mTOR Inhibitor RAD001 Promotes Metastasis in a Rat Model of Pancreatic Neuroendocrine Cancer

Pool, Stefan; Bison, Sander; Koelewijn, Stuart; Graaf, Linda M. van der; Melis, Marleen; Krenning, Eric P.; Jong, Marion de

doi:10.1158/0008-5472.can-11-2089

Cited by 41 publications

(34 citation statements)

References 15 publications

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“…Further studies are needed to determine to what extent each of the signaling effects described above influences the efficacy of rapalogs in animal models and in the clinic. Importantly, such observations may explain how in some instances rapalogs are ineffective or, worse, inadvertently promote cancer metastasis [40].…”

Section: Discussionmentioning

confidence: 99%

Signaling Mechanisms that Suppress the Cytostatic Actions of Rapamycin

et al. 2014

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While rapamycin and the “rapalogs” Everolimus and Temsirolimus have been approved for clinical use in the treatment of a number of forms of cancer, they have not met overarching success. Some tumors are largely refractory to rapamycin treatment, with some even undergoing an increase in growth rates. However the mechanisms by which this occurs are largely unknown. The results presented here reveal novel cell-signaling mechanisms that may lead to this resistance. The absence of TGFβ signaling results in resistance to rapamycin. Additionally, we observed that treatment of some cancer cell lines with rapamycin and its analogs not only potentiates mitogenic signaling and proliferation induced by HGF, but also stimulates the pro-survival kinase Akt. Together, the data show that the effectiveness of rapamycin treatment can be influenced by a number of factors and bring to light potential biomarkers for the prediction of responsiveness to treatment, and suggest combination therapies to optimize rapalog anticancer efficacy.

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Section: Discussionmentioning

confidence: 99%

Signaling Mechanisms that Suppress the Cytostatic Actions of Rapamycin

et al. 2014

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“…We have performed a combination study of the two treatments in the sst 2 -expressing CA20948 tumor-bearing rat model on which we recently reported the first data [11]. In this study, we compared either 177 Lu-DOTATATE, RAD001, or their combination for treatment of tumor-bearing rats.…”

Section: Introductionmentioning

confidence: 99%

Peptide receptor radionuclide therapy (PRRT) with [177Lu-DOTA0,Tyr3]octreotate in combination with RAD001 treatment: further investigations on tumor metastasis and response in the rat pancreatic CA20948 tumor model

et al. 2014

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BackgroundPreviously, we reported on the unexpected development of distant metastases in the subcutaneous rat pancreas CA20948 tumor model after 4.5 weeks of treatment with RAD001-only or in combination with [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE) (Cancer Res. 73:12-8, 2013). Moreover, the combination therapy was less effective compared to 177Lu-DOTATATE-only. In the current study, we address the following questions: (1) Why was the combination therapy less effective? Is 177Lu-DOTATATE tumor uptake affected by pretreatment with RAD001? (2) Could sudden cessation of RAD001 therapy cause the development of distant metastases? (3) Is 177Lu-DOTATATE an effective treatment option for these metastases?MethodsLewis rats (HanHsd or SsNHsd substrain with a slight difference in immune response) bearing subcutaneous CA20948 tumors were treated with either 125 or 275 MBq 177Lu-DOTATATE, RAD001, or their combination. RAD001 was given twice a week for 4.5 or 12 weeks, whereas 177Lu-DOTATATE was given as a single injection. When combined, RAD001 was started either 3 days prior to or 3 days post administration of 177Lu-DOTATATE. SPECT/CT was performed to quantify 177Lu-DOTATATE tumor uptake. Where indicated, primary tumors were surgically removed when tumor size is >6,000 mm3 to enable monitoring for possible metastasis. If metastases were suspected, an 111In-DTPA-octreotide SPECT/CT scan was performed. Seven rats with metastases were treated with 400 MBq 177Lu-DOTATATE.ResultsLu-DOTATATE tumor uptake was not significantly affected by RAD001 pretreatment. The occurrence of metastases after RAD001 treatment was not dose dependent in the dose range tested, nor was it related to the duration of RAD001 treatment. In the experiment in which the LEW/SsNsd substrain was used, only 12.5% of RAD001-treated rats showed complete response (CR), compared to 50% tumor regression in the control group. Re-treatment with a high dose of 177Lu-DOTATATE resulted in CR in only two out of seven animals.ConclusionLess effective anti-tumor effects after the combination of RAD001 + 177Lu-DOTATATE could not be explained by reduced 177Lu-DOTATATE tumor uptake after RAD001. Our current data support RAD001-induced immune suppression as the reason for this observation. No evidence was found that cessation of RAD001 treatment caused development of metastases. Metastases appeared to be less sensitive to 177Lu-DOTATATE treatment than primary tumors.

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“…We designed and commenced our clinical study before the publication of a report that concomitant everolimus actually impaired the therapeutic efficacy of 177 Lu-octreotate in a rat model of neuroendocrine cancer and raised the possibility of enhancing the metastatic potential of the tumor. 19 The authors, in a later publication, acknowledged that no tumor-accentuating effects, or examples of accelerated metastasis, have been seen in NET patients treated with everolimus. 20 No such deleterious events were observed in our patient population treated with combination everolimus and 177 Lu-octreotate PRRT.…”

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confidence: 99%