14. Epub 2019 Nov 14.

Aichi Cancer Center, Nagoya, Aichi, Japan.

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http://dx.doi.org/10.1001/jamaoncol.2019.5259DOI Listing
November 2019

Human epididymis protein 4 antigen-autoantibody complexes complement cancer antigen 125 for detecting early-stage ovarian cancer.

Cancer 2020 02 12;126(4):725-736. Epub 2019 Nov 12.

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Early detection of ovarian cancer could significantly improve patient outcomes. Cancer antigen 125 (CA 125) is elevated in sera from approximately 60% of patients with early-stage (I/II) disease. Sensitivity might be improved through the combination of CA 125 with other biomarkers. Among potential biomarkers, antigen-autoantibody (Ag-AAb) complexes have received relatively little attention.

Methods: Luminex-based immunoassays were used to measure human epididymis protein 4 (HE4), anti-HE4 autoantibody, and HE4 Ag-AAb complexes in sera from patients with early- (n = 73) and late-stage ovarian cancers (n = 49) at the time of diagnosis and from asymptomatic women with (n = 15) or without ovarian cancer (n = 212) enrolled in the Normal Risk Ovarian Cancer Screening Study.

Results: At 98% specificity for healthy, asymptomatic women, 7% of patients with early-stage (I/II) ovarian cancer and 4% of patients with late-stage (III/IV) disease had elevated levels of HE4 autoantibody, whereas elevated levels of HE4 Ag-AAb complexes were detected in sera from 38% of early-stage cases and 31% of late-stage cases. Complementarity was observed in receiver operating characteristic (ROC) curves between HE4 Ag-AAb complexes and CA 125 levels in early-stage ovarian cancer (P < .001). CA 125 detected 63% of cases, and a combination of CA 125 and HE4 Ag-AAb complexes detected 81%. Complementarity was also observed in ROC curves for an independent validation set with 69 early-stage patients (P = .039). HE4 Ag-AAb complexes were detected in serial preclinical serum samples from women destined to develop ovarian cancer: they correlated with CA 125 but did not provide a lead time.

Conclusions: HE4 Ag-AAb complexes could complement CA 125 in detecting a higher fraction of early-stage ovarian cancers.
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http://dx.doi.org/10.1002/cncr.32582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992519PMC
February 2020

Association Between Plasma Diacetylspermine and Tumor Spermine Synthase With Outcome in Triple-Negative Breast Cancer.

J Natl Cancer Inst 2020 06;112(6):607-616

Departments of Clinical Cancer Prevention.

Background: MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression.

Methods: Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 estrogen receptor negative (ER-) and progesterone receptor negative (PR-) and HER2 positive (HER2+), and 73 ER+ case patients, and 30 cancer-free control subjects. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis-free survival and overall survival were determined using Cox proportional hazard models; Fisher exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression.

Results: An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ≥ 1.16, hazard ratio = 3.06, 95% confidence interval [CI] = 1.15 to 8.13, two-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile hazard ratio = 2.06, 95% CI = 1.04 to 4.08, one-sided P = .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile [reference] to highest SMS quartile relative risk = 1.90, 95% CI = 0.97 to 4.06, one-sided Fisher exact test P=.03).

Conclusions: Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.
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http://dx.doi.org/10.1093/jnci/djz182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301069PMC
June 2020

Graft-Versus-Host Disease-Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology.

JCO Precis Oncol 2019 23;3. Epub 2019 May 23.

Indiana University School of Medicine, Indianapolis, IN.

Purpose: As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed.

Patients And Methods: We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen-activated T cells from a patient with post-hematopoietic cell transplantation relapse was performed.

Results: The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses.

Conclusion: Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.
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http://dx.doi.org/10.1200/po.18.00365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690359PMC
May 2019

Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes.

Cell 2019 08;178(4):795-806.e12

Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Clinical Cancer Genetics Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Most patients diagnosed with resected pancreatic adenocarcinoma (PDAC) survive less than 5 years, but a minor subset survives longer. Here, we dissect the role of the tumor microbiota and the immune system in influencing long-term survival. Using 16S rRNA gene sequencing, we analyzed the tumor microbiome composition in PDAC patients with short-term survival (STS) and long-term survival (LTS). We found higher alpha-diversity in the tumor microbiome of LTS patients and identified an intra-tumoral microbiome signature (Pseudoxanthomonas-Streptomyces-Saccharopolyspora-Bacillus clausii) highly predictive of long-term survivorship in both discovery and validation cohorts. Through human-into-mice fecal microbiota transplantation (FMT) experiments from STS, LTS, or control donors, we were able to differentially modulate the tumor microbiome and affect tumor growth as well as tumor immune infiltration. Our study demonstrates that PDAC microbiome composition, which cross-talks to the gut microbiome, influences the host immune response and natural history of the disease.
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http://dx.doi.org/10.1016/j.cell.2019.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288240PMC
August 2019