Evaluating the activity of temsirolimus in neuroendocrine cancer

O’Donnell, Peter H.; Ratain, Mark J.

doi:10.1038/sj.bjc.6603513

Cited by 8 publications

(2 citation statements)

References 5 publications

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“…These data serve as a rationale for treatment of advanced PNETs with Rapamycin and its analogues. So far, two clinical trials evaluating rapamycin and analogues recently raised hope for efficient disease control [ 49 , 50 , 51 ]. Compensatory activation of AKT might be overcome by a combination of therapies [ 52 ].…”

Section: Review Of Literaturementioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors

Ehehalt

Franke

Pilarsky

et al. 2010

Cancers

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Pancreatic neuroendocrine tumors (PNETs) are rare primary neoplasms of the pancreas and arise sporadically or in the context of genetically determined syndromes. Depending on hormone production and sensing, PNETs clinically manifest due to a hormone-related syndrome (functional PNET) or by symptoms related to tumor bulk effects (non-functional PNET). So far, radical surgical excision is the only therapy to cure the disease. Development of tailored non-surgical approaches has been impeded by the lack of experimental laboratory models and there is, therefore, a limited understanding of the complex cellular and molecular biology of this heterogeneous group of neoplasm. This review aims to summarize current knowledge of tumorigenesis of familial and sporadic PNETs on a cellular and molecular level. Open questions in the field of PNET research are discussed with specific emphasis on the relevance of disease management.

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Section: Review Of Literaturementioning

confidence: 99%

Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors

Ehehalt

Franke

Pilarsky

et al. 2010

Cancers

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“…Two rapalogues, temsirolimus and everolimus, have been clinically tested in the treatment of NETs, but the development of temsirolimus in this indication has been abandoned after the first trials [63,64]. The efficiency of everolimus has now been clearly documented, especially in pancreatic NETs, by several successive studies [65,66,67].…”

Section: Anti-angiogenic Treatments In Netsmentioning

confidence: 99%

Angiogenesis in Neuroendocrine Tumors: Therapeutic Applications

Scoazec

2012

Neuroendocrinology

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The considerable research efforts devoted to the understanding of the mechanisms of tumor angiogenesis have resulted in the development of targeted anti-angiogenic therapies and finally in their introduction in clinical practice. Neuroendocrine tumors (NETs), which are characterized by a high vascular supply and a strong expression of VEGF-A, one of the most potent pro-angiogenic factors, are an attractive indication for these new treatments. However, several lines of evidence show that the dense vascular networks associated with low-grade NETs are more likely to be a marker of differentiation than a marker of aggressiveness, as in other epithelial tumors. These observations form the basis for the so-called ‘neuroendocrine paradox’, according to which the most vascularized are the most differentiated and the less angiogenic NETs. This must be kept in mind when discussing the role of anti-angiogenic strategies in the treatment of NETs. Nevertheless, several targeted therapies, with direct or indirect anti-angiogenic properties, including anti-VEGF antibodies, tyrosine kinase inhibitors (sunitinib) and mTOR inhibitors (everolimus), have recently proven to be of clinical benefit. In addition, some drugs already used in NET treatment, such as somatostatin analogues and interferon-α, may also have anti-angiogenic properties. The main challenges for the next future are to validate biomarkers for the selection of patients and the prediction of their response to refine the indications of anti-angiogenic targeted therapies and to overcome the mechanisms of resistance, which explain the limited duration of action of most of these treatments.

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Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors

Mita

Piha-Paul

et al. 2017

Invest New Drugs

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Background Dual inhibition of activated MAPK and mTOR signaling pathways may enhance the antitumor efficacy of the MEK 1/2 inhibitor pimasertib and the mTOR inhibitor temsirolimus given in combination. Methods In this phase I study, patients with refractory advanced solid tumors (NCT01378377) received once-weekly temsirolimus plus once-daily oral pimasertib in 21-day cycles in a modified 3+3 dose-escalation design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of pimasertib in combination with temsirolimus, safety and pharmacokinetics (PK) were investigated. Results Of 33 patients evaluated, all experienced ≥1 treatment-emergent adverse event (TEAE) and 31 had treatment-related TEAEs, most frequently stomatitis and thrombocytopenia. TEAEs were reversible. No deaths were attributed to treatment. Nine patients had dose-limiting toxicities (stomatitis, thrombocytopenia, serum creatinine phosphokinase increase, visual impairment) and the MTD was determined as 45 mg/day pimasertib plus 25 mg/week temsirolimus. However, due to overlapping toxicities no further investigations were performed and the RP2D was not defined. PK profiles of both agents were not adversely affected. Seventeen patients (17/26 patients) had a best response of stable disease; five had stable disease lasting >12 weeks. Conclusions The RP2D was not defined and the pimasertib plus temsirolimus combination investigated did not warrant further study.

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Evaluating the activity of temsirolimus in neuroendocrine cancer

Cited by 8 publications

References 5 publications

Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors

Molecular Pathogenesis of Pancreatic Neuroendocrine Tumors

Angiogenesis in Neuroendocrine Tumors: Therapeutic Applications

Phase I trial of MEK 1/2 inhibitor pimasertib combined with mTOR inhibitor temsirolimus in patients with advanced solid tumors

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