Suresh S Ramalingam

Emory University, Atlanta, Georgia, United States

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Publications (144)883.99 Total impact

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    ABSTRACT: Bax, a central death regulator, is required at the decisional stage of apoptosis. We recently identified serine 184 (S184) of Bax as a critical functional switch controlling its proapoptotic activity. Here we used the structural pocket around S184 as a docking site to screen the NCI library of small molecules using the UCSF-DOCK programme suite. Three compounds, small-molecule Bax agonists SMBA1, SMBA2 and SMBA3, induce conformational changes in Bax by blocking S184 phosphorylation, facilitating Bax insertion into mitochondrial membranes and forming Bax oligomers. The latter leads to cytochrome c release and apoptosis in human lung cancer cells, which occurs in a Bax- but not Bak-dependent fashion. SMBA1 potently suppresses lung tumour growth via apoptosis by selectively activating Bax in vivo without significant normal tissue toxicity. Development of Bax agonists as a new class of anticancer drugs offers a strategy for the treatment of lung cancer and other Bax-expressing malignancies.
    Nature Communications 09/2014; 5:4935. · 10.74 Impact Factor
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    ABSTRACT: Poly (ADP) ribose polymerase (PARP) plays a key role in DNA repair and is highly expressed in small cell lung cancer (SCLC). We investigated the therapeutic impact of PARP inhibition in SCLC. In vitro cytotoxicity of veliparib, cisplatin, carboplatin, and etoposide singly and combined was determined by MTS in 9 SCLC cell lines (H69, H128, H146, H526, H187, H209, DMS53, DMS153, and DMS114). Subcutaneous xenografts in athymic nu/nu mice of H146 and H128 cells with relatively high and low platinum sensitivity, respectively, were employed for in vivo testing. Mechanisms of differential sensitivity of SCLC cell lines to PARP inhibition were investigated by comparing protein and gene expression profiles of the platinum sensitive and the less sensitive cell lines. Veliparib showed limited single-agent cytotoxicity but selectively potentiated (≥50% reduction in IC50) cisplatin, carboplatin, and etoposide in vitro in five of nine SCLC cell lines. Veliparib with cisplatin or etoposide or with both cisplatin and etoposide showed greater delay in tumor growth than chemotherapy alone in H146 but not H128 xenografts. The potentiating effect of veliparib was associated with in vitro cell line sensitivity to cisplatin (CC = 0.672; P = 0.048) and DNA-PKcs protein modulation. Gene expression profiling identified differential expression of a 5-gene panel (GLS, UBEC2, HACL1, MSI2, and LOC100129585) in cell lines with relatively greater sensitivity to platinum and veliparib combination. Veliparib potentiates standard cytotoxic agents against SCLC in a cell-specific manner. This potentiation correlates with platinum sensitivity, DNA-PKcs expression and a 5-gene expression profile.
    Cancer Medicine 08/2014;
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    ABSTRACT: BACKGROUND Platinum-based therapy combined with cetuximab is standard first-line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.METHODS Patients received carboplatin (area under the curve = 2 mg/ml/min; 3 weeks on, 1 week off), cetuximab (with a loading dose of 400 mg/m2 and then 250 mg/m2 weekly), and dose-escalating everolimus (2.5, 5.0, 7.5, and 10 mg/day) with a 3+3 design. After 4 cycles, patients without progression continued cetuximab/everolimus until progression or intolerable toxicity. Patients (age ≥ 18 years) had previously untreated, unresectable RMSCCHN not amenable to radiotherapy and an Eastern Cooperative Oncology Group performance status of 0 to 2.RESULTSThe study enrolled 20 patients (male/female = 18/2) with RMSCCHN; the median age was 65 years (44-75 years). Thirteen patients received everolimus (male/female = 92%). Two of 6 patients receiving 2.5 mg/day experienced dose-limiting toxicity (DLT) with grade 3 hyponatremia and nausea. In 7 patients receiving de-escalated everolimus (2.5 mg every other day), grade 3 hyperglycemia produced DLT in 1 of 6 patients. The objective response rate (RR) was 61.5% (all partial responses). Progression-free survival (PFS) was 8.15 months. The pharmacokinetics of everolimus was described with a 2-compartment mixed-effects model. There was a significant correlation between tumor p-p44/42 staining and response (P = .044) and a marginally significant correlation between phosphorylated mammalian target of rapamycin and overall survival.CONCLUSIONS The maximum tolerated dose of everolimus with cetuximab and carboplatin was 2.5 mg every other day. The regimen was associated with an encouraging RR and PFS, and this suggested possible clinical efficacy in a select group of patients with squamous cell carcinoma of the head and neck. Cancer 2014. © 2014 American Cancer Society.
    Cancer 08/2014; · 5.20 Impact Factor
  • Suresh S Ramalingam, Fadlo R Khuri
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    ABSTRACT: Ceritinib and other second-generation inhibitors have demonstrated promising anticancer activity in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Specifically, they can overcome resistance due to certain gatekeeper mutations acquired following crizotinib exposure. These agents now provide new options for the management of ALK-positive NSCLC. Cancer Discov; 4(6); 634-6. ©2014 AACR. See related article by Friboulet et al., p. 662.
    Cancer Discovery 06/2014; 4(6):634-6. · 15.93 Impact Factor
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    ABSTRACT: Background: AV-203 is an IgG1k humanized monoclonal antibody with high affinity and specificity for the anti-v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (ERBB3) receptor. Based on promising preclinical activity and resistance prevention data, a phase 1 study was conducted (NCT01603979). Methods: A phase 1 study using a 3+3 dose-escalation design evaluated the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics of AV-203. AV-203 was given IV at 2, 5, 9, 14 or 20 mg/kg once every 2 wks (1 cycle = 28 days, 2 doses per cycle). Included patients (pts) had advanced solid tumors and progressed on standard therapies or had no proven treatment options. Results: AV-203 was administered to 22 pts (15M/7F; median age 68 y, range 31-82; ECOG PS 0/1: 8/13). Enrolled tumor types included colorectal (4), non–small-cell lung (NSCLC; 4), squamous cell carcinoma of the head and neck (2) and other solid tumors (12). There was a single dose-limiting toxicity of inability to tolerate the study drug (serious Grade 3 diarrhea and multiple concurrent adverse events [AEs]) at 2 mg/kg in an 80-y-old pt. The maximum administered dose of 20 mg/kg was well tolerated. All grade AEs observed in ≥25% of pts were: diarrhea (68%); decreased appetite (41%); hypokalemia, dry skin and hypomagnesemia (36% each); headache, dehydration, dizziness and dyspnea (27% each). Grade 3 and 4 AEs of anemia, diarrhea and hypokalemia occurred in ≥2 pts. The most common treatment-related AEs were diarrhea (59%), dry skin and decreased appetite (32% each), hypomagnesemia (27%) and pruritus (23%). No deaths were attributed to AV-203. Preliminary data show approximately dose proportional PK and no detection of anti-drug antibodies. Median time on treatment for all pts was 43 days (range: 1-491), with 15 pts discontinuing due to progressive disease during this time. There was one confirmed partial response (PR; 6 cycles) in a pt with squamous NSCLC which expressed high levels of neuregulin 1. Conclusions: AV-203 was well tolerated in the dose range tested; RP2D is 20 mg/kg IV every 2 wks. The PR in a pt with squamous cell NSCLC warrants further testing of AV-203 in this indication. Clinical trial information: NCT01603979.
    2014 ASCO Annual Meeting; 06/2014
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    ABSTRACT: Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC.
    Cancer Chemotherapy and Pharmacology 05/2014; · 2.80 Impact Factor
  • Conor E Steuer, Suresh S Ramalingam
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    ABSTRACT: Targeted therapy has emerged as an effective treatment option for certain molecular subsets of advanced stage non-small cell lung cancer (NSCLC). The discovery of the echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) translocation as an oncogenic driver has led to the development of novel therapies with activity in vitro and in the clinic. The first-in-class tyrosine kinase inhibitor crizotinib is effective against ALK-positive NSCLC and is currently used as first-line or salvage therapy in the setting of advanced disease. However, resistance inevitably develops through a variety of mechanisms, including point mutations affecting the fusion protein, activation of bypass signaling pathways, copy number gain of ALK, and other means. Increased understanding of these pathways is essential for tailoring treatment choices to improve outcomes and minimize toxicities. Potent second-generation ALK inhibitors currently in trials are producing encouraging results in ALK-positive NSCLC, even in patients with acquired resistance to crizotinib. The success in identifying the ALK translocations and rapidly developing targeted drugs to exploit it paves the way for a better understanding of NSCLC biology and the quest to provide effective, personalized treatment for lung cancer patients. Cancer 2014. © 2014 American Cancer Society.
    Cancer 05/2014; · 5.20 Impact Factor
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    ABSTRACT: Mcl-1 is a unique antiapoptotic Bcl2 family member with a short half-life due to its rapid turnover through ubiquitination. We discovered that Ku70, a DNA double-strand break repair protein, functions as a deubiquitinase to stabilize Mcl-1. Ku70 knockout in mouse embryonic fibroblast (MEF) cells or depletion from human lung cancer H1299 cells leads to the accumulation of polyubiquitinated Mcl-1 and a reduction in its half-life and protein expression. Conversely, expression of exogenous Ku70 in Ku70(-/-) MEF cells restores Mcl-1 expression. Subcellular fractionation indicates that Ku70 extensively colocalizes with Mcl-1 in mitochondria, endoplasmic reticulum and nucleus in H1299 cells. Ku70 directly interacts with Mcl-1 via its C terminus (that is, aa 536-609), which is required and sufficient for deubiquitination and stabilization of Mcl-1, leading to suppression of apoptosis. Purified Ku70 protein directly deubiquitinates Mcl-1 by removing K48-linked polyubiquitin chains. Ku70 knockdown not only promotes Mcl-1 turnover but also enhances antitumor efficacy of the BH3-mimetic ABT-737 in human lung cancer xenografts. These findings identify Ku70 as a novel Mcl-1 deubiquitinase that could be a potential target for cancer therapy by manipulating Mcl-1 deubiquitination.Cell Death and Differentiation (2014) 0, 000-000.advance online publication, 25 April 2014; doi:10.1038/cdd.2014.42.
    Cell death and differentiation 04/2014; · 8.24 Impact Factor
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    ABSTRACT: Over the last 10 to 15 years, the landscape of lung cancer has changed dramatically. Where cancers were previously described rather simplistically according to histological subtype, now molecular understanding of tumors has particularly resulted in segmentation of nonsmall cell lung cancer into many different subtypes. A multidisciplinary approach integrating a molecular testing algorithm that ideally includes reflex testing at diagnosis is recommended. This offers clinicians the opportunity to target treatment according to subtype. Identifying patients with rearrangements, such as those associated with the echinoderm microtubule-associated protein-like 4 (EML-4) anaplastic lymphoma kinase (ALK) fusion gene (the major focus of this paper) has allowed clinicians to tailor therapy to target these mutations. The challenge that faces clinicians treating lung cancer is how best to implement the science that sits behind these targeted therapies in clinical practice through the identification of appropriate patients. Precision medicine can lead to the choice of the right medicine for the right patients and is proving to be a better approach than treating unselected patients with systemic chemotherapy.
    Asia-Pacific Journal of Clinical Oncology 04/2014; 10 Suppl 2:2-10. · 0.91 Impact Factor
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    ABSTRACT: BACKGROUND Epigenetic events play a major role in the carcinogenesis of tobacco-related cancers. The authors conducted a retrospective cohort study to evaluate the effects of exposure to the anticonvulsant agent valproic acid (VPA), a histone deacetylase inhibitor, on the risk of developing cancers of the lung, head and neck, prostate, bladder, and colon.METHODS The study was based on the 2002 through 2008 National Veterans Affairs (VA) medical SAS data set linked to the VA Central Cancer Registry. The cohort was defined as subjects aged > 40 years who were followed in the VA system for at least 1 year for 1 of 4 diagnoses for which a VPA indication exists (bipolar disorder, posttraumatic stress disorder, migraines, and seizures). Multivariable Cox proportional hazards models were used to estimate hazards ratios (HR) and 95% confidence intervals (95% CI) reflecting the association between use of VPA and cancer incidence.RESULTSVPA use was associated with a significant reduction in the risk of cancers of the head and neck (HR, 0.66; 95% CI, 0.48-0.92). Additional associations were noted with the duration of treatment and median VPA drug levels. No significant differences in cancer incidence were observed for cancers of the lung (HR, 1.00; 95% CI, 0.84-1.19), bladder (HR, 0.86; 95% CI, 0.64-1.15), colon (HR, 0.95; 95% CI, 0.74-1.22), and prostate (HR, 0.96; 95% CI, 0.88-1.12).CONCLUSIONS Use of VPA is associated with a lower risk of developing head and neck cancers. Cancer 2013. © 2013 American Cancer Society.
    Cancer 03/2014; · 5.20 Impact Factor
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    ABSTRACT: Human papillomavirus (HPV) is the etiologic risk factor for cervical cancer. Some studies have suggested an association with a subset of lung tumors, but the etiologic link has not been firmly established. We performed an international pooled analysis of cross-sectional studies (27 datasets, n = 3,249 patients) to evaluate HPV DNA prevalence in lung cancer and to investigate viral presence according to clinical and demographic characteristics. HPV16/18 were the most commonly detected, but with substantial variation in viral prevalence between geographic regions. The highest prevalence of HPV16/18 was observed in South & Central America, followed by Asia, North America and Europe (Adjusted prevalence rates = 22%, 5%, 4% and 3% respectively). Higher HPV16 prevalence was noted in each geographic region compared to HPV18, except in North America. HPV16/18-positive lung cancer was less likely observed among White race (Adjusted OR = 0.33, 95% CI = 0.12-0.90), while no associations were observed with gender, smoking history, age, histology or stage. Comparisons between tumor and normal lung tissue show that HPV was more likely to be present in lung cancer rather than normal lung tissues (OR = 3.86, 95% CI = 2.87-5.19). Among a subset of patients with HPV16-positive tumors, integration was primarily among female patients (93%, 13/14), while the physical status in male cases (N = 14) was inconsistent. Our findings confirm that HPV DNA is present in a small fraction of lung tumors, with large geographic variations. Further comprehensive analysis is needed to assess whether this association reflects a causal relationship.
    Carcinogenesis 02/2014; · 5.64 Impact Factor
  • Rathi N Pillai, Suresh S Ramalingam
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    ABSTRACT: The diagnostic and therapeutic landscape of non-small cell lung cancer (NSCLC) has changed dramatically in the past 50 years since the Surgeon General's report on smoking and lung cancer. Early detection is now a reality for lung cancer. The use of low-dose computed tomography scans for early detection decreases mortality and is beginning to be used in routine clinical practice. Technological advances such as positron emission tomography and endobronchial ultrasound have improved the accuracy of NSCLC staging. The cure rate for early-stage NSCLC has improved as a result of multimodality treatment approaches. The role of systemic therapy has also expanded to earlier stages of the disease. In recent years, the initial steps toward personalized medicine by utilization of targeted treatments based on tumor genotype have been undertaken. Emerging technological advances and greater insights into tumor biology are poised to greatly reduce the burden of lung cancer in the years to come. Mol Cancer Ther; 1-8. ©2014 AACR.
    Molecular Cancer Therapeutics 02/2014; · 5.60 Impact Factor
  • Rathi N Pillai, Suresh S Ramalingam
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    ABSTRACT: Heat shock protein 90 (Hsp90) protects cellular proteins from degradation by the ubiquitin-proteasome system in conditions of stress. Many cancers have increased expression of Hsp90 to ensure their malignant phenotype of increased proliferation, decreased apoptosis, and metastatic potential by conservation of proteins like epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2, anaplastic lymphoma kinase (ALK), v-Raf murine sarcoma viral oncogene homologue B1, AKT, B-cell lymphoma 2, and cell cycle proteins. This review discusses recent developments in the strategy of Hsp90 inhibition as a targeted therapy in nonsmall cell lung cancer (NSCLC). Hsp90 inhibitors result in growth inhibition and tumor regression in NSCLC cell lines and tumor xenograft models, both as monotherapy and in combination with other drugs. Hsp90 inhibition has particular efficacy in molecular subtypes of NSCLC, such as EGFR-mutated and ALK-rearranged NSCLC. IPI-504 and ganetespib have activity in NSCLC both as monotherapy and in combination with docetaxel. Preclinical studies and early clinical trials have confirmed the efficacy of Hsp90 inhibition as a targeted therapy in NSCLC. Ongoing trials will further define the utility of Hsp90 inhibitors in NSCLC.
    Current opinion in oncology 01/2014; · 4.09 Impact Factor
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    ABSTRACT: DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDACs) 1-3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell cycle independent increased DNMT1 stability and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter and de-repression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability.
    Cancer Prevention Research 01/2014; · 4.89 Impact Factor
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    ABSTRACT: Background Platinum compounds remain the most widely utilized systemic agents in combination with radiation for treating SCCHN in the concurrent setting. Despite recent interest in using taxanes in this setting, there is a lack of randomized clinical trials to support this approach. We conducted a systematic review of published clinical trials of taxane-containing versus standard non-taxane-based regimens used in definitive treatment of SCCHN. Methods Trials published between 1994 and 2012 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). All prospective studies were independently identified by two authors for inclusion. Studies were excluded if induction therapy was part of the regimen or if targeted agents were used. Trials using cisplatin- or carboplatin-based regimens and paclitaxel or docetaxel were included. Demographic data, treatment response, locoregional failure free rate (LFFR), progression-free and overall survival (PFS, OS) and toxicities were extracted and analyzed using Comprehensive Meta Analysis software (Version 2.0). Outcome data were pooled and reported as weighted response rate (RR), PFS and OS. Results A total of 790 studies were retrieved and 42 studies with 3120 patients were included: 804 patients were treated with taxanes (80% males, median age 57 years) and 2316 with non-taxanes (86% males, median age 56 years). Progression free survival was not different between the two groups. Weighted median survival was compared from those studies that reported these data; taxanes = 36.7 months (N = 197) versus non-taxanes = 25 months (N = 503), P < 0.001. Toxicity (grade 3 and above) was higher in non-taxane containing trials. Conclusions The improved overall survival observed supports the choice of taxane-based regimens in the concurrent setting but may also reflect the predominance of single arm multi-agent phase II trials in the taxane arm. Our findings urge the need for better standardization of taxane-based regimens.
    Oral Oncology. 01/2014;
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    ABSTRACT: Sequence-dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small-cell lung cancer (SCLC). Patients with previously untreated extensive-stage SCLC with measurable disease, ECOG performance status of 0-3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m(2)) on days 1, 2 and 3, etoposide (70 mg/m(2)) and cisplatin (20 mg/m(2)) (PET) on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m(2)) and cisplatin (20 mg/m(2)) on days 1 and 8 followed by etoposide (85 mg/m(2) PO bid) on days 3 and 10 (PIE) in a 3-week cycle. We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5 % of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70 % of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR + PR) were 69.7 % (90 % CI 59.1-78.9, 95 % CI 57.1-80.4 %) for arm A and 57.6 % (90 % CI 46.7-67.9, 95 % CI 44.8-69.7 %) for arm B. The median progression-free survival and overall survival were 6.4 months (95 % CI 5.4-7.5 months) and 11.9 months (95 % CI 9.6-13.7 months) for arm A and 6.0 months (95 % CI 5.4-7.0 months) and 11.0 months (95 % CI 8.6-13.1 months) for arm B. Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive-stage SCLC.
    Cancer Chemotherapy and Pharmacology 11/2013; · 2.80 Impact Factor
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    ABSTRACT: DNA replication stress is an inefficient DNA synthesis process that leads replication forks to progress slowly or stall. Two main factors that cause replication stress are alterations in pools of deoxyribonucleotide (dNTP) precursors required for DNA synthesis and changes in the activity of proteins required for synthesis of dNTPs. Ribonucleotide reductase (RNR), containing regulatory hRRM1 and catalytic hRRM2 subunits, is the enzyme that catalyzes the conversion of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphosphates (dNDPs) and thereby provides dNTP precursors needed for the synthesis of DNA. Here, we demonstrate that either endogenous or exogenous expression of Bcl2 results in decreases in RNR activity and intracellular dNTP, retardation of DNA replication fork progression and increased rate of fork asymmetry leading to DNA replication stress. Bcl2 co-localizes with hRRM1 and hRRM2 in the cytoplasm and directly interacts via its BH4 domain with hRRM2 but not hRRM1. Removal of the BH4 domain of Bcl2 abrogates its inhibitory effects on RNR activity, dNTP pool level and DNA replication. Intriguingly, Bcl2 directly inhibits RNR activity by disrupting the functional hRRM1/hRRM2 complex via its BH4 domain. Our findings argue that Bcl2 reduces intracellular dNTPs by inhibiting ribonucleotide reductase activity, thereby providing insight into how Bcl2 triggers DNA replication stress.
    Cancer Research 11/2013; · 9.28 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) and cyclooxygenase 2 inhibitors synergistically inhibit head and neck squamous cell carcinoma tumorigenesis in preclinical studies. We conducted a phase I and pharmacokinetic study with the erlotinib and celecoxib combination in patients with advanced premalignant lesions. 36 subjects with oral leukoplakia, mild, moderate, or severe dysplasia, or carcinoma in situ were screened for study participation; 12 consented and received therapy for a median of 5.38 months. Erlotinib was escalated following a standard 3+3 design at 50, 75, and 100mg orally daily and celecoxib was fixed at 400mg twice daily for 6 months. Biopsy of lesions and cytobrush of normal mucosa were performed at baseline, 3, 6 and 12 months. Erlotinib pharmacokinetics were analyzed in 10 subjects. The maximum tolerated dose of erlotinib with celecoxib 400mg BID was 50mg per day with skin rash being the main observed toxicity. Overall histologic response rate was 63% (complete response 43%, partial response 14%, stable disease 29%, disease progression 14%). With median follow-up of 36 months, mean time to progression to higher-grade dysplasia or carcinoma was 25.4 months. Downregulation of EGFR and p-ERK in follow-up biopsies correlated with response to treatment. Larger average erlotinib V/F (~308L) and CL/F (8.3L/hr) compared to previous studies may be related to relatively large average bodyweights. Average erlotinib t1/2 was 25.6hr. Encouraging responses to the celecoxib and erlotinib combination correlated with EGFR pathway inhibition. Although erlotinib-related rash was the main limitation to dose escalation, the intervention was well tolerated.
    Cancer Prevention Research 10/2013; · 4.89 Impact Factor
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    ABSTRACT: Prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage small cell lung cancer (SCLC) who have a complete response to chemotherapy and radiotherapy, yet to the best of the authors' knowledge, data specific to the elderly population are lacking. Using the Surveillance, Epidemiology, and End Results (SEER) database, the authors identified 1926 patients aged ≥ 70 years who were diagnosed with limited-stage SCLC between 1988 and 1997. Overall survival (OS) for patients who received PCI versus those who did not were estimated using the Kaplan-Meier method and compared with the log-rank test. A Cox proportional hazards model was further fitted to estimate the effect of PCI on OS after adjusting for age, race, sex, tumor size, lymph node status, stage of disease, and receipt of thoracic radiotherapy and surgery. The median age of the patients was 75 years (range, 70 years-94 years) and 138 patients (7.2 %) received PCI. The 2-year and 5-year OS rates were 33.3% (95% confidence interval [95% CI], 25.6%-41.2%) and 11.6% (95% CI, 6.9%-17.6%), respectively, among patients who received PCI versus 23.1% (95% CI, 21.2%-25.1%) and 8.6% (95% CI, 7.3%-9.9%), respectively, among patients who did not receive PCI (P = .028). On multivariable analysis, PCI was found to be an independent predictor of OS (hazards ratio, 0.72; 95% CI, 0.54-0.97 [P = .032]). On subgroup analysis, PCI remained an independent predictor of OS among patients aged ≥ 75 years, but not among patients aged ≥ 80 years. The receipt of PCI is associated with improved OS in patients aged ≥ 70 years with SCLC, suggesting that the benefit of PCI is maintained in the elderly population. Cancer 2013. © 2013 American Cancer Society.
    Cancer 08/2013; · 5.20 Impact Factor
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    ABSTRACT: The emergence of resistance to epidermal growth factor receptor (EGFR) inhibitor therapy is a major clinical problem for patients with non-small cell lung cancer (NSCLC). The mechanisms underlying tumor resistance to inhibitors of the kinase activity of EGFR are not fully understood. Here we found that inhibition of EGFR by erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both mRNA and protein levels in various human lung cancer cells. PTPMeg2 is a physiologic STAT3 phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with erlotinib results in downregulation of PTPMeg2 without activation of STAT3 kinases (i.e. JAK2 or c-Src), suggesting that erlotinib enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Since elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2 and Bcl-XL were observed in erlotinib-resistant lung cancer (HCC827/ER) cells as compared to erlotinib-sensitive parental HCC827 cells, we postulate that erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverses erlotinib resistance. Niclosamide in combination with erlotinib potently represses erlotinib-resistant lung cancer xenografts in association with increased apoptosis in tumor tissues, suggesting that niclosamide can restore sensitivity to erlotinib. These findings uncover a novel mechanism of erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human lung cancer.
    Molecular Cancer Therapeutics 07/2013; · 5.60 Impact Factor

Publication Stats

2k Citations
883.99 Total Impact Points

Institutions

  • 2008–2014
    • Emory University
      • • Department of Hematology and Medical Oncology
      • • Department of Internal Medicine
      Atlanta, Georgia, United States
    • Emory Hospitals
      Atlanta, Georgia, United States
  • 2012
    • University of Miami Miller School of Medicine
      Miami, Florida, United States
  • 2011
    • California State University, Sacramento
      Sacramento, California, United States
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
    • University of Southern California
      • Norris Comprehensive Cancer Center
      Los Angeles, CA, United States
    • Moffitt Cancer Center
      • Department of Cancer Epidemiology
      Tampa, Florida, United States
    • University of Colorado
      • Department of Clinical Pharmacy
      Denver, CO, United States
  • 2010
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States
  • 2004–2010
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, PA, United States
  • 2009
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
    • The Chinese University of Hong Kong
      • Department of Clinical Oncology
      Hong Kong, Hong Kong