Emin Ibrahimov - Academia.edu (original) (raw)

Papers by Emin Ibrahimov

Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer str... more Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support...

Supplemental Microarray Data

Supplemental Materials and Methods

PDF file - 319K, Inhibitory effect of sequential treatments with AZD6244 and gemcitabine on cell ... more PDF file - 319K, Inhibitory effect of sequential treatments with AZD6244 and gemcitabine on cell proliferation in TFK-1 cells

Purpose: MEK inhibition has clinical activity against biliary cancers and might therefore be succ... more Purpose: MEK inhibition has clinical activity against biliary cancers and might therefore be successfully combined with gemcitabine, one of the most active chemotherapy agents for these cancers. As gemcitabine is active in S-phase, and the extracellular signal-regulated kinase (ERK) pathway has a major role driving cell-cycle progression, concurrent use of a MEK inhibitor could potentially antagonize the effect of gemcitabine. We therefore tested the sequence dependence of the combination of gemcitabine and the MEK inhibitor AZD6244 using a series of biliary cancer models.Experimental Design: Primary xenografts were established from patients with gallbladder and distal bile duct cancer and grown in severe combined immunodeficient (SCID) mice at the subcutaneous site. Plasma and tumor drug levels and the time course for recovery of ERK signaling and S-phase were measured in tumor-bearing mice treated for 48 hours with AZD6244 and then monitored for 48 hours off treatment. On the basi...

PDF file - 42K, Inhibitory effect of sequential treatments with AZD6244 and gemcitabine on tumor ... more PDF file - 42K, Inhibitory effect of sequential treatments with AZD6244 and gemcitabine on tumor growth in vivo

PDF file - 111K, Effects of the combination of AZD6244 with gemcitabine plus cisplatin

PDF file - 161K, Time course of recovery of cell cycle phase distribution and proliferation follo... more PDF file - 161K, Time course of recovery of cell cycle phase distribution and proliferation following AZD6244 treatment in vitro

PDF file - 66K, Effect of AZD6244 on cell cycle phase distribution and DNA synthesis of human bil... more PDF file - 66K, Effect of AZD6244 on cell cycle phase distribution and DNA synthesis of human biliary cancer cells

PDF file - 99K, Characterization of biliary cancer xenografts

PDF file - 93K, Effect of single drug treatment of AZD6244 or gemcitabine on OCIP55 mice model

This dataset is linked to the following publication: Whole Genomes Define Concordance of... more This dataset is linked to the following publication: Whole Genomes Define Concordance of Matched Primary, Xenograft, and Organoid Models of Pancreas Cancer The Zipped folder contains processed WGS data pertaining to SSM, SV, and CNV analysis of WGS data for PDAC. Corresponding authors: Dr. Deena Gendoo, email: deena.gendoo1984@gmail.com Dr. Steven Gallinger, email: steven.gallinger@uhn.ca Dr. Benjamin Haibe-Kains, email: benjamin.haibe.kains@utoronto.ca Dr. Steven Gallinger & Dr. Benjamin Haibe-Kains are co-last authors of this publication.

Scientific Reports, 2021

Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitula... more Patient-derived xenograft (PDX) and their xenograft-derived organoid (XDO) models that recapitulate the genotypic and phenotypic landscape of patient cancers could help to advance research and lead to improved clinical management. PDX models were established from 276 pancreato-duodenal and biliary cancer resections. Initial, passage 0 (P0) engraftment rates were 59% (118/199) for pancreatic, 86% (25/29) for duodenal, and 35% (17/48) for biliary ductal tumors. Pancreatic ductal adenocarcinoma (PDAC), had a P0 engraftment rate of 62% (105/169). KRAS mutant and wild-type PDAC models were molecularly profiled, and XDO models were generated to perform initial drug response evaluations. Subsets of PDAC PDX models showed global copy number variants and gene expression profiles that were retained with serial passaging, and they showed a spectrum of somatic mutations represented in patient tumors. PDAC XDO models were established, with a success rate of 71% (10/14). Pathway activation of KRA...

ABSTRACTPancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies ... more ABSTRACTPancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 ‘trios’ of matched primary tumour, PDX, and PDO. We developed a new pipeline to score concordance between PDAC models and their paired human tumours for...

Clinical Cancer Research, 2016

Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer deaths in North America, ... more Pancreatic adenocarcinoma (PDAC) is the 4th most common cause of cancer deaths in North America, for both men and women with a 5-year survival rate of less than 5%. The poor prognosis rate is attributed to late presentation of the disease and the lack of effective treatment options. Large-scale genome sequencing efforts on PDAC tumors show evidence of high mutational burden and revealed a number of mutated genes affecting multiple oncogenic pathways. While there are significant endeavors in developing specific targeted agents against “driver” mutations, tumor diversity within and across patient population remains a key factor affecting therapeutic efficacy. In this context, the availability of large cohorts of genomically characterized patient-derived xenograft (PDX) tumor models may help to accelerate the development of novel therapies against this lethal cancer. PDX models provide a renewable resource to maintain a patient's tumor ex vivo for pre-clinical or co-clinical studie...

Nature, Jan 12, 2016

Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the... more Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this dis...

Molecular cancer research : MCR, Jan 27, 2016

Carcinoma associated fibroblasts (CAFs) represent a significant component of pancreatic cancer st... more Carcinoma associated fibroblasts (CAFs) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumour progression. However, evidence of both cancer promoting and restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared to non-senescent control CAFs using in vitro transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed interleukin 8 (IL8) to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicate the IL8 pathway as a mediator of the pro-invasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry (IHC) correlated with decreased survival in patients with early stage disea...

Cancer Research, 2012

Pancreatic carcinomas have been reported to be some of the most hypoxic of human tumors, although... more Pancreatic carcinomas have been reported to be some of the most hypoxic of human tumors, although the data supporting this view are limited. Our studies with pancreatic cancer xenografts and initial studies in patients suggest that like other solid tumors, they can display a wide range of oxygenation. We have previously demonstrated that tumor hypoxia correlates with high proliferation rates and metastasis in pancreatic cancer. Furthermore, tumor initiating cells (TIC) are hypothesized to reside in the hypoxic zone. The presence of TICs in pancreatic cancer has a prognostic relevance and influences the response to treatment. Recent publications suggest that metastatic potential is conferred by TICs which receive cues from the microenvironment in which they reside. Hypoxia-activated drugs, such as TH-302, target the hypoxic zone and are therefore theorized to not only increase the treatment response of the primary tumor, but also prevent tumor recurrence and metastasis by reducing the number of TIC. We used 10 patient-derived xenograft models to investigate the relationship between tumor hypoxia, tumor growth, and TIC. These models also examined the efficiency of the hypoxia-activated drug TH-302 in reducing the number of TIC in pancreatic tumors. To specifically examine the effect of TH-302 treatment on pancreatic TIC in vivo, tumor-bearing mice were treated with either TH-302, 10Gy IR, or with the combination of both. The harvested tumors cells were then reinjected into NOD/SCID mice for limiting dilution assays. The patient-derived xenograft models showed a positive correlation between not only tumor hypoxia and tumor growth rates but also between tumor hypoxia and the number TIC. Additionally, TH-302 was an effective treatment of hypoxic pancreatic tumors. Our results suggest that TH-302 efficiency correlates with the extent of tumor hypoxia, showing higher efficiency in highly hypoxic patient-derived models as compared to models with low tumor hypoxia. Although treatment with TH-302 alone was sufficient in reducing the number of TIC, the combination treatment with IR further reduced the number of TIC in all the tested xenografts. These findings demonstrate that the combination of radiation therapy and TH-302 may provide an effective treatment strategy for pancreatic cancer patients. Citation Format: Ines Lohse, Joanna Rasowski, Emin Ibrahimov, Richard Hill, Ming S. Tsao, David W. Hedley. Targeting tumor initiating cells in patient-derived pancreatic xenograft models using the hypoxia-activated prodrug TH-302. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B46.