Chemotherapy Regimens for Patients with Newly Diagnosed Malignant Bone Tumors

Roberts, Ryan D.; Wedekind, Mary Frances; Setty, Bhuvana

doi:10.1007/978-3-319-18099-1_6

Cited by 8 publications

(9 citation statements)

References 101 publications

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“…Treatment of OS involves a combination of aggressive chemotherapy and surgery [ 1 , 2 ]. Unfortunately, there have not been any significant advances in OS treatment or outcomes since the 1980s [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy

et al. 2018

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Osteosarcoma (OS) is the most common bone tumor in children. Polyamines (PAs) are ubiquitous cations involved in many cell processes including tumor development, invasion and metastasis. In other pediatric cancer models, inhibition of the PA biosynthesis pathway with ornithine decarboxylase (ODC) inhibitor alpha-difluoromethylornithine (DFMO) results in decreased cell proliferation and differentiation. In OS, the PA pathway has not been evaluated. DFMO is an attractive, orally administered drug, is well tolerated, can be given for prolonged periods, and is already used in pediatric patients. Three OS cell lines were used to study the cellular effects of PA inhibition with DFMO: MG-63, U-2 OS and Saos-2. Effects on proliferation were analyzed by cell count, flow cytometry-based cell cycle analysis and RealTime-Glo™ MT Cell Viability assays. Intracellular PA levels were measured with high-performance liquid chromatography (HPLC). Western blot analysis was used to evaluate cell differentiation. DFMO exposure resulted in significantly decreased cell proliferation in all cell lines. After treatment, intracellular spermidine levels were drastically decreased. Cell cycle arrest at G2/M was observed in U-2 OS and Saos-2. Cell differentiation was most prominent in MG-63 and U-2 OS as determined by increases in the terminal differentiation markers osteopontin and collagen 1a1. Cell proliferation continued to be suppressed for several days after removal of DFMO. Based on our findings, DFMO is a promising new adjunct to current osteosarcoma therapy in patients at high risk of relapse, such as those with poor necrosis at resection or those with metastatic or recurrent osteosarcoma. It is a well-tolerated oral drug that is currently in phase II clinical trials in pediatric neuroblastoma patients as a maintenance therapy. The same type of regimen may also improve outcomes in osteosarcoma patients in whom there have been essentially no medical advances in the last 30 years.

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Section: Introductionmentioning

confidence: 99%

Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy

et al. 2018

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“…The current standard of care for human patients diagnosed with OS remains largely unchanged from that first used in the early 1980s (185), being neoadjuvant and adjuvant MAP chemotherapy (methotrexate, doxorubicin, cisplatin) together with aggressive local control by surgical excision (186). Building on techniques pioneered in pet dogs with OS (187,188), most human patients diagnosed today benefit from limb salvage reconstructive techniques that preserve limb function.…”

Section: Standard Of Care and The Unmet Need For New Anti-metastatic mentioning

confidence: 99%

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

2020

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Osteosarcoma is a malignant primary tumor of bone, arising from transformed progenitor cells with osteoblastic differentiation and osteoid production. While categorized as a rare tumor, most patients diagnosed with osteosarcoma are adolescents in their second decade of life and underscores the potential for life changing consequences in this vulnerable population. In the setting of localized disease, conventional treatment for osteosarcoma affords a cure rate approaching 70%; however, survival for patients suffering from metastatic disease remain disappointing with only 20% of individuals being alive past 5 years post-diagnosis. In patients with incurable disease, pulmonary metastases remain the leading cause for osteosarcoma-associated mortality; yet identifying new strategies for combating metastatic progression remains at a scientific and clinical impasse, with no significant advancements for the past four decades. While there is resonating clinical urgency for newer and more effective treatment options for managing osteosarcoma metastases, the discovery of druggable targets and development of innovative therapies for inhibiting metastatic progression will require a deeper and more detailed understanding of osteosarcoma metastasis biology. Toward the goal of illuminating the processes involved in cancer metastasis, a convergent science approach inclusive of diverse disciplines spanning the biology and physical science domains can offer novel and synergistic perspectives, inventive, and sophisticated model systems, and disruptive experimental approaches that can accelerate the discovery and characterization of key processes operative during metastatic progression. Through the lens of trans-disciplinary research, the field of comparative oncology is uniquely positioned to advance new discoveries in metastasis biology toward impactful clinical translation through the inclusion of pet dogs diagnosed with metastatic osteosarcoma. Given the spontaneous course of osteosarcoma development in the context of real-time tumor microenvironmental cues and immune mechanisms, pet dogs are distinctively valuable in translational modeling given their faithful recapitulation of metastatic disease

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“…Children and adolescents diagnosed with osteosarcoma have not experienced similar advances. Those diagnosed with osteosarcoma in 2017 receive medical therapies that remain essentially unchanged since the introduction of MAP (methotrexate, doxorubicin, and cisplatin) in the late 1970s ( 4 ). Outcomes have likewise improved very little since the advent of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Osteosarcoma: Accelerating Progress Makes for a Hopeful Future

2018

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Patients who develop osteosarcoma in 2017 receive treatment that remains essentially unchanged since the 1970s. Outcomes likewise remain largely unimproved. Large, collaborative, multinational efforts to improve therapy have evaluated strategies leveraging both cytotoxic intensification and immunomodulatory agents. While these have confirmed our capacity to conduct such trials, results have proved largely disappointing. This has motivated efforts to focus on the basic biology of osteosarcoma, where understanding remains poor but has improved significantly. Recent advances have identified characteristic genetic features of osteosarcoma, including profound chromosomal disruption, marked patient-patient heterogeneity, and a paucity of recurrent mutations. Analyses suggest genesis in early catastrophic genetic events, although the nature of the inciting events remains unclear. While p53 and Rb inactivation occurs in most osteosarcomas, the landscape of associated driver mutations has proved extensive. Few mutations recur with high frequency, though patterns continue to emerge that suggest recurrent alterations within specific pathways. Biological pathways implicated in osteosarcoma biology through genetic and other preclinical studies include PI3K/mTOR, WNT/βcatenin, TGFβ, RANKL/NF-κB, and IGF. Unfortunately, clinical studies evaluating targeted agents have to date yielded disappointing results, as have studies examining modern immunotherapeutics. It remains unclear whether this pattern of clinical failures exposes inadequacies of our preclinical models, unrealistic expectations for single-agent responses in heavily pretreated patients, or biology less relevant than suggested. Nearly all patients who succumb to osteosarcoma develop lung metastases, which exhibit marked chemoresistance. Much scientific effort has recently sought to enhance our mechanistic understanding of metastasis biology. This research has potential to reveal novel targets for preventing and treating metastasis and for uncovering key vulnerabilities of osteosarcoma cells. Efforts to implement drug development strategies that leverage clinical studies in veterinary patients have potential to accelerate the translation of novel experimental regimens toward human studies. These could reduce costs and development timelines, prioritize agents, and refine regimens prior to human clinical trials. The rise of philanthropic groups focused on osteosarcoma has enhanced cross-disciplinary and cross-institutional focus and provided much needed resources. Transformative new therapies will likely arise from collaborative, interdisciplinary efforts that extend our understanding of osteosarcoma’s most basic inner workings.

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Chemotherapy Regimens for Patients with Newly Diagnosed Malignant Bone Tumors

Cited by 8 publications

References 101 publications

Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy

Polyamine Biosynthetic Pathway as a Drug Target for Osteosarcoma Therapy

Understanding and Modeling Metastasis Biology to Improve Therapeutic Strategies for Combating Osteosarcoma Progression

Osteosarcoma: Accelerating Progress Makes for a Hopeful Future

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