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Commentary and Perspective   |    
Commentary on an article by Kyucheol Noh, MD, et al.: “Targeting Inflammatory Kinase as an Adjuvant Treatment for Osteosarcomas”
John H. Healey, MD
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The author did not receive any outside funding or grants in support of his research for or preparation of this work. Neither he nor a member of his immediate family received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity.

Copyright © 2011 by The Journal of Bone and Joint Surgery, Inc.
J Bone Joint Surg Am, 2011 Apr 20;93(8):e42 1-2. doi: 10.2106/JBJS.K.00007
The main article is available here
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A subset of osteogenic sarcomas overexpresses RAS, a major initiator of the MEK and ERK1/2 pathways, which are essential for many cellular functions1. This makes inhibition of the ERK pathway a logical candidate therapeutic strategy for osteogenic sarcoma. Furthermore, a new agent that targets this pathway, PD98059, is already in clinical use to treat melanoma. Thus, it is tantalizing to think that there is an agent that could break the therapeutic logjam that has kept the cure rate of osteogenic sarcoma at about 70% for thirty years.
In the preliminary study reported herein, Noh et al. examined the therapeutic effect of PD98059 on osteogenic sarcoma in vitro with use of two cell lines and in vivo with a single cell line in a nude mouse xenograft model. They found that PD98059 increased the expression of proapoptotic proteins and was associated with increased cell death. As a stand-alone agent, PD98059 prolonged survival by 10% and, intriguingly, had an additive benefit when used in concert with doxorubicin, prolonging survival by 22%. The additive effects were noteworthy because of the compatibility of the two agents, lack of obvious overlapping toxicity, and consistency with the current practice of combining multiagent targeted agents with nonspecific therapy2. Furthermore, the reversal of the paradoxical doxorubicin-induced increase in Bcl-2, an anti-apoptotic protein, identified a possible mechanism for the interaction of these agents. Just a single cycle of three intraperitoneal injections of each agent achieved these results. It is reasonable to expect better results with optimization of the dose and administration schedule. However, a more thorough evaluation of the ERK pathway is needed before ERK signaling blockade can be considered a new targeted therapy for osteogenic sarcoma. For example, Yang et al.3 reported that stimulation of the ERK pathway was the most effective method for promoting apoptosis and cell death in osteogenic sarcoma, just the opposite of the current report. Obviously, more work is needed to clarify this relationship.
Although all progress against osteogenic sarcoma is welcomed, it should be kept in mind that the goal is to recapture the lives of the approximately 30% of patients who still die despite having received conventional chemotherapy. Disappointingly, in the current study, none of the treated mice were cured, but the longest survival time was observed in a mouse treated with PD98059 and doxorubicin. In immunocompetent mice, the results could be better.
The current study is also mute on the critical issue of which patients with osteogenic sarcoma are most suitable for this new targeted therapy. Several questions should be answered before this therapeutic approach is applied clinically. The differential response rates to targeted or conventional therapy should be defined for osteogenic sarcoma. Individualized patient-matched therapy for primary osteogenic sarcoma needs to be developed, and it may or may not include targeted therapy. Does this approach help patients with relapsed osteogenic sarcoma? The agent should be tested in these appropriate clinical scenarios next.
The authors do not provide a clear theoretical and practical justification for PD98059 in particular or inflammatory blockade in general. They suggest that inflammatory phenomena may underlie the pathogenesis of osteogenic sarcoma, citing examples of liver, skin, stomach, and other cancers. While it is an interesting argument by analogy, there are no data to support this mechanism in sarcoma. Second, blocking inflammatory pathways that are presumed to have etiologic importance may be considered "too little, too late," unless they are also involved in disease progression. Third, the widespread importance of inflammatory processes in health begs the question about what unintended effects this agent may produce and what compensatory methods osteogenic sarcoma cells will develop to maintain critical functions. Future study of this agent needs to address these questions.
The current study approaches the problem on a narrow cellular level and uses xenograft modeling to show systemic efficacy. It follows the classic "one fellow, one gene, one year" research paradigm. Although this method is helpful for understanding disease and developing treatments, it is obviously limited by personnel, scope, and time constraints. Newer research methods, such as using more advanced animal models and systems biology, will have a broader influence in the treatment of osteogenic sarcoma, so they deserve to be employed more widely.
Mouse models of osteogenic sarcoma are now available4. p53 mutations at various time points in cellular development have created different osteogenic sarcoma profiles. Mice develop these osteogenic sarcomas spontaneously, and these cancers mimic osteogenic sarcoma behavior in humans. Such models would be much more suitable than xenograft models for testing new agents. This is especially true when investigating inflammatory pathways that may be altered in immunocompromised mice. These new models open exciting avenues of research in osteogenic sarcoma biology.
An overarching principle is that of systems biology, which broadens our concepts of disease and therapy. It is analogous to how ecology sheds light on biologic systems in ways that cellular physics cannot deduce. Analysis gives unique conclusions when focused on each level of biologic organization: the cell, the organ, and the organism5.
In systems biology, the core of understanding depends on the search for organizing principles6. The essential point is that the whole is greater than the sum of its parts. Interactions between the parts create emergent qualities that are not evident from the parts alone. These qualities are irreducible, like prime numbers. Research in systems biology progresses in three dimensions: (1) hypothesis-based research such as that reported by Noh et al., (2) discovery-based research such as that done by engineers or drug developers, and (3) mathematical models that can both analyze vast amounts of data (bioinformatics) and simulate complex developmental systems over time. This work allows the crosstalk between different pathways to be analyzed, as recently demonstrated by Sreenath et al.7. Thus, the true value of the work by Noh et al. will only be revealed when it is integrated into a systems biology approach.
Geryk-Hall  M;  Hughes  DP. Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions. Curr Oncol Rep  . 2009;11:446-53.[CrossRef][PubMed]
 
Meyers  PA;  Schwartz  CL;  Krailo  MD;  Healey  JH;  Bernstein  ML;  Betcher  D;  Ferguson  WS;  Gebhardt  MC;  Goorin  AM;  Harris  M;  Kleinerman  E;  Link  MP;  Nadel  H;  Nieder  M;  Siegal  GP;  Weiner  MA;  Wells  RJ;  Womer  RB;  Grier  HE; Children's Oncology Group. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group. J Clin Oncol  . 2008;26:633-8.[CrossRef][PubMed]
 
Yang  R;  Piperdi  S;  Gorlick  R. Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clin Cancer Res.  2008;14:6396-404.[CrossRef][PubMed]
 
Janeway  KA;  Walkley  CR. Modeling human osteosarcoma in the mouse: From bedside to bench. Bone  . 2010;47:859-65.[CrossRef][PubMed]
 
Nathan  SS;  DiResta  GR;  Casas-Ganem  JE;  Hoang  BH;  Sowers  R;  Yang  R;  Huvos  AG;  Gorlick  R;  Healey  JH. Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clin Cancer Res.  2005;11:2389-97.[CrossRef][PubMed]
 
Mesarovic  MD;  Sreenath  SN;  Keene  JD. Search for organising principles: understanding in systems biology. Syst Biol (Stevenage)  . 2004;1:19-27.[CrossRef][PubMed]
 
Sreenath  SN;  Soebiyanto  R;  Mesarovic  MD;  Wolkenhauer  O. Coordination of crosstalk between MAPK-PKC pathways: an exploratory study. IET Syst Biol.  2007;1:33-40.[CrossRef] [PubMed]
 

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References

Geryk-Hall  M;  Hughes  DP. Critical signaling pathways in bone sarcoma: candidates for therapeutic interventions. Curr Oncol Rep  . 2009;11:446-53.[CrossRef][PubMed]
 
Meyers  PA;  Schwartz  CL;  Krailo  MD;  Healey  JH;  Bernstein  ML;  Betcher  D;  Ferguson  WS;  Gebhardt  MC;  Goorin  AM;  Harris  M;  Kleinerman  E;  Link  MP;  Nadel  H;  Nieder  M;  Siegal  GP;  Weiner  MA;  Wells  RJ;  Womer  RB;  Grier  HE; Children's Oncology Group. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children's Oncology Group. J Clin Oncol  . 2008;26:633-8.[CrossRef][PubMed]
 
Yang  R;  Piperdi  S;  Gorlick  R. Activation of the RAF/mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway mediates apoptosis induced by chelerythrine in osteosarcoma. Clin Cancer Res.  2008;14:6396-404.[CrossRef][PubMed]
 
Janeway  KA;  Walkley  CR. Modeling human osteosarcoma in the mouse: From bedside to bench. Bone  . 2010;47:859-65.[CrossRef][PubMed]
 
Nathan  SS;  DiResta  GR;  Casas-Ganem  JE;  Hoang  BH;  Sowers  R;  Yang  R;  Huvos  AG;  Gorlick  R;  Healey  JH. Elevated physiologic tumor pressure promotes proliferation and chemosensitivity in human osteosarcoma. Clin Cancer Res.  2005;11:2389-97.[CrossRef][PubMed]
 
Mesarovic  MD;  Sreenath  SN;  Keene  JD. Search for organising principles: understanding in systems biology. Syst Biol (Stevenage)  . 2004;1:19-27.[CrossRef][PubMed]
 
Sreenath  SN;  Soebiyanto  R;  Mesarovic  MD;  Wolkenhauer  O. Coordination of crosstalk between MAPK-PKC pathways: an exploratory study. IET Syst Biol.  2007;1:33-40.[CrossRef] [PubMed]
 
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