David Sidransky

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (461)3723.35 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We examined the relationship between the O(6)-methylguanine-methyltransferase (MGMT) methylation status and clinical outcomes in newly diagnosed glioblastoma multiforme (GBM) patients who were treated with Gliadel wafers (Eisai, Tokyo, Japan). MGMT promoter methylation has been associated with increased survival among patients with GBM who are treated with various alkylating agents. MGMT promoter methylation, in DNA from 122 of 160 newly diagnosed GBM patients treated with Gliadel, was determined by a quantitative methylation-specific polymerase chain reaction, and was correlated with overall survival (OS) and recurrence-free survival (RFS). The MGMT promoter was methylated in 40 (32.7%) of 122 patients. The median OS was 13.5 months (95% confidence interval [CI] 11.0-14.5) and RFS was 9.4 months (95% CI 7.8-10.2). After adjusting for age, Karnofsky performance score, extent of resection, temozolomide (TMZ) and radiation therapy (RT), the newly diagnosed GBM patients with MGMT methylation had a 15% reduced mortality risk, compared to patients with unmethylated MGMT (hazard ratio 0.85; 95% CI 0.56-1.31; p=0.46). The patients aged over 70years with MGMT methylation had a significantly longer median OS of 13.5months, compared to 7.6months in patients with unmethylated MGMT (p=0.027). A significant difference was also found in older patients, with a median RFS of 13.1 versus 7.6months for methylated and unmethylated MGMT groups, respectively (p=0.01). Methylation of the MGMT promoter in newly diagnosed GBM patients treated with Gliadel, RT and TMZ, was associated with significantly improved OS compared to the unmethylated population. In elderly patients, methylation of the MGMT promoter was associated with significantly better OS and RFS. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Clinical Neuroscience 08/2015; DOI:10.1016/j.jocn.2015.07.003 · 1.32 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):811-811. DOI:10.1158/1538-7445.AM2015-811 · 9.28 Impact Factor
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    ABSTRACT: To explore the potential of tumor-specific DNA as a biomarker for head and neck squamous cell carcinomas (HNSCC), we queried DNA from saliva or plasma of 93 HNSCC patients. We searched for somatic mutations or human papillomavirus genes, collectively referred to as tumor DNA. When both plasma and saliva were tested, tumor DNA was detected in 96% of 47 patients. The fractions of patients with detectable tumor DNA in early- and late-stage disease were 100% (n = 10) and 95% (n = 37), respectively. When segregated by site, tumor DNA was detected in 100% (n = 15), 91% (n = 22), 100% (n = 7), and 100% (n = 3) of patients with tumors of the oral cavity, oropharynx, larynx, and hypopharynx, respectively. In saliva, tumor DNA was found in 100% of patients with oral cavity cancers and in 47 to 70% of patients with cancers of the other sites. In plasma, tumor DNA was found in 80% of patients with oral cavity cancers, and in 86 to 100% of patients with cancers of the other sites. Thus, saliva is preferentially enriched for tumor DNA from the oral cavity, whereas plasma is preferentially enriched for tumor DNA from the other sites. Tumor DNA in saliva was found postsurgically in three patients before clinical diagnosis of recurrence, but in none of the five patients without recurrence. Tumor DNA in the saliva and plasma appears to be a potentially valuable biomarker for detection of HNSCC. Copyright © 2015, American Association for the Advancement of Science.
    Science translational medicine 06/2015; 7(293):293ra104. DOI:10.1126/scitranslmed.aaa8507 · 14.41 Impact Factor
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    ABSTRACT: Triple negative breast cancer has an extremely poor prognosis when chemotherapy is no longer effective. To overcome drug resistance, novel drug delivery systems based on nanoparticles have had remarkable success. We produced a novel nanoparticle component ‘MDC’ from milk-derived colloid. In order to evaluate the anti-cancer effect of MDC, we conducted in vitro and in vivo experiments on cancer cell lines and a primary tumor derived breast xenograft. Doxorubicin (Dox) conjugated to MDC (MDC-Dox) showed higher cancer cell growth inhibition than MDC alone especially in cell lines with high EGFR expression. In a mouse melanoma model, MDC-Dox significantly suppressed tumor growth when compared with free Dox. Moreover, in a primary tumor derived breast xenograft, one of the mice treated with MDC-Dox showed partial regression, while mice treated with free Dox failed to show any suppression of tumor growth. We have shown that a novel nanoparticle compound made of simple milk-derived colloid has the capability for drug conjugation, and serves as a tumor-specific carrier of anti-cancer drugs. Further research on its safety and ability to carry various anti-cancer drugs into multiple drug-resistant primary breast models is warranted.
    Cancer biology & therapy 05/2015; 16(8):1184-1193. DOI:10.1080/15384047.2015.1056416 · 3.63 Impact Factor
  • Evgeny Izumchenko · David Sidransky
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    ABSTRACT: With multiple clinical trials under way targeting mutant EGFR in patients with lung cancer, Maity and colleagues address important aspects of a MIG6-EGFR signaling axis using genetically engineered mouse models expressing mutated EGFRs on the MIG6-deficient background. This study extends our understanding of EGFR regulation by MIG6 and reveals that MIG6 antagonizes tumor formation in mutant EGFR-driven lung adenocarcinoma. Cancer Discov; 5(5); 472-4. ©2015 AACR. See related article by Maity et al., p. 534. ©2015 American Association for Cancer Research.
    Cancer Discovery 05/2015; 5(5):472-4. DOI:10.1158/2159-8290.CD-15-0336 · 19.45 Impact Factor
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    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.
    Seminars in Cancer Biology 04/2015; DOI:10.1016/j.semcancer.2015.03.005 · 9.33 Impact Factor
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    ABSTRACT: Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), was shown to be active in colorectal cancer. Although some patients who harbor K-ras wild-type tumors benefit from cetuximab treatment, 40 to 60% of patients with wild-type K-ras tumors do not respond to cetuximab. Currently, there is no universal marker or method of clinical utility that could guide the treatment of cetuximab in colorectal cancer. Here, we demonstrate a method to predict response to cetuximab in patients with colorectal cancer using OncoFinder pathway activation strength (PAS), based on the transcriptomic data of the tumors. We first evaluated our OncoFinder pathway activation strength model in a set of transcriptomic data obtained from patient-derived xenograft (PDx) models established from colorectal cancer biopsies. Then, the approach and models were validated using a clinical trial data set. PAS could efficiently predict patients' response to cetuximab, and thus holds promise as a selection criterion for cetuximab treatment in metastatic colorectal cancer.
    04/2015; 2. DOI:10.1038/hgv.2015.9
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    ABSTRACT: Correct apicobasal polarization and intercellular adhesions are essential for the appropriate development of normal epithelia. Here, we investigated the contribution of the cell polarity regulator PARD3 to the development of lung squamous cell carcinomas (LSCC). Tumor-specific PARD3 alterations were found in 8% of LSCCs examined, placing PARD3 among the most common tumor suppressor genes in this malignancy. Most PAR3-mutant proteins exhibited a relative reduction in the ability to mediate formation of tight junctions and actin-based protrusions, bind atypical protein kinase C, activate RAC1, and activate STAT3 at cell confluence. Thus, PARD3 alterations prevented the formation of contacts between neighboring cells and the subsequent downstream signaling. Notably, reconstituting PAR3 activity in vivo reduced tumor-invasive and metastatic properties. Our findings define PARD3 as a recurrently inactivated cell polarity regulator in LSCC that affects tumor aggressiveness and metastasis. Cancer Res; 75(7); 1287-97. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Research 04/2015; 75(7):1287-97. DOI:10.1158/0008-5472.CAN-14-2444 · 9.28 Impact Factor
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    ABSTRACT: A majority of high grade (HG) serous ovarian cancer (SOC) patients develop resistant disease despite high initial response rates to platinum/paclitaxel-based chemotherapy. We identified shed/secreted proteins in pre-clinical models of paclitaxel-resistant human HGSOC models and correlated these candidate proteins with patient outcomes using public data from HGSOC patients. Proteomic analyses of a HGSOC cell line secretome was compared to those from a syngeneic paclitaxel-resistant variant and from a line established from an intrinsically chemorefractory HGSOC patient. Associations between the identified candidate proteins and patient outcome were assessed in a discovery cohort of 545 patients and two validation cohorts totaling 795 independent SOC patients. Among the 81 differentially abundant proteins identified (q<0.05) from paclitaxel-sensitive vs -resistant HGSOC cell secretomes, AKAP12 was verified to be elevated in all models of paclitaxel-resistant HGSOC. Further, elevated AKAP12 transcript expression was associated with worse progression-free and overall survival. Associations with outcome were observed in three independent cohorts and remained significant after adjusted multivariate modeling. We further provide evidence to support that differential gene methylation status is associated with elevated expression of AKAP12 in taxol-resistant ovarian cancer cells and ovarian cancer patient subsets. Elevated expression and shedding/secretion of AKAP12 is characteristic of paclitaxel-resistant HGSOC cells and elevated AKAP12 transcript expression is a poor prognostic and predictive marker for progression-free and overall survival in SOC patients.
    Journal of Proteome Research 03/2015; 14(4). DOI:10.1021/pr5012894 · 5.00 Impact Factor
  • Seminars in Cancer Biology 03/2015; accepted for publication. · 9.33 Impact Factor
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    ABSTRACT: Genomic instability can initiate cancer, augment progression, and influence the overall prognosis of the affected patient. Genomic instability arises from many different pathways, such as telomere damage, centrosome amplification, epigenetic modifications, and DNA damage from endogenous and exogenous sources, and can be perpetuating, or limiting, through the induction of mutations or aneuploidy, both enabling and catastrophic. Many cancer treatments induce DNA damage to impair cell division on a global scale but it is accepted that personalized treatments, those that are tailored to the particular patient and type of cancer, must also be developed. In this review, we detail the mechanisms from which genomic instability arises and can lead to cancer, as well as treatments and measures that prevent genomic instability or take advantage of the cellular defects caused by genomic instability. In particular, we identify and discuss five priority targets against genomic instability: (1) prevention of DNA damage; (2) enhancement of DNA repair; (3) targeting deficient DNA repair; (4) impairing centrosome clustering; and, (5) inhibition of telomerase activity. Moreover, we highlight vitamin D and B, selenium, carotenoids, PARP inhibitors, resveratrol, and isothiocyanates as priority approaches against genomic instability. The prioritized target sites and approaches were cross validated to identify potential synergistic effects on a number of important areas of cancer biology.
    Seminars in Cancer Biology 03/2015; ePub ahead of print. · 9.33 Impact Factor
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    ABSTRACT: The Notch pathway is frequently altered in HNSCCs, however the clinical significance of NOTCH1 dysregulation is poorly understood. This study was designed to characterize expression of the transcriptionally active NOTCH1 Intracellular Domain (NICD1) in HNSCCs and evaluate its association with NOTCH1 mutation status and clinical parameters. Immunohistochemistry for NICD1 was performed on 79 previously sequenced archival HNSCCs with known NOTCH1 mutation status. Three distinct immunohistochemical staining patterns were identified: positive/peripheral (47%), positive/non-peripheral (34%) and negative (19%). NICD1 expression was associated with NOTCH1 mutation status (p<0.001). Most NOTCH1-wild type tumors were peripheral (55%), while mutated NOTCH1 tumors were most commonly negative (47%). Non-peripheral tumors were more likely than peripheral tumors to have extracapsular spread (aOR 16.01, 95%CI=1.92-133.46, p=0.010) and poor differentiation (aOR 5.27, 95%CI=0.90-30.86, p=0.066). Negative staining tumors tended to be poorly differentiated (aOR 24.71, 95%CI=1.53-399.33, p=0.024) and were less likely to be HPV-positive (aOR 0.043, 95%CI=0.001-1.59, p=0.087). NOTCH1 mutagenesis was significantly associated with HPV status, with NOTCH1-wild-type tumors more likely to be HPV-positive than NOTCH1-mutated tumors (aOR 19.06, 95%CI=1.31-276.15, p=0.031). TP53 disruptive mutations were not associated with NICD1 expression or NOTCH1 mutation. In conclusion, NICD1 is expressed in three distinct patterns in HNSCC that are significantly associated with high-risk features. These findings further support a dual role for NOTCH1 as both tumor suppressor and oncogene in HNSCC. Further research is necessary to clarify the role of NOTCH1 in HNSCC and understand the clinical and therapeutic implications therein. Copyright © 2015, American Association for Cancer Research.
    Cancer Prevention Research 01/2015; 8(4). DOI:10.1158/1940-6207.CAPR-14-0366 · 5.27 Impact Factor
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    ABSTRACT: Exposure to toxicants leads to cumulative molecular changes that over time increase a subject's risk of developing urothelial carcinoma (UC). To assess the impact of arsenic exposure at a time progressive manner, we developed and characterized a cell culture model and tested a panel of miRNAs in urine samples from arsenic exposed subjects, UC patients and controls. To prepare an in vitro model, we chronically exposed an immortalized normal human bladder cell line (HUC1) to arsenic. Growth of the HUC1 cells was increased in a time dependent manner after arsenic treatment and cellular morphology was changed. In soft agar assay, colonies were observed only in arsenic treated cells and the number of colonies gradually increased with longer periods of treatment. Similarly, invaded cells in invasion assay were observed only in arsenic treated cells. Withdrawal of arsenic treatment for 2.5 months did not reverse the tumorigenic properties of arsenic treated cells. Western blot analysis demonstrated decreased PTEN and increased AKT and mTOR in arsenic treated HUC1 cells. Levels of miR-200a, miR-200b, and miR-200c were down-regulated in arsenic exposed HUC1 cells by quantitative RT-PCR. Furthermore, in human urine, miR-200c and miR-205 were inversely associated with arsenic exposure (P=0.005 and 0.009, respectively). Expression of miR-205 discriminated cancer cases from controls with high sensitivity and specificity (AUC=0.845). Our study suggests that exposure to arsenic rapidly induces a multifaceted dedifferentiation program and miR-205 has potential to be used as a marker of arsenic exposure as well as a maker of early UC detection. Copyright © 2015, American Association for Cancer Research.
    Cancer Prevention Research 01/2015; 8(3). DOI:10.1158/1940-6207.CAPR-14-0251 · 5.27 Impact Factor
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    ABSTRACT: A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit. In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m(2) IV on day 1 followed by 250mg/m(2) IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed. Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0months in Arm A, and 5.7 and 3.2months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7months; adjusted p-value: 0.015), regardless of study arms. A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Oral Oncology 01/2015; 51(4). DOI:10.1016/j.oraloncology.2014.12.011 · 3.03 Impact Factor
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    ABSTRACT: Cysteine biology is important for the chemosensitivity of cancer cells. Our research has focused on the epigenetic silencing of cysteine dioxygenase type 1 (CDO1) in colorectal cancer (CRC). In this study, we describe detection of CDO1 methylation in the plasma of CRC patients using methylation specific PCR (Q-MSP) and extensive analysis of the PCR reaction. DNA was extracted from plasma, and analysed for methylation of the CDO1 gene using Q-MSP. The detection rate of CDO1 gene methylation was calculated and compared with that of diluted DNA extracted from "positive control" DLD1 cells. CDO1 gene methylation in the plasma of 40 CRC patients that were clinicopathologically analysed was then determined. (1) The cloned sequence analysis detected 93.3% methylation of the promoter CpG islands of the CDO1 gene of positive control DLD1 cells and 4.7% methylation of the negative control HepG2 CDO1 gene. (2) DLD1 CDO1 DNA could not be detected in this assay if the extracted DNA was diluted ∼1000 fold. The more DNA that was used for the PCR reaction, the more effectively it was amplified in Q-MSP. (3) By increasing the amount of DNA used, methylated CDO1 could be clearly detected in the plasma of 8 (20%) of the CRC patients. However, the percentage of CRC patients detected by methylated CDO1 in plasma was lower than that detected by CEA (35.9%) or CA19-9 (23.1%) in preoperative serum. Combination of CEA/CA19-9 plus plasma methylated CDO1 could increase the rate of detection of curable CRC patients (39.3%) as compared to CEA/CA19-9 (25%). We have described detection of CDO1 methylation in the plasma of CRC patients. Although CDO1 methylation was not detected as frequently as conventional tumor markers, analysis of plasma CDO1 methylation in combination with CEA/CA19-9 levels increases the detection rate of curable CRC patients.
    PLoS ONE 12/2014; 9(12):e113546. DOI:10.1371/journal.pone.0113546 · 3.23 Impact Factor
  • Molecular Cancer Research 12/2014; 12(12 Supplement):B25-B25. DOI:10.1158/1557-3125.RASONC14-B25 · 4.50 Impact Factor
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    ABSTRACT: Disruption of NOTCH1 signaling was recently discovered in head and neck cancer. This study aims to evaluate NOTCH1 alterations in the progression of oral squamous cell carcinoma (OSCC) and compare the occurrence of these mutations in Chinese and Caucasian populations. We used a high-throughput-PCR-based enrichment technology and next generation sequencing (NGS) to sequence NOTCH1 in 144 samples collected in China. Forty nine samples were normal oral mucosa from patients undergoing oral surgery, 45 were oral leukoplakia biopsies and 50 were chemoradiation naïve OSCC samples with 22 paired-normal tissues from the adjacent unaffected areas. NOTCH1 mutations were found in 54% of primary OSCC and 60% of pre-malignant lesions. Importantly, almost 60% of leukoplakia patients with mutated NOTCH1 carried mutations that were also identified in OSCC, indicating an important role of these clonal events in the progression of early neoplasms. We then compared all known NOTCH1 mutations identified in Chinese OSCC patients with those reported in Caucasians to date. Although we found obvious overlaps in critical regulatory NOTCH1 domains alterations and identified specific mutations shared by both groups, possible gain-of-function mutations were predominantly seen in Chinese population. Our findings demonstrate that pre-malignant lesions display NOTCH1 mutations at an early stage and are thus bona fide drivers of OSCC progression. Moreover, our results reveal that NOTCH1 promotes distinct tumorigenic mechanisms in patients from different ethnical populations. Copyright © 2014, American Association for Cancer Research.
    Cancer Prevention Research 11/2014; 8(4). DOI:10.1158/1940-6207.CAPR-14-0257 · 5.27 Impact Factor
  • Cancer Epidemiology Biomarkers & Prevention 11/2014; 23(11 Supplement):PR6-PR6. DOI:10.1158/1538-7755.DISP13-PR6 · 4.32 Impact Factor
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    M Nacht · T Dracheva · Y Gao · T Fujii · Y Chen · A Player · V Akmaev · B Cook · M Dufault · M Zhang · W Zhang · M Guo · J Curran · S Han · D Sidransky · K Buetow · S L Madden · J Jen
  • G. Baia · D. Vasquez · D. Ciznadija · D. Sidransky · A. Katz · K. Paz
    European Journal of Cancer 11/2014; 50. DOI:10.1016/S0959-8049(14)70321-1 · 4.82 Impact Factor

Publication Stats

24k Citations
3,723.35 Total Impact Points

Institutions

  • 1993–2015
    • Johns Hopkins University
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Medicine
      Baltimore, Maryland, United States
  • 2014
    • Hospital Universitario Madrid Sanchinarro
      Madrid, Madrid, Spain
  • 1994–2014
    • Johns Hopkins Medicine
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Sidney Kimmel Comprehensive Cancer Center
      • • Department of Pediatric Neurology
      Baltimore, Maryland, United States
  • 2012
    • Kitasato University
      Edo, Tōkyō, Japan
  • 2011
    • Greater Baltimore Medical Center
      Baltimore, Maryland, United States
  • 2006–2008
    • University of Ulsan
      • College of Medicine
      Urusan, Ulsan, South Korea
    • University of Porto
      • Department of Molecular Pahology and Immunology
      Oporto, Porto, Portugal
  • 2000–2007
    • The Australian Society of Otolaryngology Head & Neck Surgery
      Evans Head, New South Wales, Australia
  • 2002
    • National Cheng Kung University Hospital
      • Department of Pediatrics
      臺南市, Taiwan, Taiwan
  • 2001–2002
    • University of Rochester
      • Department of Surgery
      Rochester, New York, United States
    • Dong-Pusan College
      Tsau-liang-hai, Busan, South Korea