Abstract Purpose: Translation of the patient-derived xenograft (PDX) model into a method for practical personalized cancer treatment is prevented by the intense resources and time necessary to generate and test each tumorgraft. We aimed to develop a high-throughput ex vivo drug testing approach that can be used for personalized cancer treatment design. Experimental Design: We developed a unique ex vivo live tissue sensitivity assay (LTSA), in which precision-cut and uniform small tissue slices derived from pancreatic ductal adenocarcinoma PDX tumors were arrayed in a 96-well plate and screened against clinically relevant regimens within 3 to 5 days. The correlation between the sensitivities of tissue slices to the regimens and patients' clinical responses and outcome were statistically analyzed. The results of LTSA assay were further confirmed with biochemical methods in vitro and animal PDX model in vivo. Results: The ex vivo tissue slices remain viable for at least 5 days, and the tumor parenchyma, including stroma, vascular structures, and signaling pathways, are all retained. The sensitivities of the ex vivo tissue slices to gemcitabine and irinotecan was consistent with the clinical responses and outcomes of the patients from whom the tumorgrafts were derived (r = 0.77; P = 0.0002). Retrospective analysis showed that the patients who received LTSA-sensitive regimens had remarkably longer progression-free survival than patients who received LTSA-resistant regimens (16.33 vs. 3.8 months; n = 18, P = 0.011). Conclusions: The results from these PDX and LTSA methods reflect clinical patients' responses and could be used as a personalized strategy for improving systemic therapy effectiveness in patients with pancreatic cancer. Clin Cancer Res; 22(24); 6021–30. ©2016 AACR.

Overexpression and aberrant activation of signal transducer and activator of transcription 3 (STAT3) contribute to tumorigenesis, drug resistance, and tumor-immune evasion, making it a potential cancer therapeutic target. BP1003 is a neutral liposome incorporated with a nuclease-resistant P-ethoxy antisense oligodeoxynucleotide (ASO) targeting the STAT3 mRNA. Its unique design enhances BP1003 stability, cellular uptake, and target affinity. BP1003 efficiently reduces STAT3 expression and enhances the sensitivity of breast cancer cells (HER2+, triple negative) and ovarian cancer cells (late stage, invasive ovarian cancer) to paclitaxel and 5-fluorouracil (5-FU) in both 2D and 3D cell cultures. Similarly, ex vivo and in vivo patient-derived models of pancreatic ductal adenocarcinoma (PDAC) show reduced tissue viability and tumor volume with BP1003 and gemcitabine combination treatments. In addition to directly affecting tumor cells, BP1003 can modulate the tumor microenvironment. Unlike M1 differentiation, monocyte differentiation into anti-inflammatory M2 macrophages is suppressed by BP1003, indicating its potential contribution to immunotherapy. The broad anti-tumor effect of BP1003 in numerous preclinical solid tumor models, such as breast, ovarian, and pancreatic cancer models shown in this work, makes it a promising cancer therapeutic.

Supplemental Materials and Methods: Immunohistochemical staining of cleaved caspase 3, statistical analysis of the correlation of LTSA values with patients' progression free survival; Supplemental Figure legend

Supplementary Figures 6-7 from Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression

Supplementary Materials and Methods

Supplementary Figure 5 from Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression

Supplementary Figures S1-S6.

Supplementary Figure 3 from Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression

PDF - 35KB, Combination Index for dasatinib and FAK inhibitor PF562271.

Supplementary Table 1. Wild type and mutant lumican SBE oligos for EMSA. Supplementary Table 2. Clinicopathologic and oncologic outcome correlation of stromal lumican expression in PDAC. Supplementary Table 3. Amount of Lumican Secretion in HPSC and PDACs Supernatant at 8 and 24 hours.

Tissue slices after treatment with Gemcitabine (100 µM) or Irinotecan (30 µM) for 48 hours were fixed and embedded for immunohistochemical staining of cleaved-Caspase 3 (40X magnification, Bars = 20 µm).

Mutant p53-associated genes

Supplementary Figure 1 from FoxM1B Transcriptionally Regulates Vascular Endothelial Growth Factor Expression and Promotes the Angiogenesis and Growth of Glioma Cells

HPaSteC and Media: Western blot and ELISA assay: Vectra Automated Quantitative Pathology Imaging System (VAQPIS, PerkinElmer): Double Immunofluorescence staining (IF), and Vectra multispectral analysis: Supplementary figure legends:

This table summarizes the dose (multiplicity of infection, MOI) of Delta-24-RGD that causes 50% of viability inhibition of infected pancreatic cancer cell lines (IC50).

Lumican secretion associated with cell matrix migration.

PDF file, 70K, 3.Summary of synthetic lethality hits/genes.

PDAC cells matrix adhesions were affect by HPSC supernatant of 24 hour's collection.

Lumican expression and secretion in HPaSteC with or without TGF-β exposure at 8 and 24 hours.

Supplementary Tables 1- 3 from Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression