David L Rimm

Yale University, New Haven, Connecticut, United States

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Publications (365)2581.93 Total impact

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    ABSTRACT: We have previously reported the 2D PAGE-based proteomic profiling of a prospective cohort of 78 triple negative breast cancer (TNBC) patients, and the establishment of a cumulative TNBC protein database. Analysis of this database identified a number of proteins as being specifically overexpressed in TNBC samples. One such protein was D-3-phosphoglycerate dehydrogenase (Phgdh), a candidate oncogene. We analysed expression of Phgdh in normal and TNBC mammary tissue samples by 2D gel-based proteomics and immunohistochemistry (IHC), and show here that high-level expression of Phgdh in mammary epithelial cells is primarily associated with cell lineage, as we found that Phgdh expression was predominant in CK5-positive cells, normal as well as malignant, thus identifying an association of this protein with the basal phenotype. Quantitative IHC analysis of Phgdh expression in normal breast tissue showed high-level expression of Phgdh in normal CK5-positive mammary epithelial cells, indicating that expression of this protein was not associated with malignancy, but rather with cell lineage. However, proteomic profiling of Phgdh showed it to be expressed in two major protein forms, and that the ratio of expression between these variants was associated with malignancy. Overexpression of Phgdh in CK5-positive cell lineages, and differential protein isoform expression, was additionally found in other tissues and cancer types, suggesting that overexpression of Phgdh is generally associated with CK5 cells, and that oncogenic function may be determined by isoform expression. Copyright © 2015 Federation of European Biochemical Societies. All rights reserved.
    Molecular oncology 05/2015; DOI:10.1016/j.molonc.2015.05.003 · 5.94 Impact Factor
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    ABSTRACT: Studies have shown that antibodies targeting the intracellular (ICD) or extracellular domains (ECD) of human epidermal growth factor receptor 2 (HER2) are equivalent when traditional methods are used. We describe a new method to quantify ICD and ECD expression separately and assess the prognostic value of domain-specific HER2 results in patients who received adjuvant trastuzumab therapy. We measured HER2 protein expression with quantitative immunofluorescence (QIF) in tissue microarrays (TMA) using two different antibodies targeting the ICD (CB11 and A0485) and ECD (SP3 and D8F12). We assessed the prognostic value of ICD and ECD expression in 180 patients from a clinical trial of adjuvant chemotherapy followed by trastuzumab (HeCOG 10/05). We performed an exploratory univariate domain-specific, disease-free survival (DFS) analysis and compared DFS functions with Kaplan-Meier estimates. All statistical tests were two-sided. HER2 ICD expression by QIF showed slightly higher sensitivity to predict ERBB2 (HER2) gene amplification than ECD expression, which was more specific and had higher positive predictive value. In the HeCOG 10/05 trial specimens, 15% of cases showed discordant results for ICD and ECD expression. High ECD was statistically associated with longer DFS (log-rank P = .049, HR = 0.31, 95% CI = 0.144 to 0.997), while ICD status was not. Among patients with low ECD, there was no difference in DFS by ICD status. However, when ICD was high, high ECD was statistically associated with longer DFS (log-rank P = .027, HR = 0.23, 95% CI = 0.037 to 0.82) compared with low ECD. Quantitative measurements of HER2 ICD and ECD expression in breast cancer suggest a subclassification of HER2-positive tumors. Trastuzumab-treated patients with high ECD showed better DFS than patients with low ECD. This suggests differential benefit from trastuzumab therapy based on HER2 ECD expression. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.
    Cancer Research 05/2015; 75(9 Supplement):P3-06-26-P3-06-26. DOI:10.1158/1538-7445.SABCS14-P3-06-26 · 9.28 Impact Factor
  • Cancer Research 05/2015; 75(9 Supplement):S1-08-S1-08. DOI:10.1158/1538-7445.SABCS14-S1-08 · 9.28 Impact Factor
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    ABSTRACT: Triple-negative breast cancer (TNBC) accounts for a disproportionate share of the total breast cancer morbidity because of its aggressive behavior and lack of effective targeted therapies to treat the disease. MicroRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are highly dysregulated in cancer. We identified miR-34a to be aberrantly lost in TNBC lines when compared to both a luminal cancer subtype as well as normal breast cells. Re-introduction of miR-34a in TNBC lines results in inhibition of cell proliferation and invasion, reactivation of senescence, and enhanced sensitivity to apoptosis-inducing agents. Furthermore, intratumoral delivery of miR-34a into subcutaneous tumors in nude mice, as well as systemic delivery of poly(amine-co-ester) PACE-loaded miR-34a in an orthotopic setting, delayed tumor growth. In conclusion, re-introduction of miR-34a in TNBC promotes potent anti-tumorigenic phenotypes in vitro and in vivo, and could be a promising targeted therapeutic agent to treat the disease.
    Cancer Research 05/2015; 75(9 Supplement):P4-07-12. DOI:10.1158/1538-7445.SABCS14-P4-07-12 · 9.28 Impact Factor
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    ABSTRACT: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome and anatomic site of disease. We assessed PD-L1 expression and tumor infiltrating lymphocytes (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. High PD-L1 expression was associated with improved survival (P=0.02) and higher T cell content (P=0.0005). Higher T cell content (total and CD8 cells) were independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extra-cerebral metastases was associated with increased time to developing brain metastases (P=0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P=0.01). T cell infiltrated melanomas, particularly those with high CD8 T cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; DOI:10.1158/1078-0432.CCR-14-3073 · 8.19 Impact Factor
  • Nancy E Davidson, David L Rimm
    JAMA The Journal of the American Medical Association 03/2015; 313(11):1109-1110. DOI:10.1001/jama.2015.1945 · 30.39 Impact Factor
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    ABSTRACT: Many tumor cells are fueled by altered metabolism and increased glutamine (Gln) dependence. We identify regulation of the L-glutamine carrier proteins SLC1A5 and SLC38A2 (SLC1A5/38A2) by the ubiquitin ligase RNF5. Paclitaxel-induced ER stress to breast cancer (BCa) cells promotes RNF5 association, ubiquitination, and degradation of SLC1A5/38A2. This decreases Gln uptake, levels of TCA cycle components, mTOR signaling, and proliferation while increasing autophagy and cell death. Rnf5-deficient MMTV-PyMT mammary tumors were less differentiated and showed elevated SLC1A5 expression. Whereas RNF5 depletion in MDA-MB-231 cells promoted tumorigenesis and abolished paclitaxel responsiveness, SLC1A5/38A2 knockdown elicited opposing effects. Inverse RNF5(hi)/SLC1A5/38A2(lo) expression was associated with positive prognosis in BCa. Thus, RNF5 control of Gln uptake underlies BCa response to chemotherapies. Copyright © 2015 Elsevier Inc. All rights reserved.
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    ABSTRACT: Purpose Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment but also missed opportunities for curative therapy. Experimental design An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish 'favorable' versus 'non-favorable' pathology independently and relative to current risk classification systems (NCCN and D'Amico). Results A favorable biomarker risk score of ≤0.33, and a non-favorable risk score of >0.80 (possible range between 0 and 1) were defined on 'false negative' and 'false positive' rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low- and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for non-favorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two co-primary endpoints, separating favorable from non-favorable pathology (AUC, 0.68, P<0.0001, odds ratio=20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65, P<0.0001, OR=12.95). Conclusion The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision-making following prostate biopsy. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 03/2015; 21(11). DOI:10.1158/1078-0432.CCR-14-2603 · 8.19 Impact Factor
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    ABSTRACT: Background: Tumor-infiltrating lymphocytes (TILs) are usually measured using subjective methods. Studies suggest that TIL subtypes have independent roles in cancer and that they could support the use of novel immunostimulatory therapies. We simultaneously measured TIL subtypes in non-small cell lung cancer (NSCLC) samples using objective methods and determined their relationship with clinico-pathologic characteristics and survival. Methods: Using multiplexed quantitative fluorescence (QIF), we measured the levels of CD3, CD8, and CD20 in 552 NSCLC from two independent collections represented in tissue microarrays (YTMA79, n = 202 and YTMA140, n = 350). The level of TILs was obtained in different tumor compartments using cytokeratin stain to define tumor cells and 4',6-Diamidino-2-Phenylindole. Association of TILs with clinical parameters was determined using univariate and multivariable analyses. All statistical tests were two-sided. Results: In both NSCLC collections there was a low correlation between the three TIL markers (linear regression coefficients (R-2) = 0.19-0.22, P < .001 for YTMA79 and R2 = 0.23-0.32, P < .001 for YTMA140). No consistent association between the level of TIL subtypes and age, sex, smoking history, tumor size, stage, and histology type was found. In univariate analysis, an elevated CD3 or CD8 signal was statistically significantly associated with longer survival in both collections. However, only CD8 was independent from age, tumor size, histology, and stage in multivariable analysis. High CD20 was associated with longer survival in the YTMA79 cohort. Conclusions: Increased levels of CD3 and CD8 + TILs are associated with better outcome in NSCLC, but only CD8 is independent from other prognostic variables. Objective measurement of TIL subpopulations could be useful to predict response or evaluate the local immune effect of anticancer immune checkpoint inhibitors.
    JNCI Journal of the National Cancer Institute 03/2015; 107(3). DOI:10.1093/jnci/dju435 · 15.16 Impact Factor
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    ABSTRACT: Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2,674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB, and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53, and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Human Molecular Genetics 01/2015; 24(8). DOI:10.1093/hmg/ddu749 · 6.68 Impact Factor
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    ABSTRACT: Programmed death 1 ligand 1 (PD-L1) is an immune regulatory molecule that limits anti-tumor immune activity. Targeting of PD-L1 and other immune checkpoint proteins has shown therapeutic activity in various tumor types. The expression of PD-L1 and its correlation with response to neoadjuvant chemotherapy in breast cancer has not been studied extensively. Our goal was to assess PD-L1 expression in a cohort of breast cancer patients treated with neoadjuvant chemotherapy.Pre-treatment biopsies from 105 breast cancer patients from Yale New Haven Hospital that subsequently received neoadjuvant chemotherapy were assessed for PD-L1 protein expression by automated quantitative analysis (AQUA) with a rabbit monoclonal antibody (E1L3N) to the cytoplasmic domain. Additionally, tumor infiltrating lymphocytes (TILs) were assessed on H&E slides.PD-L1 expression was observed in 30% of patients and it was positively associated with hormone receptor negative and triple-negative status and high levels of TILs. Both TILs and PD-L1 measured in the epithelium or stroma predicted pathological complete response (pCR) to neoadjuvant chemotherapy in univariate and multivariate analysis. However, since they are strongly associated, TILs and PD-L1 cannot both be included in a significant multivariate model.PD-L1 expression is prevalent in breast cancer, particularly hormone receptor negative and triple-negative patients, indicating a subset of patients which may benefit from immune therapy. Furthermore, PD-L1 and TILs correlate with pCR and high PD-L1 predicts pCR in multivariate analysis. Copyright © 2014, American Association for Cancer Research.
    12/2014; 3(4). DOI:10.1158/2326-6066.CIR-14-0133
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    ABSTRACT: Detection of biomolecules in tissues provides contextual information and the possibility to assess the interaction of different cell types and markers. Routine qualitative assessment of immune- and oligonucleotide-based methods in research and the clinic has been associated with assay variability because of lack of stringent validation and subjective interpretation of results. As a result, the vast majority of in situ assays in clinical usage are nonquantitative and, although useful, often of questionable scientific validity. Here, we revisit the reporters and methods used for single- and multiplexed in situ visualization of protein and RNA. Then we examine methods for the use of quantitative platforms for in situ measurement of protein and mRNA levels. Finally, we discuss the challenges of the transition of these methods to the clinic and their potential role as tools for development of companion diagnostic tests.Laboratory Investigation advance online publication, 15 December 2014; doi:10.1038/labinvest.2014.157.
    Laboratory Investigation 12/2014; 95(4). DOI:10.1038/labinvest.2014.157 · 3.83 Impact Factor
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    ABSTRACT: Context: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood. Objective: Utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations (CNA) present in ACC. Design: Screening for somatic mutation events and CNAs by comparative analysis of tumors and matched normal samples from 41 patients with ACC. Results: In total, 966 non-synonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2 and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41; 9.8% and 3/41; 7.3% respectively). Somatic mutations in ACC established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs. Conclusions: These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.
    Journal of Clinical Endocrinology &amp Metabolism 12/2014; 100(3):jc20143282. DOI:10.1210/jc.2014-3282 · 6.31 Impact Factor
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    ABSTRACT: Triple-negative breast cancer (TNBC) accounts for a disproportionate share of the total breast cancer morbidity because of its aggressive behavior and lack of effective targeted therapies to treat the disease. MicroRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are highly dysregulated in cancer. We identified miR-34a to be aberrantly lost in TNBC lines when compared to both a luminal cancer subtype as well as normal breast cells. Re-introduction of miR-34a into subcutaneous tumors in nude mice, as well as systemic delivery of poly(amine-co-ester) PACE-loaded miR-34a in an orthotopic setting, delayed tumor growth. In conclusion, re-introduction of miR-34a in TNBC promotes potent anti-tumorigenic phenotypes in vitro and in vivo, and could be promising targeted therapeutic agent to treat the disease.
    San Antonio Breast Cancer Symposium, San Antonio, TX; 12/2014
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    ABSTRACT: Triple-negative breast cancer (TNBC) accounts for a disproportionate share of the total breast cancer morbidity because of its aggressive behavior and lack of effective targeted therapies to treat the disease. MicroRNAs, global regulators of survival and proliferation pathways important in tumor development and maintenance, are highly dysregulated in cancer. We identified miR-34a to be aberrantly lost in TNBC lines when compared to both a luminal cancer subtype as well as normal breast cells. Re-introduction of miR-34a in TNBC lines results in inhibition of cell proliferation and invasion, reactivation of senescence, and enhanced sensitivity to apoptosis-inducing agents. Furthermore, intratumoral delivery of miR-34a into subcutaneous tumors in nude mice, as well as systemic delivery of poly(amine-co-ester) PACE-loaded miR-34a in an orthotopic setting, delayed tumor growth. In conclusion, re-introduction of miR-34a in TNBC promotes potent anti-tumorigenic phenotypes in vitro and in vivo, and could be a promising targeted therapeutic agent to treat the disease.
    The 37th Annual San Antonio Breast Cancer Symposium, San Antonio, TX; 12/2014
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    ABSTRACT: Background:Aberrant expression of microRNAs (miRNAs) is associated with cancer progression, initiation and metastasis. MiR34a is a miRNA that has been previously described as a tumour suppressor. Herein, we assess the expression of miR34a in three independent breast cancer cohorts using a quantitative in situ hybridisation assay (qISH) and determined its association with disease-specific death in breast cancer.Methods:The qISH method was applied to three independent primary breast cancer cohorts (Cohort 1 with 461, Cohort 2 with 279 and Cohort 3 with 795 patients) using 5' and 3' double DIG-labelled LNA-modified probe against miR34a using the protocol described previously. Level of expression measured as automated quantitative analysis (AQUA) score for miR34a was determined for each patient and assessed for association with risk of disease-specific death. An optimal cutpoint was determined using the X-tile software for disease-specific survival in Cohort 1 and this cutpoint was then applied to the other two cohorts after median normalisation of AQUA scores.Results:Loss of miR34a is associated with poor outcome in three independent breast cancer cohorts (uncorrected log-rank P=0.0188 for Cohort 1, log-rank P=0.0024 for Cohort 2 and log-rank P=0.0455 for Cohort 3). In all three cohorts, loss of miR34a is able to stratify patients with poor disease-specific survival among node-negative patients, but not in node-positive population. Multivariate Cox proportional hazards analysis in Cohort 1 (P=0.0381) and Cohort 2 (P=0.0468) revealed that loss of miR34a is associated with poor outcome, independent of age, node status, receptor status and tumour size.Conclusion:Loss of the tumour suppressor, miR34a, identifies a subgroup of breast cancer patients with poor disease-specific survival. This study is consistent with the well-established preclinical observations for miR34a as a tumour suppressor and suggests that miR34a may have future value as a biomarker in breast cancer.British Journal of Cancer advance online publication, 4 December 2014; doi:10.1038/bjc.2014.573 www.bjcancer.com.
    British Journal of Cancer 12/2014; 112(1). DOI:10.1038/bjc.2014.573 · 4.82 Impact Factor
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    ABSTRACT: Individualized targeted therapies for cancer patients require accurate and reproducible assessment of biomarkers to be able to plan treatment accordingly. Recent studies have shown highly variable effects of preanalytical variables on gene expression profiling and protein levels of different tissue types. Several publications have described protein degradation of tissue samples as a direct result of delay of formalin fixation of the tissue. Phosphorylated proteins are more labile and epitope degradation can happen within 30 min of cold ischemic time. To address this issue, we evaluated the change in antigenicity of a series of phosphoproteins in paraffin-embedded samples from breast tumors as a function of time to formalin fixation. A tissue microarray consisting of 93 breast cancer specimens with documented time-to-fixation was used to evaluate changes in antigenicity of 12 phosphoepitopes frequently used in research settings as a function of cold ischemic time. Analysis was performed in a quantitative manner using the AQUA technology for quantitative immunofluorescence. For each marker, least squares univariate linear regression was performed and confidence intervals were computed using bootstrapping. The majority of the epitopes tested revealed changes in expression levels with increasing time to formalin fixation. Some phosphorylated proteins, such as phospho-HSP27 and phospho-S6 RP, involved in post-translational modification and stress response pathways increased in expression or phosphorylation levels. Others (like phospho-AKT, phosphor-ERK1/2, phospho-Tyrosine, phospho-MET, and others) are quite labile and loss of antigenicity can be reported within 1-2 h of cold ischemic time. Therefore specimen collection should be closely monitored and subjected to quality control measures to ensure accurate measurement of these epitopes. However, a few phosphoepitopes (like phospho-JAK2 and phospho-ER) are sufficiently robust for routine usage in companion diagnostic testing.Laboratory Investigation advance online publication, 24 November 2014; doi:10.1038/labinvest.2014.139.
    Laboratory Investigation 11/2014; 95(3). DOI:10.1038/labinvest.2014.139 · 3.83 Impact Factor
  • International journal of radiation oncology, biology, physics 11/2014; 90(5). DOI:10.1016/j.ijrobp.2014.08.148 · 4.18 Impact Factor
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    ABSTRACT: Purpose: Approximately 40% of metastatic melanoma patients develop brain metastases. Our purpose was to identify genes aberrantly expressed in melanoma that might be associated with propensity for brain homing. Experimental Design: We studied gene expression profiles in a cell line model of brain metastasis (cerebrotropic A375Br cells versus parental A375P cells) and compared them to profiles of patients who developed early brain metastases and who did not. A tissue microarray containing 169 metastatic melanoma cases with variable time to brain metastasis was constructed to further study marker expression by quantitative immunofluorescence. An in vitro model of the blood brain barrier (BBB) was generated to evaluate potential mediators of brain metastases. Results:PLEKHA5 was differentially expressed in both the A375 cell line model and patient samples subjected to gene expression profiling. At the protein level, by quantitative immunofluorescence, PLEKHA5 was associated with decreased brain metastasis free survival. PLEKHA5 over-expression was not associated with other metastatic sites. Knock-down of PLEKHA5 decreases viability of A375Br cells, inhibits BBB transmigration and invasion in vitro. Similar results were found with YUMUL cells, cultured from a patient with overwhelming brain metastases. PLEKHA5 knock-down did not affect the viability of A375P cells. Conclusions: PLEKHA5 expression in melanoma tumors was associated with early development of brain metastases. Inhibition of PLEKHA5 might decrease passage across the BBB and decrease proliferation and survival of melanoma cells both in the brain and in extra-cerebral sites.
    Clinical Cancer Research 10/2014; 21(9). DOI:10.1158/1078-0432.CCR-14-0861 · 8.19 Impact Factor

Publication Stats

14k Citations
2,581.93 Total Impact Points

Institutions

  • 2000–2015
    • Yale University
      • School of Medicine
      New Haven, Connecticut, United States
  • 1994–2015
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 2013
    • University of Pennsylvania
      • "Abramson" Cancer Center
      Philadelphia, Pennsylvania, United States
  • 2012
    • Dana-Farber Cancer Institute
      • Department of Medical Oncology
      Boston, MA, United States
  • 2011
    • University of Texas MD Anderson Cancer Center
      • Department of Systems Biology
      Houston, Texas, United States
  • 2008
    • NYU Langone Medical Center
      • Department of Cell Biology
      New York, New York, United States
  • 2007
    • Fox Chase Cancer Center
      Filadelfia, Pennsylvania, United States
  • 2005
    • George Washington University
      Washington, Washington, D.C., United States
  • 2003
    • Los Alamos National Laboratory
      Лос-Аламос, California, United States
    • Robert Wood Johnson University Hospital
      New Brunswick, New Jersey, United States
  • 1999
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
    • University of Michigan
      • Medical School
      Ann Arbor, Michigan, United States
  • 1998
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York City, NY, United States
  • 1996–1997
    • Virginia Commonwealth University
      • Department of Pathology
      Richmond, Virginia, United States
  • 1986–1997
    • Johns Hopkins University
      • • Department of Cell Biology
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 1995
    • Cold Spring Harbor Laboratory
      Cold Spring Harbor, New York, United States
  • 1988–1991
    • Johns Hopkins Medicine
      • Department of Molecular Biology and Genetics
      Baltimore, Maryland, United States