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Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY-1816, in pancreatic ductal adenocarcinoma.

ABSTRACT: Despite tremendous efforts, the clinical prognosis of pancreatic ductal adenocarcinoma (PDAC) remains disappointing. There is an urgent need to develop more effective treatment strategies to improve the prognosis of patients with PDAC. In this study, we evaluate the anti-PDAC effects of LY-1816, a new multikinase inhibitor developed by us. In in vitro assays, LY-1816 showed significant inhibitory effects on the proliferation, migration, and invasion of human PDAC cells, and induced PDAC cell apoptosis. Western blot analysis revealed that LY-1816 markedly suppressed the Src signaling, and downregulated the expression of FOSL1; FOSL1 is an oncogene vulnerability in KRAS-driven pancreatic cancer. In in vivo models of PDAC xenografts (Aspc-1 and Bxpc-3), LY-1816 showed more potent antitumor activity than dasatinib and gemcitabine. Moreover, mice treated with LY-1816 showed a much more significant survival advantage in a metastatic model of PDAC compared with those treated with vehicle, dasatinib, or gemcitabine. These results provide effective support for the subsequent clinical evaluation of LY-1816 in the treatment of PDAC.

SUBMITTER: Yang W

PROVIDER: S-EPMC6447837 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY-1816, in pancreatic ductal adenocarcinoma.

Yang Wei W Meng Lingwei L Chen Kai K Tian Chenyu C Peng Bing B Zhong Lei L Zhang Chunhui C Yang Xin X Zou Jun J Yang Shengyong S Li Linli L

Cancer science 20190306 4

Despite tremendous efforts, the clinical prognosis of pancreatic ductal adenocarcinoma (PDAC) remains disappointing. There is an urgent need to develop more effective treatment strategies to improve the prognosis of patients with PDAC. In this study, we evaluate the anti-PDAC effects of LY-1816, a new multikinase inhibitor developed by us. In in vitro assays, LY-1816 showed significant inhibitory effects on the proliferation, migration, and invasion of human PDAC cells, and induced PDAC cell apo ...[more]

PMID: 30618127

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Project description:Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models-patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)-were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

Project description:BACKGROUND:Signaling pathways critical for embryonic development re-emerge in adult pancreas during tumorigenesis. Aspartate β-hydroxylase (ASPH) drives embryonic cell motility/invasion in pancreatic development/differentiation. We explored if dysregulated ASPH is critically involved in pancreatic cancer pathogenesis. METHODS:To demonstrate if/how ASPH mediates malignant phenotypes, proliferation, migration, 2-D/3-D invasion, pancreatosphere formation, immunofluorescence, Western blot, co-immunoprecipitation, invadopodia formation/maturation/function, qRT-PCR, immunohistochemistry (IHC), and self-developed in vitro metastasis assays were performed. Patient-derived xenograft (PDX) models of human pancreatic ductal adenocarcinoma (PDAC) were established to illustrate in vivo antitumor effects of the third-generation small molecule inhibitor specifically against ASPH's β-hydroxylase activity. Prognostic values of ASPH network components were evaluated with Kaplan-Meier plots, log-rank tests, and Cox proportional hazards regression models. RESULTS:ASPH renders pancreatic cancer cells more aggressive phenotypes characterized by epithelial-mesenchymal transition (EMT), 2-D/3-D invasion, invadopodia formation/function as demonstrated by extracellular matrix (ECM) degradation, stemness (cancer stem cell marker upregulation and pancreatosphere formation), transendothelial migration (mimicking intravasation/extravasation), and sphere formation (mimicking metastatic colonization/outgrowth at distant sites). Mechanistically, ASPH activates SRC cascade through direct physical interaction with ADAM12/ADAM15 independent of FAK. The ASPH-SRC axis enables invadopodia construction and initiates MMP-mediated ECM degradation/remodeling as executors for invasiveness. Pharmacologic inhibition of invadopodia attenuates in vitro metastasis. ASPH fosters primary tumor development and pulmonary metastasis in PDX models of PDAC, which is blocked by a leading compound specifically against ASPH enzymatic activity. ASPH is silenced in normal pancreas, progressively upregulated from pre-malignant lesions to invasive/advanced stages of PDAC. Expression profiling of ASPH-SRC network components independently/jointly predicts clinical outcome of PDAC patients. Compared to a negative-low level, a moderate-very high level of ASPH, ADAM12, activated SRC, and MMPs correlated with curtailed overall survival (OS) of pancreatic cancer patients (log-rank test, ps < 0.001). The more unfavorable molecules patients carry, the more deleterious prognosis is destinated. Patients with 0-2 (n = 4), 3-5 (n = 8), 6-8 (n = 24), and 9-12 (n = 73) unfavorable expression scores of the 5 molecules had median survival time of 55.4, 15.9, 9.7, and 5.0 months, respectively (p < 0.001). CONCLUSION:Targeting the ASPH-SRC axis, which is essential for propagating multi-step PDAC metastasis, may specifically/substantially retard development/progression and thus improve prognosis of PDAC.

Project description:Metabolic reprogramming, due in part to the overexpression of metabolic enzymes, is a key hallmark of cancer cells. Lactate dehydrogenase (LDHA), a metabolic enzyme that catalyzes the interconversion of lactate and pyruvate, is overexpressed in a wide variety of cancer types, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, the genetic or pharmacological inhibition of LDHA suppresses cancer growth, demonstrating a cancer-promoting role for this enzyme. Therefore, several pharmacological LDHA inhibitors are being developed and tested as potential anti-cancer therapeutic agents. Because cancer cells are known to rapidly adapt and become resistant to anti-cancer therapies, in this study, we modeled the adaptation of cancer cells to LDHA inhibition. Using PDAC as a model system, we studied the molecular aspects of cells resistant to the competitive LDHA inhibitor sodium oxamate. We performed unbiased RNA-sequencing (RNA-seq), assay for transposase-accessible chromatin with sequencing (ATAC-seq), and metabolomics analyses of parental and oxamate-resistant PDAC cells treated with and without oxamate to identify the transcriptional, chromatin, and metabolic landscapes of these cells. We found that oxamate-resistant PDAC cells were significantly different from parental cells at the levels of mRNA expression, chromatin accessibility, and metabolites. Additionally, an integrative analysis combining the RNA-seq and ATAC-seq datasets identified a subset of differentially expressed mRNAs that directly correlated with changes in chromatin accessibility. Finally, functional analysis of differentially expressed metabolic genes in parental and oxamate-resistant PDAC cells treated with and without oxamate, together with an integrative analysis of RNA-seq and metabolomics data, revealed changes in metabolic enzymes that might explain the changes in metabolite levels observed in these cells. Collectively, these studies identify the transcriptional, chromatin, and metabolic landscapes of LDHA inhibitor resistance in PDAC cells. Future functional studies related to these changes remain necessary to reveal the direct roles played by these changes in the development of LDHA inhibitor resistance and uncover approaches for more effective use of LDHA inhibitors in cancer therapy.

Dataset Information

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY-1816, in pancreatic ductal adenocarcinoma.

Publications

Preclinical pharmacodynamic evaluation of a new Src/FOSL1 inhibitor, LY-1816, in pancreatic ductal adenocarcinoma.

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