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Papers by Melinda Merchant

SummaryNeutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; patho... more SummaryNeutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. We identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies reveal increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatini...

European Journal of Cancer, 2020

Téléchargé pour Anonymous User (n/a) à Gustave Roussy à partir de ClinicalKey.fr par Elsevier sur... more Téléchargé pour Anonymous User (n/a) à Gustave Roussy à partir de ClinicalKey.fr par Elsevier sur août 10, 2020. Pour un usage personnel seulement. Aucune autre utilisation n´est autorisée.

Nature Reviews Clinical Oncology, 2019

Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The... more Despite decades of research, brain tumours remain among the deadliest of all forms of cancer. The ability of these tumours to resist almost all conventional and novel treatments relates, in part, to the unique cell-intrinsic and microenvironmental properties of neural tissues. In an attempt to encourage progress in our understanding and ability to successfully treat patients with brain tumours, Cancer Research UK convened an international panel of clinicians and laboratory-based scientists to identify challenges that must be overcome if we are to cure all patients with a brain tumour. The seven key challenges summarized in this Position Paper are intended to serve as foci for future research and investment.

$Research paper thumbnail of {"__content__"=>"Antitumor Activity Associated with Prolonged Persistence of Adoptively Transferred NY-ESO-1T Cells in Synovial Sarcoma.", "sup"=>{"__content__"=>"c259"}}$

Cancer discovery, Jan 11, 2018

We evaluated the safety and activity of autologous T cells expressing NY-ESO-1, an affinity-enhan... more We evaluated the safety and activity of autologous T cells expressing NY-ESO-1, an affinity-enhanced T-cell receptor (TCR) recognizing an HLA-A2-restricted NY-ESO-1/LAGE1a-derived peptide, in patients with metastatic synovial sarcoma (NY-ESO-1T cells). Confirmed antitumor responses occurred in 50% of patients (6/12) and were characterized by tumor shrinkage over several months. Circulating NY-ESO-1T cells were present postinfusion in all patients and persisted for at least 6 months in all responders. Most of the infused NY-ESO-1T cells exhibited an effector memory phenotype following expansion, but the persisting pools comprised largely central memory and stem-cell memory subsets, which remained polyfunctional and showed no evidence of T-cell exhaustion despite persistent tumor burdens. Next-generation sequencing of endogenous TCRs in CD8 NY-ESO-1T cells revealed clonal diversity without contraction over time. These data suggest that regenerative pools of NY-ESO-1T cells produced a ...

Molecular Therapy, 2015

CanCer-Immunotherapy, CanCer VaCCInes I model. Since AAT protein and gene therapies have been pro... more CanCer-Immunotherapy, CanCer VaCCInes I model. Since AAT protein and gene therapies have been proven to be safe in humans, our results not only demonstrate novel functions of AAT, but also imply a new strategy for the treatment of osteoporosis.

Cancer, Jan 13, 2017

Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to can... more Programmed death 1 (PD-1) signaling in the tumor microenvironment dampens immune responses to cancer, and blocking this axis induces antitumor effects in several malignancies. Clinical studies of PD-1 blockade are only now being initiated in pediatric patients, and little is known regarding programmed death-ligand 1 (PD-L1) expression in common childhood cancers. The authors characterized PD-L1 expression and tumor-associated immune cells (TAICs) (lymphocytes and macrophages) in common pediatric cancers. Whole slide sections and tissue microarrays were evaluated by immunohistochemistry for PD-L1 expression and for the presence of TAICs. TAICs were also screened for PD-L1 expression. Thirty-nine of 451 evaluable tumors (9%) expressed PD-L1 in at least 1% of tumor cells. The highest frequency histotypes comprised Burkitt lymphoma (80%; 8 of 10 tumors), glioblastoma multiforme (36%; 5 of 14 tumors), and neuroblastoma (14%; 17 of 118 tumors). PD-L1 staining was associated with inferior ...

Cancer research, Aug 2, 2016

Ewing's sarcoma (EWS) is a primitive round cell sarcoma with a peak incidence in adolescence ... more Ewing's sarcoma (EWS) is a primitive round cell sarcoma with a peak incidence in adolescence that is driven by a chimeric oncogene created from the fusion of the EWSR1 gene with a member of the ETS family of genes. Patients with metastatic and recurrent disease have dismal outcomes and need better therapeutic options. We screened a library of 309,989 chemical compounds for growth inhibition of EWS cells to provide the basis for the development of novel therapies, and to discover vulnerable pathways that might broaden our understanding of the pathobiology of this aggressive sarcoma. This screening campaign identified a class of benzyl-4-piperidone compounds which selectively inhibit growth of EWS cell lines by inducing apoptosis. These agents disrupt 19S proteasome function through inhibition of the deubiquitinating enzymes USP14 and UCHL5. Functional genomic data from a genome-wide shRNA screen in EWS cells also identified the proteasome as a node of vulnerability in EWS cells, ...

$Research paper thumbnail of Multi-Dimensional ClinOmics for Precision Therapy of Children and Adolescent Young Adults with Relapsed and Refractory Cancer: A report from the Center for Cancer Research$

Clinical cancer research : an official journal of the American Association for Cancer Research, Aug 18, 2016

Purpose We undertook a multi-dimensional clinical genomics study of children and adolescent young... more Purpose We undertook a multi-dimensional clinical genomics study of children and adolescent young adults with relapsed and refractory cancers to determine the feasibility of genome guided precision therapy. Experimental Design Patients with non-central nervous system solid tumors underwent a combination of whole exome sequencing (WES), whole transcriptome sequencing (WTS), and high-density single nucleotide polymorphism array analysis of the tumor, with WES of matched germline DNA. Clinically actionable alterations were identified as a reportable germline mutation, a diagnosis change, or a somatic event (including a single nucleotide variant, an indel, an amplification, a deletion, or a fusion gene), which could be targeted with drugs in existing clinical trials or with Food and Drug Administration approved drugs. Results Fifty-nine patients in 20 diagnostic categories were enrolled from 2010 to 2014. Ages ranged from 7-months-old to 25-years-old. Seventy-three percent of the patien...

Background: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, ... more Background: Ewing's sarcoma cells express c-kit, a receptor tyrosine kinase, and its ligand, stem cell factor (SCF), cre- ating a potential autocrine loop that may promote tumor survival. We thus examined whether the specific tyrosine kinase inhibitor imatinib mesylate (hereafter imatinib; for- merly STI571) could inhibit the proliferation of Ewing's sar- coma cells in vitro and in vivo. Methods: The

Clinical cancer research : an official journal of the American Association for Cancer Research, Jul 28, 2016

Patients with metastatic or relapsed pediatric sarcomas receive cytotoxic regimens that induce hi... more Patients with metastatic or relapsed pediatric sarcomas receive cytotoxic regimens that induce high remission rates associated with profound lymphocyte depletion, but ultimately few survive long-term. We administered adjuvant immunotherapy to patients with metastatic and recurrent pediatric sarcomas in an effort to improve outcomes. Mononuclear cells were collected via apheresis and tumor lysate was acquired via percutaneous biopsy at enrollment. Participants received standard anti-neoplastic therapy, followed by autologous lymphocytes, tumor lysate/KLH pulsed dendritic cell vaccinations ± recombinant human interleukin-7. Primary outcomes were toxicity and vaccine responses. Secondary outcomes were immune reconstitution, EFS and OS. Forty-three patients enrolled and 29 received immunotherapy. The regimen was well tolerated. Intent-to-treat analysis demonstrated 5-yr OS of 51% with significant differences based upon histologic group (63% vs 0% for Ewing/rhabdomyosarcoma vs other sarc...

Cancer, 2016

Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in ... more Adolescent and young adult (AYA) patients with cancer have not attained the same improvements in overall survival as either younger children or older adults. One possible reason for this disparity may be that the AYA cancers exhibit unique biologic characteristics, resulting in differences in clinical and treatment resistance behaviors. This report from the biologic component of the jointly sponsored National Cancer Institute and LiveStrong Foundation workshop entitled “Next Steps in Adolescent and Young Adult Oncology” summarizes the current status of biologic and translational research progress for 5 AYA cancers; colorectal cancer breast cancer, acute lymphoblastic leukemia, melanoma, and sarcoma. Conclusions from this meeting included the need for basic biologic, genomic, and model development for AYA cancers as well as translational research studies to elucidate any fundamental differences between pediatric, AYA, and adult cancers. The biologic questions for future research are ...

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 3, 2015

Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic m... more Ipilimumab is a first-in-class immune checkpoint inhibitor approved for treatment of metastatic melanoma but not studied in children until this phase 1 protocol. This study examined safety, pharmacokinetics, and immunogenicity, and immune correlates of ipilimumab administered to subjects ≤21 years old with recurrent or progressive solid tumors. Dose escalation cohorts received 1, 3, 5, or 10mg/m2 intravenously every 3 weeks in a 3 + 3 design. Response was assessed after 6 weeks and 12 weeks, and then every 3 months. Treatment was continued until disease progression or unacceptable toxicity. Thirty-three patients received 72 doses of ipilimumab. Patients enrolled had melanoma (n=12), sarcoma (n=17), or other refractory solid tumors (n= 4). Immune-related adverse events included pancreatitis, pneumonitis, colitis, endocrinopathies, and transaminitis with dose-limiting toxicities observed at 5mg/kg and 10mg/kg dose levels. Pharmacokinetics revealed a half-life of 8-15 days. At day 21, ...

Nature Reviews Clinical Oncology, 2014

After decades of research, immunotherapies for cancer are demonstrating increasing success. These... more After decades of research, immunotherapies for cancer are demonstrating increasing success. These agents can amplify existent antitumour immunity or induce durable antitumour immune responses in a wide array of cancers. The spectrum of immunotherapeutics is broad, spanning monoclonal antibodies and their derivatives, tumour vaccines, and adoptive therapies using T cells and natural killer cells. Only a small number of immunotherapies have been tested in paediatric cancers, but impressive antitumour effects have already been observed. Mononclonal antibodies targeting GD2 that induce antibody-dependent cell-mediated cytotoxicity improve survival in high-risk neuroblastoma. Bi-specific monoclonal antibodies that simultaneously target CD19 and activate T cells can induce remission in acute B-cell lymphoblastic leukaemia (B-ALL) and adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors targeting CD19 induce impressive responses in BALL. Efforts are underway to generate and test new immunotherapies in a wider array of paediatric cancers. Major challenges include a need to identify immunotherapy targets on the most lethal childhood cancers, to expand availability of technology-intense platforms, such as adoptive cell therapy, to optimize management of novel toxicities associated with this new class of cancer therapies and to determine how best to incorporate these therapies into standard treatment paradigms.

Blood, Jan 29, 2015

Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following all... more Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NK cells post-HSCT, we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 10(4) T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3(+)-depleted, CD56(+)-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL(+)IL-15Rα(+) artificial antigen-presenting cells. aNK-...

Oncogene, 2003

The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in t... more The Ewing's sarcoma family of tumors (ESFT) contain a translocation, t(11;22), which results in the novel oncogenic fusion protein EWS/FLI1. Platelet-derived growth factors (PDGF) and their receptors (PDGFR) are involved in the induction and proliferation of numerous solid tumors and are the potential candidates for novel targeted antitumor therapy. Since a relation was reported between PDGF-C and EWS/FLI1, we sought to characterize the PDGF signaling pathway in ESFT. Eight out of nine ESFT cell lines were found to express significant levels of b-PDGFR. Interestingly, none of the tested cell lines expressed a-PDGFR, which is the receptor isotype required for PDGF-C binding. By immunohistochemical staining 47 of 52 (90.4%) archival tumor samples from patients with ESFT were positive for b-PDGFR. ESFT cell lines were treated with PDGF-AA or PDGF-BB ligands to evaluate downstream signaling. Autophosphorylation of b-PDGFR and tyrosine phosphorylation of PLC-c, PI3Kp85 and Shc were detected only in PDGF-BB-stimulated cells that express b-PDGFR. Receptor function was further evaluated using chemotaxis assays that showed TC-32 cell migration towards PDGF-BB. A specific PDGFR kinase inhibitor AG1295 blocked b-PDGFR activation, downstream signaling, growth in cell culture and chemotaxis of TC-32 cells. AG1295 also delayed tumor formation and prolonged survival in an ESFT animal model. We conclude that ESFT express b-PDGFR and that this is a functional and potentially crucial signaling pathway. Therefore, b-PDGFRs may provide a novel therapeutic target in ESFT that can be utilized to design better treatment modalities.

Nature Medicine, 2009

Many sarcomas and leukemias carry non-random chromosomal translocations encoding mutant fusion tr... more Many sarcomas and leukemias carry non-random chromosomal translocations encoding mutant fusion transcription factors that are essential to their molecular pathogenesis. These novel, tumorspecific proteins provides a unique opportunity for the development of highly selective anticancer drugs that has yet to be exploited. A particularly clear example is provided by Ewing's Sarcoma Family Tumors (ESFT) which contain a characteristic t(11;22) translocation leading to expression of the oncogenic fusion protein EWS-FLI1. EWS-FLI1 is a disordered protein that precluded standard structure-based small molecule inhibitor design. Using surface plasmon resonance screening, we discovered a lead compound, NSC635437. A derivative compound, YK-4-279, blocks RHA binding to EWS-FLI1, induces apoptosis in ESFT cells, and reduces the growth of ESFT orthotopic xenografts. These findings provide proof of principle that inhibiting the interaction of mutant cancer-specific transcription factors with the normal cellular binding partners required for their oncogenic activity provides a promising strategy for the development of uniquely effective, tumor-specific anticancer agents. There is a significant need for new cancer therapies that enhance efficacy and reduce longterm morbidity. Protein products of tumor-specific chromosomal translocations, which are present only in cancer cells, provide unique targets for anti-tumor therapies1. These translocations span a broad range of malignancies, including carcinomas, hematopoietic malignancies, and sarcomas2-4. In many cancers, these translocations lead to novel fusion proteins that both initiate and maintain oncogenesis. While some of these translocations, such as BCR-ABL5, lead to constitutively activated kinases, the majority lead to fusion proteins that function as transcription factors and lack intrinsic enzymatic activity. These translocation-generated transcription factor fusion proteins are ideal targets of anti-cancer therapies, yet no pharmaceuticals have been developed towards these targets. The Ewing's sarcoma family of tumors (ESFT) can occur anywhere in the body and most often in the 2 nd and 3 rd decades. ESFT often respond well to initial chemotherapy, yet 40% of patients will develop recurrent disease. The majority of patients with recurrent disease will die from ESFT, while 75-80% of patients who present with metastatic ESFT will die Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Journal of Thoracic Oncology, 2010

Introduction: Primary lung adenocarcinoma is extremely rare in the pediatric age group. There hav... more Introduction: Primary lung adenocarcinoma is extremely rare in the pediatric age group. There have been anecdotal reports of lesions that are histologically indistinguishable from adult-type pulmonary adenocarcinoma in young patients after treatment for nonpulmonary cancers. Herein, we present clinical, histopathologic, and molecular data on eight such cases. Methods: Histopathologic evaluation of the tumors was performed according to the World Health Organization classification. Molecular studies for EGFR and KRAS mutations were performed on six patients with sufficient material. Results: All eight patients were never smokers, four males and four females. Median age at nonpulmonary cancer diagnosis was 14 years (range, 3-23 years). Pulmonary adenocarcinomas were diagnosed at a median age of 15 years (range, 10-24 years); tumors were 0.1 to 2.0 cm in size and in some cases coexisted with metastases from the original cancer. Retrospective review showed that in at least three patients, the nodules were radiographically present before chemotherapy. Of six patients whose tumors were tested for common EGFR and KRAS mutations, two were positive for the former and one for the latter. At a median follow-up of 11 months (range, 2-29 months), six patients remained well without lung nodules and two had additional small, peripheral lung nodules that have not been biopsied. Conclusions: Pulmonary lesions found in young patients with pediatric cancers can be histologically indistinguishable from lung adenocarcinoma seen in adults, may display typical adenocarcinoma-associated mutations of EGFR and KRAS, and may precede the administration of cytotoxic chemotherapy.

JNCI Journal of the National Cancer Institute, 2004

Background: Alternative treatment options are needed for advanced neuroblastoma patients because ... more Background: Alternative treatment options are needed for advanced neuroblastoma patients because their prognosis remains poor after intensive chemotherapy. Neuroblastoma cells express platelet-derived growth factor (PDGF), stem cell factor (SCF), and vascular endothelial growth factor (VEGF) and their respective receptors, PDGFR, c-Kit, and Flk-1. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the tyrosine kinase activities of c-Kit and PDGFR, on the growth of neuroblastoma cells in vivo and in vitro. Methods: We tested seven human neuroblastoma cell lines for their sensitivity to imatinib. Cell viability was assessed by trypan blue dye exclusion. Apoptosis was evaluated by nuclear staining, flow cytometry, and western blotting. Protein assays included immunoprecipitation, western blotting, enzyme-linked immunosorbent assays, and immunohistochemistry. mRNA expression was assessed by northern blotting. We used a xenograft model in SCID mice (10 mice per group) to evaluate the effects of imatinib oral therapy (50 or 100 mg/kg every 12 hours for 14 days) on neuroblastoma tumor growth. All statistical tests were two-sided. Results: All seven neuroblastoma cell lines treated with imatinib displayed concentrationdependent decreases in cell viability, which coincided with an induction of apoptosis, and with ligand-stimulated phosphorylation of c-Kit and PDGFR. The imatinib concentrations that caused 50% inhibition of growth and 50% inhibition of ligand-induced phosphorylation of these receptors were 9-13 M and 0.1-0.5 M, respectively. Expression of VEGF, but not phosphorylation of Flk-1, its receptor, was reduced in neuroblastoma cells treated with imatinib at 10 M or higher. Mice treated with imatinib at 50 mg/kg or 100 mg/kg had statistically significantly smaller tumors than control mice treated with vehicle (mean tumor volume in mice treated with imatinib at 50 mg/kg ‫؍‬ 1546 mm 3 , in control mice ‫؍‬ 2954 mm 3 ; difference ‫؍‬ 1408 mm 3 , 95% confidence interval [CI] ‫؍‬ 657 to 2159 mm 3 ; P<.001; mean tumor volume in mice treated with imatinib at 100 mg/kg ‫؍‬ 463 mm 3 ; difference ‫؍‬ 2491 mm 3 , 95% CI ‫؍‬ 1740 to 3242 mm 3 ; P<.001). Conclusions: Imatinib inhibited the growth of neuroblastoma cells in vitro and in vivo. This inhibition was associated with suppression of PDGFR and c-Kit phosphorylation and inhibition of VEGF expression. [J Natl Cancer Inst 2004;96:46-55] Neuroblastoma is the most common solid extracranial tumor of early childhood (1). Several tumor characteristics, such as amplification of the N-myc oncogene and loss of heterozygosity at chromosome 1p, are statistically significant indicators of poor prognosis for neuroblastoma patients (3). Neuroblastoma patients with high-risk or disseminated disease continue to have a poor prognosis, even after they have undergone intensive chemotherapy and autologous bone marrow transplantation (2). Alternative treatments are therefore needed to improve the prognosis of neuroblastoma patients with high-risk disease. Receptor tyrosine kinases have been proposed as potential targets for antitumor therapy. For example, imatinib mesylate (also known as STI571 or Gleevec, and hereafter called imatinib) was initially shown to inhibit in vitro growth of Abltransformed cells and Bcr-Abl-positive chronic myelogenous leukemia (CML) cells through selective inhibition of the Abl tyrosine kinase (4). Imatinib is also a highly selective inhibitor of the tyrosine kinase activities of c-Kit, the receptor for stem cell factor (SCF), and platelet-derived growth factor receptor (PDGFR) (5). Results of recent clinical studies (7) have shown that imatinib therapy is well tolerated and leads to remission in patients with Bcr-Abl-positive CML or c-Kit-positive gastrointestinal stromal tumor (GIST). Preclinical data suggest that imatinib has cytotoxic and cytostatic activities and effectively inhibits the growth of tumor cell lines that contain gain-offunction mutations in Abl and c-Kit as well as tumor cells that express autocrine growth loops (5). Imatinib has also been reported to inhibit the growth of glioblastoma, dermatofibrosarcoma protuberans, and small-cell lung cancer, all of which may express the PDGF/PDGFR or SCF/c-Kit autocrine growth loops (8-10). Recently, we have shown that imatinib interferes with the in vitro and in vivo growth of Ewing's sarcoma which, like neuroblastoma, is a tumor of peripheral neuroectodermal origin (11). SCF and c-Kit mRNAs are expressed in neuroblastoma cell lines and in neuroblastoma tumor samples (12). The SCF/c-Kit autocrine growth loop is thought to be important for cell survival because neuroblastoma cells treated with an antibody to c-Kit undergo increased levels of apoptosis (13). Neuroblastoma cell lines also express functional PDGFR-␣, PDGFR-␤, and their respective ligands, PDGF-AA and PDGF-BB (14). These observations led us to hypothesize that imatinib might inhibit neuroblastoma cell growth and survival via inhibition of the SCF/c-Kit and PDGF/PDGFR autocrine growth loops. Tyrosine kinase receptors also play a role in angiogenesis, an essential step for tumor growth and metastasis. Tumor cell growth and metastasis require perturbation of the local balance of pro-angiogenic and anti-angiogenic factors, which is referred

Journal of Clinical Oncology, 2012

Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis facto... more Purpose Lexatumumab is an agonistic, fully human monoclonal antibody against tumor necrosis factor–related apoptosis-inducing ligand receptor 2 with preclinical evidence of activity in pediatric solid tumors. Patients and Methods This phase I dose-escalation study examined the safety, tolerability, pharmacokinetics, and immunogenicity of lexatumumab at doses up to, but not exceeding, the adult maximum-tolerated dose (3, 5, 8, and 10 mg/kg), administered once every 2 weeks to patients age ≤ 21 years with recurrent or progressive solid tumors. Results Twenty-four patients received a total of 56 cycles of lexatumumab over all four planned dose levels. One patient had grade 2 pericarditis consistent with radiation recall, and one patient developed grade 3 pneumonia with hypoxia during the second cycle. Five patients experienced stable disease for three to 24 cycles. No patients experienced complete or partial response, but several showed evidence of antitumor activity, including one pat...

Cancer research, 2003

The resistance of neuroblastoma (NB) cells to tumor necrosis factorrelated apoptosis-inducing lig... more The resistance of neuroblastoma (NB) cells to tumor necrosis factorrelated apoptosis-inducing ligand (TRAIL)-induced apoptosis has been attributed to a lack of caspase 8 expression. Here we demonstrate a clinically applicable molecular targeting strategy that not only increases caspase 8 expression ex vivo in NB cell lines but also in the tumor tissues of NB patients receiving IFN-␥ treatment. We identify the functional caspase 8 promoter, which is different from the methylated region reported previously, and show promoter activity is up-regulated by IFN-␥ through a IFN-␥ activation site-containing region. IFN-␥ also induces TRAIL expression in NB cell lines. However, the IFN-␥ restoration of caspase 8 in some NB cells revealed persistent TRAIL resistance in most NB cell lines examined. This additional lesion in the TRAIL path is because of a loss of cell membrane TRAIL receptors (TR1/TR2) not only in cell lines but in most of the NB tumor tissues evaluated. Restoration of TR2 expression by transfection enhances IFN-␥-induced TRAIL sensitivity. Furthermore, we have found that we can improve TRAIL sensitivity in NB by reconstituting caspase 8 with IFN-␥ and TR2 with chemotherapeutic agents.