Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients

Stallone, Giovanni; Schena, Antonio; Infante, Barbara; S, Di Paolo; Loverre, Antonia; Maggio, G. Di; Ranieri, Elena; Gesualdo, Loreto; Fp, Schena; Grandaliano, Giuseppe

doi:10.1056/nejmoa042831

Cited by 882 publications

(645 citation statements)

References 23 publications

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“…Activation of these receptors stimulates multiple pro-growth and anti-apoptotic pathways via PI3kinase/Akt/mTOR and extracellular receptor kinase (ERK) [23]. Pertinently, biopsies of KS tissue have been shown by immunohistochemistry to express elevated levels of phosphorylated Akt, p70 S6 kinase, PDGF-receptor (PDGFR) and ERK [23,24]. These observations and others have formed the rationale for small clinical trials of imatinib (which inhibits both PDGFR and c-kit) and rapamycin (which inhibits phosphorylation/activation of the p70 S6 kinase downstream of mTOR); early suggestions of antitumor efficacy have been observed in these trials [23,24].…”

Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

“…Pertinently, biopsies of KS tissue have been shown by immunohistochemistry to express elevated levels of phosphorylated Akt, p70 S6 kinase, PDGF-receptor (PDGFR) and ERK [23,24]. These observations and others have formed the rationale for small clinical trials of imatinib (which inhibits both PDGFR and c-kit) and rapamycin (which inhibits phosphorylation/activation of the p70 S6 kinase downstream of mTOR); early suggestions of antitumor efficacy have been observed in these trials [23,24]. KS cells also over-express matrix metalloproteinases (MMPs) [25], enzymes involved in the destruction of extracellular matrix proteins during angiogenesis and metastasis, and express high levels of the vitronectin receptor α v β 3 , a vascular integrin that is strongly up-regulated on activated endothelium [26].…”

Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

“…Unlike many agents recently investigated as potential KS treatments (e.g., the MMP inhibitor COL-3 [73], rapamycin [24] and imatinib [23]), which are purported to narrowly target proteins and signaling pathways that are over-expressed or activated in KS and are subject to focused analysis using serial sampling of blood or tumor tissue during the course of clinical trials, the multiplicity of IFN's potential mechanisms of action in KS is daunting. Most of the relatively large clinical trials of IFNα in KS were conducted well before the introduction of HAART, the discovery and characterization of KSHV, the elucidation of IFN's many potentially relevant activities and the technical capacity to study these as part of clinical trials.…”

Section: Multiple Potential Mechanisms Of Actionmentioning

confidence: 99%

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AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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Interferon alfa (IFNA) was one of the first agents to be used therapeutically in AIDS-associated Kaposi's sarcoma (KS) more than 25 years ago, and induces tumor regression in a subset of patients. Although much has been learned about the clinical role of IFNα in KS treatment, little is currently known about the mechanism(s) by which IFNA causes KS regression. This is despite a growing understanding of both KS pathogenesis and relevant IFNA activities. To a large extent other agents have supplanted IFNA as treatments for KS, but there may still remain a therapeutic role for IFNA, possibly in combination with other agents targeting angiogenesis and/or HHV-8-encoded human gene homologs that encode proteins involved in cell cycle regulation and signaling. KeywordsInterferon; Kaposi's sarcoma In 1995, when I was honored as a recipient of the ISICR Milstein Award, the AIDS epidemic had recently begun its 15 th year and the human immunodeficiency virus (HIV-1) had been isolated some 12 years previously [1]. However, the virus associated with Kaposi's sarcoma (KS), the most common AIDS-associated malignancy, had been described less than a year earlier [2], its significance was still in some question and its role in KS development had not been characterized, and the active combination drug regimens with which we now treat HIV infection had not yet become widely available. Recombinant interferon alfa preparations (IFNα2a and IFNα2b), which had received approval from the U.S. Food and Drug Administration (FDA) for treatment of AIDS-associated KS in 1988, were still the only approved drugs for systemic treatment of KS (the chemotherapeutic agent, liposomal doxorubicin, would receive FDA approval later in 1995, as did liposomal daunorubicin in 1996 and paclitaxel in 1997). Now, more than a quarter century after the first published reports describing AIDS and its association with KS [3-6] and our first modestly successful attempts to treat KS with IFNα [7], this agent is used infrequently to treat KS, although it still finds use in HIV-infected individuals co-infected with hepatitis C. In this brief review, I will summarize some of the history of IFNα in the treatment of AIDS-associated KS, concentrating on examples of clinical trials in which I have personally been involved, and consider whether there remains a potentially valuable role for this agent in KS treatment.

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Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

Section: Developing a Better Understanding Of Ks Pathogenesismentioning

confidence: 99%

Section: Multiple Potential Mechanisms Of Actionmentioning

confidence: 99%

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AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Krown

2007

Cytokine & Growth Factor Reviews

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“…El principio de la estrategia terapéutica pasa por reducir o retirar la inmunosupresión, obteniendo una remisión de las lesiones cutáneas con el consiguiente riesgo de pérdida del injerto por rechazo 3 . A partir de estudios experimentales que demuestran que la ciclosporina favorece el desarrollo de neoplasias 4 , entre ellas el KS por un incremento en la expresión del factor de crecimiento vascular endotelial (VEGF) 5 , se cree que gran parte del efecto de retirada de la inmunosupresión se debe al cese de la ciclosporina.…”

Section: Discussionunclassified

“…Datos procedentes del grupo de Cincinnati indican que sólo se obtiene un 17% de remisión parcial o completa al retirar la ciclosporina. Estudios recientes han obtenido una alta tasa de remisiones al sustituir la ciclosporina por el sirolimus, ya que al beneficio de la retirada de la ciclosporina se le suma el doble efecto beneficioso del sirolimus en estos pacientes: su acción antineoplá-sica que inhibe la progresión del KS y su acción inmunosupresora que permite preservar la función del injerto 3,6 . Sin embargo, todos estos hallazgos se refieren a la forma cutánea de la enfermedad, quedando por demostrar su beneficio en las formas más graves con afectación visceral.…”

Section: Discussionunclassified

Sarcoma de Kaposi sobre injerto renal

Moldes

García

Abal

et al. 2008

Actas Urológicas Españolas

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RESUMENSARCOMA DE KAPOSI SOBRE INJERTO RENAL El sarcoma de Kaposi es un tumor infrecuente de causa desconocida, pero con una mayor incidencia en pacientes inmunodeprimidos, sobre todo en trasplantados y VIH positivos. Habitualmente se presenta como lesiones cutáneas de buen pronóstico, siendo la forma invasiva visceral rara, agresiva y rara su remisión.Presentamos un paciente con un sarcoma de Kaposi a nivel del injerto renal y mala respuesta a pesar de retirar la inmunosupresión.Palabras clave: Sarcoma de Kaposi. Trasplante renal. Inmunosupresión. ABSTRACT KAPOSI´S SARCOMA IN A RENAL GRAFTKaposi´s sarcoma is an infrequent tumor of unknown cause, but with a higher impact in immune depressed individuals, particularly in HIV and transplant patients. It usually appears as a benign cutaneous lesions, while the invasive visceral form is uncommon with malignant evolution and wit rare remission.We present a patient with a Kaposi´s sarcoma localised in a renal graft and bad response even when immuno suppression was discontinued.

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AKT1 Overexpression in Endothelial Cells Leads to the Development of Cutaneous Vascular Malformations In Vivo

Perry¹,

Banyard²,

McLaughlin³

et al. 2007

Arch Dermatol

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Background: Vascular malformations are clinical disorders in which endothelial cells fail to remodel and/or undergo programmed cell death, leading to abnormal persistence of blood vessels. The abnormal persistence of vessels makes therapy difficult because these lesions are resistant to interventions that are effective against hemangiomas. Akt1 is a serine-threonine protein kinase, which is a key mediator of resistance to programmed cell death. Our objective was to determine whether sustained activation of Akt1 could lead to vascular malformation in mice.Observations: We examined the effect of constitutive activation of Akt1 in murine endothelial cells (MS1 cells). Overexpression of active AKT1 in MS1 cells led to the development of vascular malformations, characterized by wide endothelial lumens and minimal investment of smooth muscle surrounding the vessels. The histologic features of these vascular malformations is distinct from ras-transformed MS1 cells (angiosarcoma) and suggest that differing signal abnormalities give rise to human vascular malformations vs malignant vascular tumors.Conclusions: Inhibition of Akt signaling may be useful in the treatment of vascular malformations. Examination of problematic hemangiomas and vascular malformations for the presence of activated Akt or downstream targets of Akt, such as mammalian target of rapamycin (mTOR), may predict response to treatment with Akt inhibitors or rapamycin. This study provides a potential rationale for the systemic and topical use of these inhibitors for vascular malformations and hemangiomas.

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Sirolimus for Kaposi's Sarcoma in Renal-Transplant Recipients

Abstract: Sirolimus inhibits the progression of dermal Kaposi's sarcoma in kidney-transplant recipients while providing effective immunosuppression.

Cited by 882 publications

References 23 publications

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

AIDS-associated Kaposi's sarcoma: Is there still a role for interferon alfa?

Sarcoma de Kaposi sobre injerto renal

AKT1 Overexpression in Endothelial Cells Leads to the Development of Cutaneous Vascular Malformations In Vivo

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