Lee M Ellis

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (354)2743.04 Total impact

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    ABSTRACT: The decision by journals to append protocols to published reports of randomized trials was a landmark event in clinical trial reporting. However, limited information is available on how this initiative effected transparency and selective reporting of clinical trial data. We analyzed 74 oncology-based randomized trials published in Journal of Clinical Oncology, the New England Journal of Medicine, and The Lancet in 2012. To ascertain integrity of reporting, we compared published reports with their respective appended protocols with regard to primary end points, nonprimary end points, unplanned end points, and unplanned analyses. A total of 86 primary end points were reported in 74 randomized trials; nine trials had greater than one primary end point. Nine trials (12.2%) had some discrepancy between their planned and published primary end points. A total of 579 nonprimary end points (median, seven per trial) were planned, of which 373 (64.4%; median, five per trial) were reported. A significant positive correlation was found between the number of planned and nonreported nonprimary end points (Spearman r = 0.66; P < .001). Twenty-eight studies (37.8%) reported a total of 65 unplanned end points; 52 (80.0%) of which were not identified as unplanned. Thirty-one (41.9%) and 19 (25.7%) of 74 trials reported a total of 52 unplanned analyses involving primary end points and 33 unplanned analyses involving nonprimary end points, respectively. Studies reported positive unplanned end points and unplanned analyses more frequently than negative outcomes in abstracts (unplanned end points odds ratio, 6.8; P = .002; unplanned analyses odd ratio, 8.4; P = .007). Despite public and reviewer access to protocols, selective outcome reporting persists and is a major concern in the reporting of randomized clinical trials. To foster credible evidence-based medicine, additional initiatives are needed to minimize selective reporting. © 2015 by American Society of Clinical Oncology.
    Journal of Clinical Oncology 08/2015; DOI:10.1200/JCO.2015.62.4148 · 18.43 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):2337-2337. DOI:10.1158/1538-7445.AM2015-2337 · 9.33 Impact Factor
  • Lee M Ellis ·

    The Lancet Oncology 07/2015; 16(7). DOI:10.1016/S1470-2045(15)00085-6 · 24.69 Impact Factor
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    ABSTRACT: A large number of pseudogenes have been found to be transcribed in human cancers. However, only a few pseudogenes are functionally characterized. Here, we identified a transcribed pseudogene of vascular endothelial growth factor receptor-1 (VEGFR1), or fmsrelated tyrosine kinase 1 (FLT1), in human colorectal cancer (CRC) cells. Interestingly, this pseudogene (designated as FLT1P1) was found to be transcribed bidirectionally and functionally modulated cognate VEGFR1 protein expression in the cells. Mechanistically, expression of FLT1P1 antisense transcript not only inhibited the VEGFR1 expression, but also inhibited non-cognate VEGF-A expression through interaction with miR-520a. Perturbation of FLT1P1 expression by RNA interference (RNAi) markedly inhibited tumor cell proliferation and xenograft tumor growth. This study identifies FLT1P1 antisense as a critical regulator of VEGFR1 and VEGF-A expression in CRC cells, and highlights its role in regulation of the pathogenesis of CRC. The VEGFR1 pseudogene, FLT1P1, is a novel and functional regulator of VEGF signaling and its targeting could be an alternative strategy to modulate its cognate/target gene expression and downstream activity in cancer. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Research 06/2015; 13(9). DOI:10.1158/1541-7786.MCR-15-0061 · 4.38 Impact Factor
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    ABSTRACT: TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours. A tremendous effort has been made to restore p53 activity in cancer therapies. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53 loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity. However, we found that α-amanitin-based antibody-drug conjugates are highly effective therapeutic agents with reduced toxicity. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.
    Nature 04/2015; 520(7549). DOI:10.1038/nature14418 · 41.46 Impact Factor
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    F Fan · S Bellister · J Lu · X Ye · D R Boulbes · F Tozzi · E Sceusi · S Kopetz · F Tian · L Xia · Y Zhou · R Bhattacharya · L M Ellis ·
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    ABSTRACT: Background: Isolation of colorectal cancer (CRC) cell populations enriched for cancer stem cells (CSCs) may facilitate target identification. There is no consensus regarding the best methods for isolating CRC stem cells (CRC-SCs). We determined the suitability of various cellular models and various stem cell markers for the isolation of CRC-SCs. Methods: Established human CRC cell lines, established CRC cell lines passaged through mice, patient-derived xenograft (PDX)-derived cells, early passage/newly established cell lines, and cells directly from clinical specimens were studied. Cells were FAC-sorted for the CRC-SC markers CD44, CD133, and aldehyde dehydrogenase (ALDH). Sphere formation and in vivo tumorigenicity studies were used to validate CRC-SC enrichment. Results: None of the markers studied in established cell lines, grown either in vitro or in vivo, consistently enriched for CRC-SCs. In the three other cellular models, CD44 and CD133 did not reliably enrich for stemness. In contrast, freshly isolated PDX-derived cells or early passage/newly established CRC cell lines with high ALDH activity formed spheres in vitro and enhanced tumorigenicity in vivo, whereas cells with low ALDH activity did not. Conclusions: PDX-derived cells, early passages/newly established CRC cell lines and cells from clinical specimen with high ALDH activity can be used to identify CRC-SC-enriched populations. Established CRC cell lines should not be used to isolate CSCs.
    British Journal of Cancer 12/2014; 112(3). DOI:10.1038/bjc.2014.620 · 4.84 Impact Factor
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    ABSTRACT: Purpose: This study aimed to detect cell-surface vimentin (CSV) on the surface of epithelial-mesenchymal transitioned (EMT) circulating tumor cells (CTCs) from blood of patients with epithelial cancers. Experimental Design: In this study, 101 patients undergoing post-surgery adjuvant chemotherapy for metastatic colon cancer were recruited. EMT CTCs were detected from blood of patients using 84-1 monoclonal antibody against CSV as a marker. EMT CTCs isolated were characterized further using EMT-specific markers, fluorescent in situ hybridization and single cell mutation analysis. Results: Using 84-1 antibody, we detected CSV exclusively on EMT CTCs from a variety of tumor types but not in the surrounding normal cells in the blood. The antibody exhibited very high specificity and sensitivity towards different epithelial cancer cells. With this antibody, we detected and enumerated EMT CTCs from patients. From our observations, we defined a cutoff of < five or ≥ five EMT CTCs as optimal threshold with respect to therapeutic response using ROC curves. Using this defined threshold, the presence of ≥ five EMT CTCs was associated with progressive disease, while patients with less than five EMT CTCs showed therapeutic response. Conclusion: Taken together, number of EMT CTCs detected correlated with the therapeutic outcome of the disease. These results establish cell-surface vimentin as a universal marker for EMT CTCs from a wide variety of tumor types and thus provide the foundation for emerging CTC detection technologies and for studying the molecular regulation of these EMT CTCs. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 12/2014; 21(4). DOI:10.1158/1078-0432.CCR-14-0894 · 8.72 Impact Factor

  • Molecular Cancer Research 12/2014; 12(12 Supplement):B47-B47. DOI:10.1158/1557-3125.RASONC14-B47 · 4.38 Impact Factor
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    ABSTRACT: Predictive biomarkers are becoming increasingly important tools in drug development and clinical research. The importance of using both guidelines for specimen acquisition and analytical methods for biomarker measurements that are standardized has become recognized widely as an important issue, which must be addressed in order to provide high-quality, validated assays. Herein, we review the major challenges in biomarker validation processes, including pre-analytical (sample-related), analytical, and post-analytical (data-related) aspects of assay development. Recommendations for improving biomarker assay development and method validation are proposed to facilitate the use of predictive biomarkers in clinical trials and the practice of oncology.
    Nature Reviews Clinical Oncology 11/2014; 12(4). DOI:10.1038/nrclinonc.2014.202 · 14.18 Impact Factor
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    ABSTRACT: Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies. Experimental design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥ 6 months, complete response, or partial response. Two odds ratios (OR) for achieving clinical benefit were calculated: one for patients treated with VEGF/R inhibitors (OR with VEGF/R) and another for patients treated without (OR without VEGF/R). To compare these two ORs, an interaction term was included in the multivariate model: (chemotherapy/factor of interest)×(VEGF/R). We took significant interaction terms (Pinteraction < 0.05) to suggest effect modification (either synergy or antagonism) with VEGF/R inhibitors. Results: All patients treated with VEGF/R inhibitors exhibited higher OR for clinical benefit than those who were not [OR = 1.9; 95% confidence interval (CI), 1.5-2.4; P < 0.0001]. Use of chemotherapy agents concomitant with VEGF/R inhibitors was associated with significantly higher OR for clinical benefit compared with chemotherapy use without VEGF/R inhibitors [OR with VEGF/R = 1.6 (95% CI, 1.1-2.5) vs. OR without VEGF/R = 0.4 (95% CI, 0.3-0.6), Pinteraction = 0.02]. Specifically, the antimetabolite class was associated with the greatest increase in OR for clinical benefit [OR with VEGF/R = 2.7 (95% CI, 1.5-4.7) vs. OR without VEGF/R = 0.2 (95% CI 0.1-0.3), Pinteraction = 0.004]. Conclusions: VEGF/R inhibitor was found to synergize with chemotherapeutics. This effect was most pronounced with the antimetabolite class.
    Clinical Cancer Research 10/2014; 20(23). DOI:10.1158/1078-0432.CCR-14-1582 · 8.72 Impact Factor
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    ABSTRACT: Despite being amongst the most common oncogenes in human cancer, to date there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking-down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed anti-proliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nano-liposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were utilized to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis and down-stream signaling. KRAS siRNA sequences induced >90% knock-down of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, while significant increases in caspase-3 activity was only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional "undruggable" targets.
    Molecular Cancer Therapeutics 10/2014; 13(12). DOI:10.1158/1535-7163.MCT-14-0074 · 5.68 Impact Factor
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    ABSTRACT: Anticancer drugs are combined in an effort to treat a heterogeneous tumor or to maximize the pharmacodynamic effect. The development of combination regimens, while desirable, poses unique challenges. These include the selection of agents for combination therapy that may lead to improved efficacy while maintaining acceptable toxicity, the design of clinical trials that provide informative results for individual agents and combinations, and logistic and regulatory challenges. The phase I trial is often the initial step in the clinical evaluation of a combination regimen. In view of the importance of combination regimens and the challenges associated with developing them, the Clinical Trial Design (CTD) Task Force of the National Cancer Institute Investigational Drug Steering Committee developed a set of recommendations for the phase I development of a combination regimen. The first two recommendations focus on the scientific rationale and development plans for the combination regimen; subsequent recommendations encompass clinical design aspects. The CTD Task Force recommends that selection of the proposed regimens be based on a biologic or pharmacologic rationale supported by clinical and/or robust and validated preclinical evidence, and accompanied by a plan for subsequent development of the combination. The design of the phase I clinical trial should take into consideration the potential pharmacokinetic and pharmacodynamic interactions as well as overlapping toxicity. Depending on the specific hypothesized interaction, the primary endpoint may be dose optimization, pharmacokinetics, and/or pharmacodynamics (i.e., biomarker). Clin Cancer Res; 20(16); 4210-7. ©2014 AACR.
    Clinical Cancer Research 08/2014; 20(16):4210-4217. DOI:10.1158/1078-0432.CCR-14-0521 · 8.72 Impact Factor
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    Journal of Clinical Oncology 03/2014; 32(12). DOI:10.1200/JCO.2013.53.8009 · 18.43 Impact Factor
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    ABSTRACT: The current study was conducted to determine whether quantified pathologic response assessed as a percentage of residual tumor cells is predictive of recurrence-free survival (RFS) in patients with rectal cancer. The authors studied 251 patients with rectal adenocarcinoma who were treated with neoadjuvant chemoradiation and radical resection. Quantified pathologic response was defined as an estimated percentage of residual cancer cells in relation to the tumor bed: complete, no residual cancer cells; near-complete, ≤ 5% residual cancer cells; major, > 5%, and < 50% residual cancer cells; and minor, ≥ 50% residual cancer cells. The reproducibility of quantified pathologic response between 2 pathologists was assessed using tumors from 55 randomly selected patients who did not demonstrate a complete response. Pathologic response was complete in 21% of patients, near-complete in 20% of patients, major in 37% of patients, and minor in 22% of patients. Nineteen percent of patients had ypT0N0 disease, 27% had ypT1-2N0 disease, 21% had ypT3-4N0 disease, and 33% had N+ disease. The 5-year RFS rates by category of quantified pathologic response were as follows: complete, 95%; near-complete, 88%; major, 69%; and minor, 61% (P < .001). Major and minor response, high histologic grade, and perineural invasion were found to be significant predictors of decreased RFS on multivariate analysis. The 5-year RFS rates for patients with ypT3-4 or N+ disease were better for those with a near-complete response (94%) compared with those with a major (64%) or minor (61%) response (P < .02). Moderate to substantial agreement was observed between the 2 pathologists (κ = 0.72). Quantified pathologic response is a predictor of RFS in patients with rectal adenocarcinoma and stratifies patients with high pathologic stage disease. Cancer 2013. © 2013 American Cancer Society.
    Cancer 12/2013; 119(24). DOI:10.1002/cncr.28331 · 4.89 Impact Factor
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    ABSTRACT: Metastasis and drug resistance are the major limitations in the survival and management of cancer patients. This study aimed to identify the mechanisms underlying HT29 colon cancer cell chemoresistance acquired after sequential exposure to 5-fluorouracil (5FU), a classical anticancer drug for treatment of epithelial solid tumors. We examined its clinical relevance in a cohort of colon cancer patients with liver metastases after 5FU-based neoadjuvant chemotherapy and surgery. We show that a clonal 5F31 cell population, resistant to 1μM 5FU, express a typical cancer stem cell-like phenotype and enter into a reversible quiescent G0-state upon re-exposure to higher 5FU concentrations. These quiescent cells overexpressed the tyrosine kinase c-Yes that became activated and membrane-associated upon 5FU exposure. This enhanced signaling pathway induced the dissociation of the Yes/YAP (Yes-associated protein) molecular complex and depleted nuclear YAP levels. Consistently, c-Yes silencing decreased nuclear YAP accumulation and induced cellular quiescence in 5F31 cells cultured in 5FU-free medium. Importantly, c-Yes and YAP transcript levels were higher in liver metastases of colon cancer patients after 5FU-based neoadjuvant chemotherapy. Moreover, the c-Yes and YAP levels positively correlated with colon cancer relapse and shorter patient survival (p<0.05 and p<0.025, respectively). We identified c-Yes and YAP as potential molecular targets to eradicate quiescent cancer cells and dormant micrometastases during 5FU chemotherapy and resistance and as predictive survival markers for colon cancer.
    Clinical Cancer Research 12/2013; 20(4). DOI:10.1158/1078-0432.CCR-13-1854 · 8.72 Impact Factor
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    Jing Yi · Wei Xiong · Xing Gong · Seth Bellister · Lee M Ellis · Qingyun Liu ·
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    ABSTRACT: LGR4 is an R-spondin receptor with strong positive effect on Wnt signaling. It plays a critical role in development as its ablation in the mouse led to total embryonic/neonatal lethality with profound defects in multiple organs. Haplotype insufficiency of LGR4 in human was associated with several diseases, including increased risk of squamous cell carcinoma of the skin, reduced birth weights, electrolyte imbalance, and decreased levels of testosterone, which are similar to the phenotypes of LGR4-hypomorphic mice. Tissue distribution of LGR4 was extensively analyzed in the mouse using gene-trap reporter enzyme alleles. However, its expression pattern in human tissues remained largely unknown. We have developed LGR4-specific monoclonal antibodies and used them to examine the expression of LGR4 in selected adult human and mouse tissues by immunohistochemical analysis. Intense LGR4-like immunoreactivity was observed in the epidermis and hair follicle of the skin, pancreatic islet cells, and epithelial cells in both the male and female reproductive organs. Of particular interest is that LGR4 is highly expressed in germ cells and pancreatic islet cells, which have important implications given the role of R-spondin-LGR4 signaling in the survival of adult stem cells. In addition, the majority of colon tumors showed elevated levels of LGR4 receptor. Overall, the expression pattern of LGR4 in human tissues mapped by this IHC analysis is similar to that in the mouse as revealed from gene trap alleles. Importantly, the pattern lends strong support to the important role of LGR4 in the development and maintenance of skin, kidney, reproductive systems, and other organs.
    PLoS ONE 10/2013; 8(10):e78144. DOI:10.1371/journal.pone.0078144 · 3.23 Impact Factor
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    ABSTRACT: Combination chemotherapy is standard for metastatic colorectal cancer (CRC); however, nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may enable identification of novel targets and more effective therapy. Irinotecan is commonly used in first- and second-line therapy for patients with metastatic CRC, with the active metabolite being SN38. Emerging evidence suggests that altered metabolism in cancer cells is fundamentally involved in the development of drug resistance. Using Oncomine and unbiased proteomic profiling, we found that ATP citrate lyase (ACLy), the first-step rate-limiting enzyme for de novo lipogenesis, was upregulated in CRC compared to its levels in normal mucosa and in chemoresistant CRC cells compared to isogenic chemo-naïve CRC cells. Overexpression of exogenous ACLy by lentivirus transduction in chemo-naïve CRC cells led to significant chemoresistance to SN38 but not to 5-fluorouracil or oxaliplatin. Knockdown of ACLy by siRNA or inhibition of its activity by a small-molecule inhibitor sensitized chemo-naïve CRC cells to SN38. Furthermore, ACLy was significantly increased in cancer cells that had acquired resistance to SN38. In contrast to chemo-naïve cells, targeting ACLy alone was not effective in re-sensitizing resistant cells to SN38, due to a compensatory activation of the AKT pathway triggered by ACLy suppression. Combined inhibition of AKT signaling and ACLy successfully re-sensitized SN38-resistant cells to SN38. We conclude that targeting ACLy may improve the therapeutic effects of irinotecan and that simultaneous targeting of ACLy and AKT may be warranted to overcome SN38 resistance.
    Molecular Cancer Therapeutics 10/2013; 12(12). DOI:10.1158/1535-7163.MCT-13-0098 · 5.68 Impact Factor
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    ABSTRACT: Circulating angiogenic factors are altered in patients with mCRC receiving bevacizumab. Evaluation of alterations in levels of VEGF ligands may provide insights into possible resistance mechanisms. PlGF, VEGF-A, VEGF-C, and VEGF-D were measured from two cohorts of patients. Sequential plasma samples were obtained from a discovery cohort of 42 patients treated with chemotherapy and bevacizumab. A validation cohort included plasma samples from a cross-sectional of 403 patients prior to chemotherapy, or after progression on a regimen with or without bevacizumab. In the discovery cohort, VEGF-C was increased prior to progression and at progression (+49% and +95%, respectively, p<0.01), consistent with previously reported elevations in PlGF. Levels of VEGF-D were increased (+23%) at progression (p=0.05). In the validation cohort, samples obtained from patients after progression on a regimen with bevacizumab had higher levels of PlGF and VEGF-D (+43% and +6%, p=0.02, p=0.01, respectively) compared to untreated patients, but failed to validate the increase in VEGF-C seen in the first cohort. Patients who progressed on chemotherapy with bevacizumab had significantly elevated levels of PlGF (+88%) but not VEGF-C and VEGF-D compared to patients treated with chemotherapy alone. Elevations of PlGF and VEGF-D appeared transient and returned to baseline with a half-life of 6 weeks. Increases in PlGF and VEGF-D were observed after progression on chemotherapy with bevacizumab. These changes appear to be reversible after discontinuing therapy. These ligands are associated with resistance to bevacizumab-containing chemotherapy in mCRC, but causation remains to be established.
    PLoS ONE 10/2013; 8(10):e77117. DOI:10.1371/journal.pone.0077117 · 3.23 Impact Factor
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    ABSTRACT: Therapeutic antibody development is one of the fastest growing areas of the pharmaceutical industry. Generating high-quality monoclonal antibodies against a given therapeutic target is crucial for successful drug development. However, due to immune tolerance, making it difficult to generate antibodies using conventional approaches. Mixed four human gastric cancer (GC) cell lines were used as the immunogen in A/J mice; sixteen highly positive hybridoma colonies were selected via fluorescence-activated cell sorting-high throughput screening (FACS-HTS) using a total of 20,000 colonies in sixty-seven 96-well plates against live cells (mixed human GC cells versus human PBMC controls). MS17-57 and control commercial Alkaline Phosphatase (ALP) mAbs were used to confirm the target antigens (Ags), which were identified as ALPs expressed on the GC cell surface through a combination of western blot, immunoprecipitation and mass spectrometry (MS). MS identified the Ags recognized by MS17-57 to be two variants of a secreted ALP, PALP and IALP (Placental and intestinal ALP). These proteins belong to a hydrolase enzyme family responsible for removing phosphate groups from many types of molecules. Immunofluorescence staining using MS17-57 demonstrated higher staining of gastrointestinal (GI) cancer tissues compared to normal GI tissues (P<0.03), and confirmed binding of MS17-57 to be restricted to a functional epitope expressed on the cancer cell surface. Proliferation assays using the PALP/IALP-expressing GC cell lines demonstrated that MS17-57 inhibited cell growth by 32±8%. Transwell cell migration assays documented that MS17-57 can inhibit PALP/IALP-expressing GI cancer cell migration by 25±5%. MS17-57 mAb inhibited tumor growth in nude mice. Our findings indicate that PALP and IALP can be ectopically expressed on extracellular matrix of GI cancers, and that MS17-57 directed against PALP/IALP can inhibit GI cancer cells growth and migration in vitro and in vivo. This investigation provides an example of identification of cancer biomarkers representing promising therapeutic targets using mAb generated through a novel HTS technology.
    PLoS ONE 10/2013; 8(10):e77398. DOI:10.1371/journal.pone.0077398 · 3.23 Impact Factor
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    ABSTRACT: Chemotherapy for patients with metastatic colorectal cancer (CRC) is the standard of care, but ultimately nearly all patients develop drug resistance. Understanding the mechanisms that lead to resistance to individual chemotherapeutic agents may help identify novel targets and drugs that will, in turn, improve therapy. Oxaliplatin is a common component combination therapeutic regimen for use in patients with metastatic CRC, but is also used as a component of adjuvant therapy for patients at risk for recurrent disease. In this study, unbiased microRNA array screening revealed that the miR-203 microRNA is up-regulated in three of three oxaliplatin-resistant CRC cell lines, and therefore we investigated the role of miR-203 in chemoresistance. Exogenous expression of miR-203 in chemo-naïve CRC cells induced oxaliplatin resistance. Knockdown of miR-203 sensitized chemoresistant CRC cells to oxaliplatin. In silico analysis identified ataxia telangiectasia mutated (ATM), a primary mediator of the DNA damage response, as a potential target of miR-203. ATM mRNA and protein levels were significantly down-regulated in CRC cells with acquired resistance to oxaliplatin. Using TCGA database, we identified a significant reverse correlation of miR-203 and ATM expression in CRC tissues. We validated ATM as a bona fide target of miR-203 in CRC cells. Mutation of the putative miR-203 binding site in the 3' untranslated region (3'UTR) of the ATM mRNA abolished the inhibitory effect of miR-203 on ATM. Furthermore, stable knockdown of ATM induced resistance to oxaliplatin in chemo-naïve CRC cells. This is the first report of oxaliplatin resistance in CRC cells induced by miR-203-mediated suppression of ATM.
    Molecular Oncology 10/2013; DOI:10.1016/j.molonc.2013.09.004 · 5.33 Impact Factor

Publication Stats

27k Citations
2,743.04 Total Impact Points


  • 1992-2015
    • University of Texas MD Anderson Cancer Center
      • • Department of Surgical Oncology
      • • Department of Cancer Biology
      • • Department of Surgery
      Houston, Texas, United States
  • 2008
    • Mayo Clinic - Rochester
      Рочестер, Minnesota, United States
  • 2007
    • Hospital Sirio Libanes
      Potengy, Rio Grande do Norte, Brazil
  • 2006
    • John Wayne Cancer Institute
      Santa Monica, California, United States
  • 1993-2006
    • University of Houston
      Houston, Texas, United States
  • 2005
    • The University of Calgary
      Calgary, Alberta, Canada
  • 1998-2003
    • Kanazawa University
      • • Cancer Research Institute
      • • Department of Community Surgical Oncology
      Kanazawa-shi, Ishikawa-ken, Japan
  • 2001
    • Massachusetts General Hospital
      Boston, Massachusetts, United States