A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

Grignani, Giovanni; Palmerini, Emanuela; Dileo, Palma; Asaftei, Sebastian Dorin; D’Ambrosio, Lorenzo; Pignochino, Ymera; Mercuri, Mario; Picci, Piero; Fagioli, Franca; Casali, Paolo G.; Ferrari, Stefano; Aglietta, Massimo

doi:10.1093/annonc/mdr151

Cited by 313 publications

(295 citation statements)

References 40 publications

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“…Unfortunately, none of these receptors represents a "clinicallyrelevant" target, likely because the biologic forces driving osteosarcoma progression do not succumb to a single hit. Recently, we reported that the multikinase inhibitor sorafenib negatively impacted osteosarcoma growth (6), but that the effect was brief (11). Surely, these considerations, make a compelling case to explore drug combinations to enhance sorafenib activity in sorafenib-based regimens that can be effectively translated into therapeutic approaches.…”

Section: Discussionmentioning

confidence: 99%

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The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Pignochino

Dell'Aglio²,

Basiricò³

et al. 2013

Clinical Cancer Research

107

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Section: Discussionmentioning

confidence: 99%

“…Nonetheless, sorafenib shows only minor activity in terms of temporary disease stabilization and slight tumor shrinkage in patients with advanced and unresectable osteosarcoma (11). Therefore, despite sorafenib activity, it is insufficient to halt osteosarcoma progression for both primary and secondary drug resistance.…”

Section: Introductionmentioning

confidence: 99%

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Pignochino

Dell'Aglio²,

Basiricò³

et al. 2013

Clinical Cancer Research

107

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“…In addition, recent reports have suggested the utility of sorafenib for the treatment of unresectable high-grade osteosarcoma, a malignancy where excess osteoid is produced by the malignant cells (Grignani et al 2012). Biochemical markers of bone turnover were not assessed in this study.…”

Section: Vegf Inhibitorsmentioning

confidence: 98%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment. Key Words" bone " calcium " metastasis " parathyroid hormone " tyrosine kinase inhibitor

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“…Osteosarcoma therapy has been changed, at least in Europe, with the demonstration of the activity if mifurmatide in a phase III clinical trial (48,49), work that was propelled by translational research (50). A fraction of osteosarcomas respond to multitargeted tyrosine kinase inhibitors (51). Furthermore, pazopanib was approved in 2012 for use in patients with soft tissue sarcomas other than GIST or liposarcoma that are refractory to other systemic therapeutics (52).…”

Section: Challenges and Opportunities In Identifying Novel Agents Formentioning

confidence: 99%

New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents

Janeway

Maki

2012

Clinical Cancer Research

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The ability to better interrogate the genetic state of a given cancer is giving rise to a new paradigm in cancer therapeutics in which the specific genetic alterations that give rise to the cancer inform the therapeutic decision-making for that specific patient. Sarcomas of soft tissue and bone represent model diseases that underscore this paradigm. However, many barriers prevent linkage of one of the 75 or more different types of sarcoma to novel therapeutic agents. In the present perspective, the authors outline key therapeutic opportunities and hurdles in clinical sarcoma research, focusing on specific examples of sarcomas that are on the verge of new breakthroughs, as well as those in which promise has not lived up to expectations. Focused clinical trial design, ideally with several biomarker or histology-specific arms, is one means to be simultaneously parsimonious and inclusive. Clin Cancer Res; 18(21); 5837-44. Ó2012 AACR.

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A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study

Abstract: Sorafenib demonstrated activity as a second- or third-line treatment in terms of PFS at 4 months with some unprecedented long-lasting responses. Sorafenib, the first targeted therapy showing activity in osteosarcoma patients, deserves further investigations.

Cited by 313 publications

References 40 publications

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

The Combination of Sorafenib and Everolimus Abrogates mTORC1 and mTORC2 Upregulation in Osteosarcoma Preclinical Models

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

New Strategies in Sarcoma Therapy: Linking Biology and Novel Agents

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