A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors

Chamberlain, Chester E.; German, Michael S.; Yang, Katherine; Wang, Jason; VanBrocklin, Henry F.; Regan, Melanie; Shokat, Kevan M.; Ducker, Gregory S.; Kim, Grace; Hann, Byron; Donner, David B.; Warren, Robert S.; Venook, Alan P.; Bergsland, Emily K.; Lee, Danny; Wang, Yucheng; Nakakura, Eric K.

doi:10.1158/1535-7163.mct-17-1204

Cited by 35 publications

(29 citation statements)

References 57 publications

(71 reference statements)

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“…However, as complete responses to LuTate are rare, novel approaches are needed to further potentiate its clinical activity. Preclinical efficacy studies are of great value for evaluating novel treatments but the lack of robust and well validated preclinical models of SSTR2-expressing NET available for the assessment of novel combination regimens incorporating SSTR2 targeted PRRT is well documented [40][41][42] . In this study, we therefore characterised a panel of cell lines with neuroendocrine features to identify a line suitable for such studies.…”

Section: Discussionmentioning

confidence: 99%

Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP

Cullinane

Waldeck

Kirby

et al. 2020

Sci Rep

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peptide receptor radionuclide therapy (pRRt) is an important treatment option for patients with somatostatin receptor-2 (SSTR2)-expressing neuroendocrine tumour (NET) though tumour regression occurs in only a minority of patients. Therefore, novel PRRT regimens with improved therapeutic activity are needed. Radiation induced DNA damage repair is an attractive therapeutic target to increase PRRT efficacy and consequently, we have characterised a panel of preclinical models for their SSTR2 expression, in vivo growth properties and response to 177 Lu-DotA-octreotate (Lutate) pRRt to identify models with features suitable for evaluating novel therapeutic combinations. In vitro studies using the SSTR2 expressing AR42J model demonstrate that the combination of LuTate and the small molecule Poly(ADP-ribose) polymerase-1 (PARP) inhibitor, talazoparib led to increased DNA double strand breaks, as assessed by γ-H2AX foci formation, as compared to LuTate alone. Furthermore, using the AR42J tumour model in vivo we demonstrate that the combination of LuTate and talazoparib significantly improved the anti-tumour efficacy of LuTate alone. These findings support the clinical evaluation of the combination of LuTate and PARP inhibition in SSTR2-expressing NET. Neuroendocrine tumours (NET) represent a rare and heterogeneous group of tumours. Characteristically slow growing, these tumours are often diagnosed late in the disease course with locally-advanced or metastatic tumours. A subgroup has associated hypersecretion of hormones that can cause significant morbidity. NET arises from neuroendocrine cells of the diffuse endocrine system with the highest incidence observed in the gastrointestinal tract (70%) and lung (30%) 1,2. Classification of NET is based on the cell-type, organ of origin or associated hormone secretion, while grading is based on the cell differentiation and, in particular, on proliferation rate 3. Clinical management is highly complex and may involve surgery, chemotherapy and molecularly targeted therapies. More recently peptide receptor radionuclide therapy (PRRT) has become well established as a key therapeutic modality for NET, particularly those involving the gastrointestinal tract 4. Neuroendocrine cells are regulated by hormones acting via G-protein coupled receptors such as the somatostatin receptor (SSTR2). Since many NET share high level expression of SSTR2, this feature has been exploited for diagnosis, staging and the therapeutic targeting of NET 5. The 111 In-labelled somatostatin analogue, octreotide and the more recently developed 68 Ga-labelled analogues have been used widely for diagnostic imaging of SSTR2-expressing tumours by SPECT and PET, respectively 6,7. Incorporation of other therapeutic radionuclides such as 177 Lu and 90 Y, optimisation of the chelating agent and replacement of octreotide with the higher affinity

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Section: Discussionmentioning

confidence: 99%

Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP

Cullinane

Waldeck

Kirby

et al. 2020

Sci Rep

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“…Nevertheless, Nölting et al showed that combination of everolimus and BYL719 had synergistic effects on cell proliferation (Nölting et al 2017). In addition, combination of BYL719 with everolimus re-established everolimus sensitivity in a resistant cell line model (Aristizabal Prada et al 2018 (Chamberlain et al 2018). They show that sapanisertib overcomes everolimus resistance.…”

Section: Dual Pi3k and Mtor Inhibitorsmentioning

confidence: 91%

Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors

Beyens

Vandamme

Peeters

et al. 2019

Endocrine-Related Cancer

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“…PDXs of pancreatic NEN can develop resistance to everolimus. In this study, the inhibitor of the mTOR pathway sapanisertib showed a potent antitumor effect also on everolimus-resistant PDXs, leading to the suggestion of a new alternative pharmacological strategy for everolimus-resistant NEN (71). However, the use of murine NEN-PDX models is very limited in the research of PM strategies probably due to the rarity of NENs, the limited size of post-surgical samples for most of these tumors and the low rate of successful tumor engraftment (72).…”

Section: In Vivo Modelsmentioning

confidence: 86%

MANAGEMENT OF ENDOCRINE DISEASE: Precision medicine in neuroendocrine neoplasms: an update on current management and future perspectives

Gaudenzi

Dicitore

Carra

et al. 2019

European Journal of Endocrinology

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Neuroendocrine neoplasms (NENs) are traditionally considered as a single group of rare malignancies that originate from the highly spread neuroendocrine system. The clinical management is complex due to the high heterogeneity of these neoplasms in terms of clinical aggressiveness and response to the therapy. Indeed, a multidisciplinary approach is required to reach a personalization of the therapy, including cancer rehabilitation. In this review, we discuss the possibility to adopt a precision medicine (PM) approach in the management of NENs. To this purpose, we summarize current knowledge and future perspectives about biomarkers and preclinical in vitro and in vivo platforms, potentially useful to inform clinicians about the prognosis and for tailoring therapy in patients with NENs. This approach may represent a breakthrough in the therapy and tertiary prevention of these tumors.

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A Patient-derived Xenograft Model of Pancreatic Neuroendocrine Tumors Identifies Sapanisertib as a Possible New Treatment for Everolimus-resistant Tumors

Cited by 35 publications

References 57 publications

Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP

Enhancing the anti-tumour activity of 177Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP

Resistance to targeted treatment of gastroenteropancreatic neuroendocrine tumors

MANAGEMENT OF ENDOCRINE DISEASE: Precision medicine in neuroendocrine neoplasms: an update on current management and future perspectives

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