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Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.

ABSTRACT: Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability to progress to invasive cancer, leading to prolonged survival. In addition, mouse pancreatic cancer cell lines with differing p53 status are all sensitive to pharmacologic and genetic inhibition of autophagy. Finally, a mouse preclinical trial using cohorts of genetically characterized patient-derived xenografts treated with hydroxychloroquine showed responses across the collection of tumors. Together, our data support the critical role of autophagy in pancreatic cancer and show that inhibition of autophagy may have clinical utility in the treatment of these cancers, independent of p53 status.Recently, a mouse model with embryonic homozygous Trp53 deletion showed paradoxical effects of autophagy inhibition. We used a mouse model with Trp53 LOH (similar to human tumors), tumor cell lines, and patient-derived xenografts to show that p53 status does not affect response to autophagy inhibition. These findings have important implications on ongoing clinical trials.

SUBMITTER: Yang A

PROVIDER: S-EPMC4125497 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.

Yang Annan A Rajeshkumar N V NV Wang Xiaoxu X Yabuuchi Shinichi S Alexander Brian M BM Chu Gerald C GC Von Hoff Daniel D DD Maitra Anirban A Kimmelman Alec C AC

Cancer discovery 20140529 8

<h4>Unlabelled</h4>Pancreatic ductal adenocarcinoma is refractory to available therapies. We have previously shown that these tumors have elevated autophagy and that inhibition of autophagy leads to decreased tumor growth. Using an autochthonous model of pancreatic cancer driven by oncogenic Kras and the stochastic LOH of Trp53, we demonstrate that although genetic ablation of autophagy in the pancreas leads to increased tumor initiation, these premalignant lesions are impaired in their ability ...[more]

PMID: 24875860

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Project description:BackgroundLanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo.MethodsDuring CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR0); 12-24 weeks before randomization versus baseline; each treatment visit versus baseline (TGRTx-0); between consecutive treatment visits (TGRTx-Tx). To assess TGR as a measure of prognosis, PFS was compared for TGR0 subgroups stratified by optimum TGR0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS.ResultsTGR0 revealed tumors growing during pre-treatment (median [interquartile range] TGR0: lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR0-12 of - 2.9 [- 5.1, - 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR0 > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5-6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR0, hepatic tumor load, and primary tumor type were independently associated with PFS.ConclusionsTGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity.Trial registrationRetrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

Project description:Recently, we identified the homeodomain transcription factor Cut homeobox 1 (CUX1) as mediator of tumour de-differentiation and metastatic behaviour in human insulinoma patients. In insulinomas, CUX1 enhanced tumour progression by stimulating proliferation and angiogenesis in vitro and in vivo. In patients with non-functional pancreatic neuroendocrine tumours (PanNET), however, the impact of CUX1 remains to be elucidated. Here, we analysed CUX1 expression in two large independent cohorts (n = 43 and n = 141 tissues) of non-functional treatment-naïve and pre-treated PanNET patients, as well as in the RIP1Tag2 mouse model of pancreatic neuroendocrine tumours. To further assess the functional role of CUX1, expression profiling of DNA damage-, proliferation- and apoptosis-associated genes was performed in CUX1-overexpressing Bon-1 cells. Validation of differentially regulated genes was performed in Bon-1 and QGP1 cells with knock-down and overexpression strategies. CUX1 expression assessed by a predefined immunoreactivity score (IRS) was significantly associated with shorter progression-free survival (PFS) of pre-treated PanNET patients (23 vs. 8 months; p = 0.005). In treatment-naïve patients, CUX1 was negatively correlated with grading and recurrence-free survival (mRFS of 39 versus 8 months; p = 0.022). In both groups, high CUX1 levels indicated a metastatic phenotype. Functionally, CUX1 upregulated expression of caspases and death associated protein kinase 1 (DAPK1), known as mediators of tumour progression and resistance to cytotoxic drugs. This was also confirmed in both cell lines and human tissues. In the RIP1Tag2 mouse model, CUX1 expression was associated with advanced tumour stage and resistance to apoptosis. In summary, we identified the transcription factor CUX1 as mediator of tumour progression in non-functional PanNET in vitro and in vivo, indicating that the CUX1-dependent signalling network is a promising target for future therapeutic intervention.

Dataset Information

Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.

Publications

Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations.

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