Article Figures & Data
Figures
- Figure 1.
Generation and characterization of the patient-derived xenograft model of PNET (PDX-PNET). A, nondiagnostic portion of metastasized PNETs were removed during the hepatic resection and expanded in a cohort of female athymic nude mice. Comparison of neuroendocrine biomarkers in original patient tumor and passage-6 PDX-PNET using RNA sequencing (B) and immunofluorescence (C). In B, a “+” means a gene is expressed. In C, DNA is in blue while CHGA, INS, and 5-HT are in green.
- Figure 2.
68Ga-DOTATATE PET-CT imaging of the PDX-PNET model. A, 3D rendered PET/CT image showing flank tumor tracer uptake. B, Axial view at the level of the tumor. C, Relationship between tumor size and normalized 68Ga-DOTATATE PET/CT counts.
- Figure 3.
PDX-PNETs harbor mutations in genes commonly associated with PNETs and mTOR pathway activation. A, Whole-exome sequencing of PDX-PNET reveals mutations in genes commonly found in PNET. B, Two frameshift mutations were identified in PTEN. Green, phosphatase domain; blue, C2 domain; red, PDZ-binding domain.
- Figure 4.
Response of PDX-PNETs to the mTOR inhibitor drugs everolimus and sapanisertib. A, Growth chart of PDX-PNETs treated with vehicle control, everolimus, or sapanisertib for 28 days (vehicle control n = 5, everolimus n = 6, sapanisertib n = 6). The P values were calculated by two-tailed Student t test (*, P < 0.05, **, P < 0.01). Error bars indicate the SD from the mean. B, Western blot analysis of mTOR pathway targets in PDX-PNETs harvested after 28 days of treatment with either vehicle control, everolimus, or sapanisertib. Each lane represents a single xenograft harvested from a unique mouse.
- Figure 5.
Response of everolimus-resistant PDX-PNETs to sapanisertib. A, The best response of tumors treated with everolimus, as compared with pretreatment baseline (n = 34). Numbers along the x-axis indicate arbitrarily assigned animal numbers in order of increasing percentage response to everolimus. The bars indicate the percent change in tumor burden from baseline. B, The best response to sapanisertib in 10 animals with everolimus-resistant PDX-PNETs. Selected tumor characteristics are listed in the table below the graph. Animals are listed in order of increasing percentage response to sapanisertib, with listed numbers corresponding to those in Fig. 5A. Sapanisertib treatment ended when tumors either regressed (n = 1), developed sapanisertib resistance, and exceeded five times the original volume (n = 6), or animals died (n = 3). Underlined numbers indicate animals that died during treatment.
Additional Files
Supplementary Data
- Supplementary Figure 1 - Pharmacodynamic studies of everolimus and sapanisertib treated PDX-PNETs using Western blot analysis of mTOR pathway targets.
Volume 17, Issue 12
