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      • Record: found
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      Is Open Access

      Molecular profiling of childhood cancer: Biomarkers and novel therapies

      review-article
      Author(s): a , b , b , c , b , c , b , d , b , a , e , *
      Publication date (Electronic):
      Journal: BBA Clinical
      Publisher: Elsevier
      Keywords: ALK, anaplastic lymphoma kinase, ALL, acute lymphoblastic leukemia, AML, acute myeloid leukemia, ARMS, alveolar rhabdomyosarcoma, AT/RT, atypical teratoid/rhabdoid tumor, AURKA, aurora kinase A, AURKB, aurora kinase B, BET, bromodomain and extra terminal, CAR, chimeric antigen receptor, CML, chronic myeloid leukemia, DFMO, difluoromethylornithine, DIPG, diffuse intrinsic pontine glioma, EGFR, epidermal growth factor receptor, ERMS, embryonal rhabdomyosarcoma, HDAC, histone deacetylases, Hsp90, heat shock protein 90, IGF/IGFR, insulin-like growth factor/receptor, IGF-1R, insulin-like growth factor type 1 receptor, mAb, monoclonal antibody, mAbs, monoclonal antibodies, mTOR, mammalian target of rapamycin, NSCLC, non-small cell lung cancer, ODC1, ornithine decarboxylase 1, PARP, poly(ADP-ribose) polymerase, PDGFRA/B, platelet derived growth factor alpha/beta, Ph +, Philadelphia chromosome-positive, PI3K, phosphatidylinositol 3′-kinase, PLK1, polo-like kinase 1, RMS, rhabdomyosarcoma, SHH, sonic hedgehog, SMO, smoothened, SYK, spleen tyrosine kinase, TOP1/TOP2, DNA topoisomerase 1/2, TRAIL, TNF-related apoptosis-inducing ligand, VEGF/VEGFR, vascular endothelial growth factor/receptor, Childhood cancer, Molecular diagnostics, Targeted therapy, Biomarkers

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          Abstract

          Background

          Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies.

          Scope of review

          This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type.

          Major conclusions

          There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies.

          General significance

          The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.

          Highlights

          • •

            Increasing numbers of targeted therapies are being tested for pediatric cancers.

          • •

            Molecularly targeted therapies are proving most effective in combination regimes.

          • •

            More rigorous preclinical testing should further improve clinical trial results.

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          Most cited references285

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          Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers.

          Daniel D. Von Hoff, Joseph J. Stephenson, Peter Rosen … (2010)
          To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.
          Article 0 comments Cited 215 times – based on 0 reviews     Review now
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            The BATTLE trial: personalizing therapy for lung cancer.

            Edward S. Kim, Roy S. Herbst, Ignacio Wistuba … (2011)
            The Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial represents the first completed prospective, biopsy-mandated, biomarker-based, adaptively randomized study in 255 pretreated lung cancer patients. Following an initial equal randomization period, chemorefractory non-small cell lung cancer (NSCLC) patients were adaptively randomized to erlotinib, vandetanib, erlotinib plus bexarotene, or sorafenib, based on relevant molecular biomarkers analyzed in fresh core needle biopsy specimens. Overall results include a 46% 8-week disease control rate (primary end point), confirm prespecified hypotheses, and show an impressive benefit from sorafenib among mutant-KRAS patients. BATTLE establishes the feasibility of a new paradigm for a personalized approach to lung cancer clinical trials. The BATTLE study is the first completed prospective, adaptively randomized study in heavily pretreated NSCLC patients that mandated tumor profiling with "real-time" biopsies, taking a substantial step toward realizing personalized lung cancer therapy by integrating real-time molecular laboratory findings in delineating specific patient populations for individualized treatment.
            Article 0 comments Cited 209 times – based on 0 reviews     Review now
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              Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism.

              X. Wan, B Harkavy, N Shen … (2007)
              Rapamycin and several analogs, such as CCI-779 and RAD001, are currently undergoing clinical evaluation as anticancer agents. In this study, we show that inhibition of mammalian target of rapamycin (mTOR) signaling by rapamycin leads to an increase of Akt phosphorylation in Rh30 and RD human rhabdomyosarcoma cell lines and xenografts, and insulin-like growth factor (IGF)-II-treated C2C12 mouse myoblasts and IGF-II-overexpressing Chinese hamster ovary cells. RNA interference-mediated knockdown of S6K1 also results in an increase of Akt phosphorylation. These data suggest that mTOR/S6K1 inhibition either by rapamycin or small interfering RNA (siRNA) triggers a negative feedback loop, resulting in the activation of Akt signaling. We next sought to investigate the mechanism of this negative feedback regulation from mTOR to Akt. Suppression of insulin receptor substrate (IRS)-1 and tuberous sclerosis complex-1 by siRNAs failed to abrogate rapamycin-induced upregulation of Akt phosphorylation in both Rh30 and RD cells. However, pretreatment with h7C10 antibody directed against insulin-like growth factor-1 receptor (IGF-1R) led to a blockade of rapamycin-induced Akt activation. Combined mTOR and IGF-1R inhibition with rapamycin and h7C10 antibody, respectively, resulted in additive inhibition of cell growth and survival. These data suggest that rapamycin mediates Akt activation through an IGF-1R-dependent mechanism. Thus, combining an mTOR inhibitor and an IGF-1R antibody/inhibitor may be an appropriate strategy to enhance mTOR-targeted anticancer therapy.
              Article 0 comments Cited 205 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jennifer A. Byrne
                Journal
                Journal ID (nlm-ta): BBA Clin
                Journal ID (iso-abbrev): BBA Clin
                Title: BBA Clinical
                Publisher: Elsevier
                ISSN (Electronic): 2214-6474
                Publication date PMC-release: 28 June 2014
                Publication date Collection: June 2014
                Publication date (Electronic): 28 June 2014
                Volume: 1
                Pages: 59-77
                Affiliations
                [a ]Children's Cancer Research Unit, Kids Research Institute, Westmead 2145, New South Wales, Australia
                [b ]Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
                [c ]Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, New South Wales, Australia
                [d ]The Children's Hospital at Westmead, Westmead 2145, New South Wales, Australia
                [e ]The University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Westmead 2145, New South Wales, Australia
                Author notes
                [* ]Corresponding author at: Children's Cancer Research Unit, Kids Research Institute, The Children's Hospital at Westmead, Locked Bag 4001, Westmead 2145, New South Wales, Australia. Tel.: + 61 2 9845 3027, fax: + 61 2 9845 3078. jennifer.byrne@ 123456health.nsw.gov.au
                Article
                Publisher ID: S2214-6474(14)00010-5
                DOI: 10.1016/j.bbacli.2014.06.003
                PMC ID: 4633945
                PubMed ID: 26675306
                SO-VID: 2dcf273d-f7fe-4dc7-8d9c-f5db4cb70052
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY-NC-SA license (http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                Date received : 20 December 2013
                Date revision received : 16 June 2014
                Date accepted : 24 June 2014
                Categories
                Subject: Review

                Keywords: alk, anaplastic lymphoma kinase,all, acute lymphoblastic leukemia,aml, acute myeloid leukemia,arms, alveolar rhabdomyosarcoma,at/rt, atypical teratoid/rhabdoid tumor,aurka, aurora kinase a,aurkb, aurora kinase b,bet, bromodomain and extra terminal,car, chimeric antigen receptor,cml, chronic myeloid leukemia,dfmo, difluoromethylornithine,dipg, diffuse intrinsic pontine glioma,egfr, epidermal growth factor receptor,erms, embryonal rhabdomyosarcoma,hdac, histone deacetylases,hsp90, heat shock protein 90,igf/igfr, insulin-like growth factor/receptor,igf-1r, insulin-like growth factor type 1 receptor,mab, monoclonal antibody,mabs, monoclonal antibodies,mtor, mammalian target of rapamycin,nsclc, non-small cell lung cancer,odc1, ornithine decarboxylase 1,parp, poly(adp-ribose) polymerase,pdgfra/b, platelet derived growth factor alpha/beta,ph +, philadelphia chromosome-positive,pi3k, phosphatidylinositol 3′-kinase,plk1, polo-like kinase 1,rms, rhabdomyosarcoma,shh, sonic hedgehog,smo, smoothened,syk, spleen tyrosine kinase,top1/top2, dna topoisomerase 1/2,trail, tnf-related apoptosis-inducing ligand,vegf/vegfr, vascular endothelial growth factor/receptor,childhood cancer,molecular diagnostics,targeted therapy,biomarkers
                Data availability:
                Keywords: alk, anaplastic lymphoma kinase, all, acute lymphoblastic leukemia, aml, acute myeloid leukemia, arms, alveolar rhabdomyosarcoma, at/rt, atypical teratoid/rhabdoid tumor, aurka, aurora kinase a, aurkb, aurora kinase b, bet, bromodomain and extra terminal, car, chimeric antigen receptor, cml, chronic myeloid leukemia, dfmo, difluoromethylornithine, dipg, diffuse intrinsic pontine glioma, egfr, epidermal growth factor receptor, erms, embryonal rhabdomyosarcoma, hdac, histone deacetylases, hsp90, heat shock protein 90, igf/igfr, insulin-like growth factor/receptor, igf-1r, insulin-like growth factor type 1 receptor, mab, monoclonal antibody, mabs, monoclonal antibodies, mtor, mammalian target of rapamycin, nsclc, non-small cell lung cancer, odc1, ornithine decarboxylase 1, parp, poly(adp-ribose) polymerase, pdgfra/b, platelet derived growth factor alpha/beta, ph +, philadelphia chromosome-positive, pi3k, phosphatidylinositol 3′-kinase, plk1, polo-like kinase 1, rms, rhabdomyosarcoma, shh, sonic hedgehog, smo, smoothened, syk, spleen tyrosine kinase, top1/top2, dna topoisomerase 1/2, trail, tnf-related apoptosis-inducing ligand, vegf/vegfr, vascular endothelial growth factor/receptor, childhood cancer, molecular diagnostics, targeted therapy, biomarkers

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