mTOR Inhibitors (Rapamycin and its Derivatives) and Nitrogen Containing Bisphosphonates: Bi-Functional Compounds for the Treatment of Bone Tumours

Ory, Benjamin; Moriceau, Gatien; Rédini, Françoise; Heymann, Dominique

doi:10.2174/092986707780831159

Cited by 37 publications

(31 citation statements)

References 58 publications

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“…Many of the known translational targets of mTOR have been connected to cancer, including cmyc, VEGFR, hypoxia-inducible factor, and transforming growth factor-β . That mTOR may be an important target for osteosarcoma is also supported by mTOR's importance in mesenchymal stem cell and bone biology [ 47 ].…”

Section: Potential Targets Linked To Established Metastatic Lesionsmentioning

confidence: 97%

Novel targets with potential therapeutic applications in osteosarcoma

Khanna

2008

Curr Oncol Rep

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For patients with osteosarcoma, the development of metastases, often to the lungs, is the most common cause of death. Long-term outcomes for patients who present with localized or disseminated disease have largely remained unchanged over the past 20 years. Further improvements in outcome are not likely to come from intensification of cytotoxic chemotherapy; as such, new targets for treatment are needed. A view toward such targets in osteosarcoma may be constructed based on three common clinical features of the disease. These include the origin of osteosarcoma in the bone or primitive mesenchymal cells, the predictable process of metastatic progression characterized by this disease, and the development of metastatic lesions almost exclusively in the lung. It is likely and potentially favorable for some targets to be relevant for more than one process. This review summarizes novel targets under evaluation for the treatment of osteosarcoma based on these three features of the disease.

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Section: Potential Targets Linked To Established Metastatic Lesionsmentioning

confidence: 97%

Novel targets with potential therapeutic applications in osteosarcoma

Khanna

2008

Curr Oncol Rep

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“…Indeed, as predicted by studies with ezrin, the inhibition of mTOR signaling reduces growth and metastasis in OS models by blocking S6 kinase 1 and 4EBP-1 phosphorylation [ 121 ]. The rapalog inhibitors of mTOR, including rapamycin have been found to inhibit ezrin-mediated metastatic behavior [ 120 , 122 ].…”

Section: Inhibition Of Ezrin Functions As Therapeutic Target In Os Mementioning

confidence: 99%

Role of Ezrin in Osteosarcoma Metastasis

Ren

Khanna

2014

Advances in Experimental Medicine and Biology

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The cause of death for the vast majority of cancer patients is the development of metastases at sites distant from that of the primary tumor. For most pediatric sarcoma patients such as those with osteosarcoma (OS), despite successful management of the primary tumor through multimodality approaches, the development of metastases, commonly to the lungs, is the cause of death. Significant improvements in long-term outcome for these patients have not been seen in more than 30 years. Furthermore, the long-term outcome for patients who present with metastatic disease is grave [1-5]. New treatment options are needed.Opportunities to improve outcomes for patients who present with metastases and those at-risk for progression and metastasis require an improved understanding of cancer progression and metastasis. With this goal in mind we and others have identified ezrin as a metastasis-associated protein that associated with OS and other cancers. Ezrin is the prototypical ERM (Ezrin/Radixin/Moesin) protein family member. ERMs function as linker proteins connecting the actin cytoskeleton and the plasma membrane. Since our initial identification of ezrin in pediatric sarcoma, an increasing understanding the role of ezrin in metastasis has emerged. Briefly, ezrin appears to allow metastatic cells to overcome a number of stresses experienced during the metastatic cascade, most notably the stress experienced as cells interact with the microenvironment of the secondary site. Cells must rapidly adapt to this environment in order to survive. Evidence now suggests a connection between ezrin expression and a variety of mechanisms linked to this important cellular adaptation including the ability of metastatic cells to initiate the translation of new proteins and to allow the efficient generation of ATP through a variety of sources. This understanding of the role of ezrin in the biology of metastasis is now sufficient to consider ezrin as an important therapeutic target in osteosarcoma patients. This chapter reviews our understanding of ezrin and the related ERM proteins in normal tissues and physiology, summarizes the expression of ezrin in human cancers and associations with clinical parameters of disease progression, reviews reports that detail a biological understanding of ezrin's role in metastatic progression, and concludes with a rationale that may be considered to target ezrin and ezrin biology in osteosarcoma.

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“…Furthermore, factors downstream of the mevalonate pathway are also involved in the control of cell proliferation, tumor progression, and cell death induced by anticancer therapies [61]. In addition to its effects on the mevalonate pathway, ZOL also may influence mTOR, inhibition of which has been shown to reduce osteoclast and tumor cell proliferation [62][63][64]. For example, ZOL, everolimus (an mTOR inhibitor), and docetaxel each reduced tumor volume in a mouse model when used individually, but the combination of all 3 agents was more effective than single agents [62].…”

Section: Interrupting Communication Between Tumor Cells and Bonementioning

confidence: 99%

Relevance of Micrometastases and Targeting the Bone Marrow Niche with Zoledronic Acid in Breast Cancer

Aft¹

2012

CCTR

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During the course of cancer metastasis development, invasive tumor cells circulate through the blood stream and disseminate to other tissues. Circulating and disseminated tumor cells (CTCs and DTCs, respectively) may be the source of local and distant metastases and are a promising target for anticancer therapy. Multiple studies have shown that the detection of DTCs or CTCs correlates with increased risk of disease recurrence, suggesting that reducing the prevalence and persistence of these cells is clinically relevant. The development of metastases is a multistep process that involves complex biologic processes and a multitude of growth factors. The bone marrow provides a portion of these growth factors and a nutrient-rich microenvironment in which dormant cancer cells can survive and transition to metastasis-initiating cells. The molecular interactions between DTCs and the bone marrow microenvironment enable DTCs to evade cytotoxic chemotherapy, allowing them to lie dormant for extended periods of time before becoming active and metastasizing to secondary sites. Alteration of the bone marrow microenvironment with antiresorptive agents, such as bisphosphonates, may render the bone marrow less suitable for cancer cell growth, possibly interfering with the metastatic cascade. Clinical studies have shown that the nitrogen-containing bisphosphonate zoledronic acid can reduce the persistence and prevalence of DTCs in patients with breast cancer, suggesting that zoledronic acid may improve clinical outcomes. Targeting the metastatic niche by altering the microenvironment in the bone marrow may be an effective anticancer strategy.

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mTOR Inhibitors (Rapamycin and its Derivatives) and Nitrogen Containing Bisphosphonates: Bi-Functional Compounds for the Treatment of Bone Tumours

Cited by 37 publications

References 58 publications

Novel targets with potential therapeutic applications in osteosarcoma

Novel targets with potential therapeutic applications in osteosarcoma

Role of Ezrin in Osteosarcoma Metastasis

Relevance of Micrometastases and Targeting the Bone Marrow Niche with Zoledronic Acid in Breast Cancer

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