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Osteosarcoma: Lessons Learned and Future Avenues

Osteosarcoma: Lessons Learned and Future Avenues Hindawi Publishing Corporation Sarcoma Volume 2013, Article ID 641687, 2 pages http://dx.doi.org/10.1155/2013/641687 Editorial 1 2 3 Ajay Puri, Norman Jaffe, and Hans Gelderblom Department of Surgical Oncology, Tata Memorial Hospital, Mumbai 400012, India Children’s Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, eTh Netherlands Correspondence should be addressed to Hans Gelderblom; a.j.gelderblom@lumc.nl Received 28 July 2013; Accepted 28 July 2013 Copyright © 2013 Ajay Puri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Osteosarcoma is the most common malignant bone tumor in improved in the interferon arm, although the results may men. The incidence peaks around puberty, with a broader and have been influenced by the low randomization and high lowerpeakaeft r60years of age. Risk factorsare (pubertal) treatment refusal rate. Definite results and results of the poor growth, genetic factors, Paget’s disease, and prior radiother- responder randomization are pending. The study has proven apy. More than 90% of tumors are of high grade, and their that a worldwide platform for potential practice changing prognosis, even without metastasis at presentation, remains rapidly accruing randomized phase III studies is feasible in dismal in up to 30–45% of cases despite great improvements this rare disease and therefore should be used in the future. due to the introduction of chemotherapy some decades ago. The Birmingham experience with low-grade conven- The contribution “ Osteosarcoma: evolution of treatment tional osteosarcoma (LGCO), a rare (1.2%) and difficult to paradigms” to this osteosarcoma special issue is truly unique diagnose variant of osteosarcoma, is also part of this special as it describes the history of systemic treatment from rfi st issue. The diagnosis of LGCO is challenging due to the hand, as the rfi st author N. Jaeff coauthored the rfi st studies relatively nonspecific radiological and histological ndin fi gs. on the dramatic improvement of long-term survival from 10– Since treatment of LGCO is so different compared to a 15% to 55–70% due to addition of multiagent chemotherapy. benign lesion as well as to high-grade osteosarcoma, accurate This magnitude of improvement has never been observed in diagnosis is essential. eTh authors therefore advise that any other solid tumors, with the exception of germ cell tumors difficult or nondiagnostic biopsies of solitary bone lesions and some childhood cancers such as rhabdomyosarcoma should be referred to a specialist (bone) tumor unit for a and Ewing’s sarcoma. However, these percentages have not second opinion: a conclusion that we fully agree with and further improved over the last decades, and new therapies are should be part of all guidelines. needed urgently to cure the remaining one-third of patients N. Federman et al. describe a novel osteosarcoma-ass- and increase the chances for patients with metastatic disease. ociated cell surface antigen, ALCAM. eTh authors created The authors describe the design of the current EURAMOS an anti-ALCAM-hybrid polymerized liposomal nanoparti- study. Meanwhile, the rfi st results of the PEG interferon cle immunoconjugate (𝛼 -AL-HPLN) to specifically target randomization in the good responder arm were presented at osteosarcoma cells and deliver a cytotoxic agent such as dox- the 2013 annual meeting of the American Society of Clinical orubicin. If feasible in clinical practice, these𝛼 -AL-HPLNs Oncology [1]. From the2260includedpatients, 1034 hada are a promising new strategy to specifically deliver cyto- good pathological response to preoperative chemotherapy. Of toxic agents in osteosarcoma. A similar approach recently these patients 715, were randomized to either PEG interferon took place in breast cancer where the antibody-drug con- or observation. Only 76% of the patients randomized to jugate trastuzumab-DM1 (T-DM1) was designed to com- interferon started treatment, mainly due to refusal. The bine the biological activity of trastuzumab with the tar- event-free survival (primary endpoint) was not statistically geted delivery of a highly potent chemotherapeutic agent to 2 Sarcoma HER2-overexpressing breast cancer cells. eTh success of the designed studies that can be performed rapidly in interna- approach in breast cancer underlines the promise of𝛼 -AL- tional collaboration of bone centers. This osteosarcoma issue HPLN in osteosarcoma. of Sarcoma is just a tiny step in this process that will need Y. Suehara et al. focus on proteomics to provide protein perseverance. expression profiles of osteosarcoma that can be used to Ajay Puri develop novel diagnostic and therapeutic biomarkers as well Norman Jaeff as to understand its biology. The authors provide a brief Hans Gelderblom description of the methodology as well as examples of the recent proteomic studies that have generated new informa- tion regarding osteosarcomas. This approach should lead the References way to predictive and prognostic information as well as neces- [1] S. S. Bielack, S. Smeland, J. Whelan et al., “MAP plus mainte- sary new drug targets in order to bring the necessary further nance pegylated interferon𝛼 -2b (MAPIfn) versus MAP alone improvement of our therapeutic strategies in osteosarcoma. in patients with resectable high-grade osteosarcoma and good M. M. Hagleitner et al. show us a single center experience histologic response to preoperative MAP: First results of the with osteosarcoma patients under the age of 20. In this EURAMOS-1 “good response” randomization,” Journal of Clin- retrospective series, improvement in toxicity and outcome ical Oncology, vol. 31, Article ID LBA10504, 2013. was observed over the past 30 years that was attributed to [2] A.-M. Cleton-Jansen, J. K. Anninga, I. H. Briaire-De Bruijn et improved supportive care allowing the intended full-dose al., “Profiling of high-grade central osteosarcoma and its puta- chemotherapy regimen to be given. It is very well possible tive progenitor cells identifies tumourigenic pathways,” British that improved experience due to centralization may also have Journal of Cancer,vol.101,no. 11, pp.1909–1918,2009. added to this eeff ct. [3] S. P. Chawla, A. P. Staddon, L. H. Baker et al., “Phase II study of S. Piperdietal. presentapreclinicalevaluationofthe role the mammalian target of rapamycin inhibitor ridaforolimus in of𝛽 -catenin in osteosarcoma development thought to orig- patients with advanced bone and soft tissue sarcomas,” Journal inate from the mesenchymal stem cell. Despite fostering of Clinical Oncology,vol.30, no.1,pp. 78–84, 2012. osteogenic differentiation, 𝛽 -catenin does not induce the [4] G.D.Demetri,S.P.Chawla, I. Ray-Coquardetal.,“Resultsofan malignant features and tumorigenicity conveyed by onco- international randomized phase III trial of the mammalian tar- genic H-RAS when introduced into partly transformed mes- get of rapamycin inhibitor ridaforolimus to control metastatic enchymal stem cells. Despite this observation, C. H. Lin et sarcoma in patients aeft r benefit from prior chemotherapy,” Journal of Clinical Oncology,vol.31, no.19, pp.2485–2492,2013. al. show, using in vivo and in vitro studies, that Dickkopf-3 protein (Dkk-3) transfected 143B cells inhibited tumorigen- esis and metastasis in an orthotopic xenograft model of OS. As Dkk-3 is known to inhibit the canonical Wnt/𝛽 -catenin pathway and its expression has been shown to be down- regulatedinosteosarcomacelllines,wemustrealize that a delicate interplay of this pathway is present in osteosarcoma and requires further understanding before it can be targeted in the clinic. In the paper by R. Muff et al., forty-eight common genes that are differentially expressed in metastatic cell lines compared to parental cells were identified. This subset of metastasis relevant genes in osteoblastic osteosarcoma over- lapped only minimally with differentially expressed genes in the other four preosteoblast or nonosteoblastic cell line systems. These studies add to the microarray studies that were performed in the clinical research setting [2]. X. Mu et al. present a preclinical rationale for m-TOR inhibition for the treatment and prevention of osteosarcoma metastases. A phase II study including osteosarcoma patients was promising [3]. However, the Sarcoma mUltiCenter Clin- ical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial did not lead to registration of maintenance mTOR- targeted therapy in metastatic (osteo)sarcoma as the FDA rejected the application in May 2012 [4]. Maybe earlier treat- ment in nonmetastatic patients or combination treatment or patient selection based on prospectively collected biomarkers mayleadthe waytofutureclinicaluse. In our opinion, the holy grail towards further survival benefit in osteosarcoma is thorough preclinical studies lead- ing to new targets and biomarkers, followed by properly MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Sarcoma Hindawi Publishing Corporation

Osteosarcoma: Lessons Learned and Future Avenues

Sarcoma , Volume 2013 – Sep 4, 2013

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Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2013 Ajay Puri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
1357-714X
eISSN
1369-1643
DOI
10.1155/2013/641687
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See Article on Publisher Site

Abstract

Hindawi Publishing Corporation Sarcoma Volume 2013, Article ID 641687, 2 pages http://dx.doi.org/10.1155/2013/641687 Editorial 1 2 3 Ajay Puri, Norman Jaffe, and Hans Gelderblom Department of Surgical Oncology, Tata Memorial Hospital, Mumbai 400012, India Children’s Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, eTh Netherlands Correspondence should be addressed to Hans Gelderblom; a.j.gelderblom@lumc.nl Received 28 July 2013; Accepted 28 July 2013 Copyright © 2013 Ajay Puri et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Osteosarcoma is the most common malignant bone tumor in improved in the interferon arm, although the results may men. The incidence peaks around puberty, with a broader and have been influenced by the low randomization and high lowerpeakaeft r60years of age. Risk factorsare (pubertal) treatment refusal rate. Definite results and results of the poor growth, genetic factors, Paget’s disease, and prior radiother- responder randomization are pending. The study has proven apy. More than 90% of tumors are of high grade, and their that a worldwide platform for potential practice changing prognosis, even without metastasis at presentation, remains rapidly accruing randomized phase III studies is feasible in dismal in up to 30–45% of cases despite great improvements this rare disease and therefore should be used in the future. due to the introduction of chemotherapy some decades ago. The Birmingham experience with low-grade conven- The contribution “ Osteosarcoma: evolution of treatment tional osteosarcoma (LGCO), a rare (1.2%) and difficult to paradigms” to this osteosarcoma special issue is truly unique diagnose variant of osteosarcoma, is also part of this special as it describes the history of systemic treatment from rfi st issue. The diagnosis of LGCO is challenging due to the hand, as the rfi st author N. Jaeff coauthored the rfi st studies relatively nonspecific radiological and histological ndin fi gs. on the dramatic improvement of long-term survival from 10– Since treatment of LGCO is so different compared to a 15% to 55–70% due to addition of multiagent chemotherapy. benign lesion as well as to high-grade osteosarcoma, accurate This magnitude of improvement has never been observed in diagnosis is essential. eTh authors therefore advise that any other solid tumors, with the exception of germ cell tumors difficult or nondiagnostic biopsies of solitary bone lesions and some childhood cancers such as rhabdomyosarcoma should be referred to a specialist (bone) tumor unit for a and Ewing’s sarcoma. However, these percentages have not second opinion: a conclusion that we fully agree with and further improved over the last decades, and new therapies are should be part of all guidelines. needed urgently to cure the remaining one-third of patients N. Federman et al. describe a novel osteosarcoma-ass- and increase the chances for patients with metastatic disease. ociated cell surface antigen, ALCAM. eTh authors created The authors describe the design of the current EURAMOS an anti-ALCAM-hybrid polymerized liposomal nanoparti- study. Meanwhile, the rfi st results of the PEG interferon cle immunoconjugate (𝛼 -AL-HPLN) to specifically target randomization in the good responder arm were presented at osteosarcoma cells and deliver a cytotoxic agent such as dox- the 2013 annual meeting of the American Society of Clinical orubicin. If feasible in clinical practice, these𝛼 -AL-HPLNs Oncology [1]. From the2260includedpatients, 1034 hada are a promising new strategy to specifically deliver cyto- good pathological response to preoperative chemotherapy. Of toxic agents in osteosarcoma. A similar approach recently these patients 715, were randomized to either PEG interferon took place in breast cancer where the antibody-drug con- or observation. Only 76% of the patients randomized to jugate trastuzumab-DM1 (T-DM1) was designed to com- interferon started treatment, mainly due to refusal. The bine the biological activity of trastuzumab with the tar- event-free survival (primary endpoint) was not statistically geted delivery of a highly potent chemotherapeutic agent to 2 Sarcoma HER2-overexpressing breast cancer cells. eTh success of the designed studies that can be performed rapidly in interna- approach in breast cancer underlines the promise of𝛼 -AL- tional collaboration of bone centers. This osteosarcoma issue HPLN in osteosarcoma. of Sarcoma is just a tiny step in this process that will need Y. Suehara et al. focus on proteomics to provide protein perseverance. expression profiles of osteosarcoma that can be used to Ajay Puri develop novel diagnostic and therapeutic biomarkers as well Norman Jaeff as to understand its biology. The authors provide a brief Hans Gelderblom description of the methodology as well as examples of the recent proteomic studies that have generated new informa- tion regarding osteosarcomas. This approach should lead the References way to predictive and prognostic information as well as neces- [1] S. S. Bielack, S. Smeland, J. Whelan et al., “MAP plus mainte- sary new drug targets in order to bring the necessary further nance pegylated interferon𝛼 -2b (MAPIfn) versus MAP alone improvement of our therapeutic strategies in osteosarcoma. in patients with resectable high-grade osteosarcoma and good M. M. Hagleitner et al. show us a single center experience histologic response to preoperative MAP: First results of the with osteosarcoma patients under the age of 20. In this EURAMOS-1 “good response” randomization,” Journal of Clin- retrospective series, improvement in toxicity and outcome ical Oncology, vol. 31, Article ID LBA10504, 2013. was observed over the past 30 years that was attributed to [2] A.-M. Cleton-Jansen, J. K. Anninga, I. H. Briaire-De Bruijn et improved supportive care allowing the intended full-dose al., “Profiling of high-grade central osteosarcoma and its puta- chemotherapy regimen to be given. It is very well possible tive progenitor cells identifies tumourigenic pathways,” British that improved experience due to centralization may also have Journal of Cancer,vol.101,no. 11, pp.1909–1918,2009. added to this eeff ct. [3] S. P. Chawla, A. P. Staddon, L. H. Baker et al., “Phase II study of S. Piperdietal. presentapreclinicalevaluationofthe role the mammalian target of rapamycin inhibitor ridaforolimus in of𝛽 -catenin in osteosarcoma development thought to orig- patients with advanced bone and soft tissue sarcomas,” Journal inate from the mesenchymal stem cell. Despite fostering of Clinical Oncology,vol.30, no.1,pp. 78–84, 2012. osteogenic differentiation, 𝛽 -catenin does not induce the [4] G.D.Demetri,S.P.Chawla, I. Ray-Coquardetal.,“Resultsofan malignant features and tumorigenicity conveyed by onco- international randomized phase III trial of the mammalian tar- genic H-RAS when introduced into partly transformed mes- get of rapamycin inhibitor ridaforolimus to control metastatic enchymal stem cells. Despite this observation, C. H. Lin et sarcoma in patients aeft r benefit from prior chemotherapy,” Journal of Clinical Oncology,vol.31, no.19, pp.2485–2492,2013. al. show, using in vivo and in vitro studies, that Dickkopf-3 protein (Dkk-3) transfected 143B cells inhibited tumorigen- esis and metastasis in an orthotopic xenograft model of OS. As Dkk-3 is known to inhibit the canonical Wnt/𝛽 -catenin pathway and its expression has been shown to be down- regulatedinosteosarcomacelllines,wemustrealize that a delicate interplay of this pathway is present in osteosarcoma and requires further understanding before it can be targeted in the clinic. In the paper by R. Muff et al., forty-eight common genes that are differentially expressed in metastatic cell lines compared to parental cells were identified. This subset of metastasis relevant genes in osteoblastic osteosarcoma over- lapped only minimally with differentially expressed genes in the other four preosteoblast or nonosteoblastic cell line systems. These studies add to the microarray studies that were performed in the clinical research setting [2]. X. Mu et al. present a preclinical rationale for m-TOR inhibition for the treatment and prevention of osteosarcoma metastases. A phase II study including osteosarcoma patients was promising [3]. However, the Sarcoma mUltiCenter Clin- ical Evaluation of the Efficacy of riDaforolimus (SUCCEED) trial did not lead to registration of maintenance mTOR- targeted therapy in metastatic (osteo)sarcoma as the FDA rejected the application in May 2012 [4]. Maybe earlier treat- ment in nonmetastatic patients or combination treatment or patient selection based on prospectively collected biomarkers mayleadthe waytofutureclinicaluse. In our opinion, the holy grail towards further survival benefit in osteosarcoma is thorough preclinical studies lead- ing to new targets and biomarkers, followed by properly MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

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SarcomaHindawi Publishing Corporation

Published: Sep 4, 2013

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