bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B36: Modifier genes and cancer susceptibility: Lessons from inbred mouse strains
Authors: Nnadi Stephanie , Wang Xiang , Crist Richard C. , Buchberg Arthur M. , Siracusa Linda D. 
Published: May 2015

Abstract
The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), an inherited disorder that predisposes individuals to developing intestinal polyposis and eventually leads to cancer. In the Min mouse model, the genetic background of mice carrying a mutation in the murine homolog of the APC gene (ApcMin) is critical to the manifestation of tumor phenotypes, as inbred strains have been demonstrated to differ dramatically in their susceptibility to polyposis. Complex trait analyses from several laboratories, including our own, have identified modifier loci that alter intestinal tumor number and size in ApcMin/+ mice, but less than a handful of modifier genes have been identified to date. We review the results of several quantitative trait loci (QTL) studies that have exploited the genomic diversity among inbred mouse strains and report the identification of novel modifier loci that protect against polyposis. We compare the results with cancer susceptibility loci identified through GWAS and other studies in the human genome. The usefulness of using the mouse as a model organism for optimizing complex trait screens for cancer phenotypes and speeding the process of causative gene identification is discussed. Research supported in part by NCI grants to LDS.
Citation Format: Stephanie Nnadi, Xiang Wang, Richard C. Crist, Arthur M. Buchberg, Linda D. Siracusa. Modifier genes and cancer susceptibility: Lessons from inbred mouse strains. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B36.
Abstract B41: Paclitaxel and carboplatin loaded pegylated liposomes for ovarian cancer
Authors: Tandel Hemal T. 
Published: May 2015

Abstract
Ovarian cancer is the fifth leading cause of death in women. The current chemotherapy and the standard first line treatment for ovarian cancer is combination of ‘platinum plus taxanes’ which associated with serious side effects such as neutropenia and neurotoxicity due to ‘the non-specific biodistribution’ and ‘low therapeutic index of anticancer agents’. Therefore liposomal formulations are now being developed with the aim to reduce problems related to conventional marketed formulations and increase efficiency of the drugs. The present work focuses on development of long circulating PEGylated liposomal formulation of paclitaxel and carboplatin. Paclitaxel liposomal formulation was prepared with the aim to increase the therapeutic efficiency without use of cremophor EL so as to avoid serious side effects associated with vehicle and carboplatin liposomal formulation was prepared to overcome the side effects, occurrence of resistance to platinum drugs, increase its bioavailability and therapeutic efficacy.
Liposomes of paclitaxel and carboplatin were prepared by ‘thin film hydration’ method with lipids like HSPC, DPPG and cholesterol; and were PEGylated by ‘pre-insertion technique’. The optimized PEGylated liposomes of paclitaxel and carboplatin having the mean average particle size of 93.67 ± 2.1 nm and 96.44 ± 3.13 nm, respectively and hence we can expect maximum accumulation of liposomes in solid tumors and improved therapeutic index of loaded paclitaxel and carboplatin. To study the effect of PEGylation on the release characteristics of drugs, comparative diffusion studies for both the drugs were carried out with marketed formulations, conventional liposomes and PEGylated liposomes. Release of drug about 5% and 9% of paclitaxel and carboplatin respectively was observed in 52 hours from their PEGylated formulations. It was very less compared to their marketed and conventional liposomal formulations. The study reveals that there will be less systemic side effects of drugs after administration with increase bioavailability and therapeutic efficacy.
Citation Format: Hemal T. Tandel, Jr. Paclitaxel and carboplatin loaded pegylated liposomes for ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B41.
Abstract B45: Combinatorial activation of PI3-kinase and Ras-Raf signaling in mouse models of advanced prostate cancer
Authors: Wang Jingqiang , Aytes Alvaro , Abate-Shen Cory 
Published: May 2015

Abstract
Concomitant activation of the PI3K and MAP kinase pathways is a hallmark of aggressive prostate cancer. Here, we describe a series of new genetically engineered mouse models of prostate cancer in which PI3K-Akt-mTOR signaling is activated through inducible deletion of PTEN, while MAP kinase signaling is activated through inducible expression of oncogenic mutants of either BRAF or KRAS oncogenes [BRAFV600E (NPB mice) and KRASG12D (NPK mice), respectively]. Activation of PI3K-Akt-mTOR and MAPK signaling pathways in NPB mice results in the formation of lethal prostate tumors that are inherently resistant to castration. These tumors bypass cellular senescence and disseminate to lymph nodes, bone marrow, and lungs where they form overt metastases in approximately 30% of the cases. Molecularly, tumors in the NPB mice cooperate to up-regulate c-MYC oncogene and accordingly, therapeutic treatments with an mTOR inhibitor (rapamycin) and the MEK1/2 inhibitor (PD0325901) results in attenuation of c-MYC levels and reduction primary tumor and metastatic burden. These findings suggest a generalized therapeutic approach to target c-MYC activation in prostate cancer by combinatorial targeting of the PI3K-Akt-mTOR and ERK1/2 MAPK signaling pathways. On the other hand, activation of PI3K-Akt-mTOR and MAP kinase signaling pathways in the NPK mice, results in prostate tumors that are also inherently castration resistant and metastasize to distant organs with 100% penetrance. Our studies show that in the NPK mice, dissemination is an early event in tumorigenesis although overt metastatic growth only occurs in late stage tumors coinciding with the upregulation of the ETS family member ETV4 in the primary tumor. Functional studies have shown that silencing of Etv4 in a metastatic cell line derived from this mouse model (NPK mice) abrogates the metastatic phenotype but does not affect tumor growth. These findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer. Taken together, our analysis of the molecular mechanisms involved in the distinct metastatic potential of these two new mouse models provides us with clinically relevant tools to conduct preclinical studies.
Citation Format: Jingqiang Wang, Alvaro Aytes, Cory Abate-Shen. Combinatorial activation of PI3-kinase and Ras-Raf signaling in mouse models of advanced prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B45.
Abstract IA14: Functional genomics and cancer vulnerabilities
Authors: Hahn William C. 
Published: May 2015

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. These approaches will yield critical information regarding the identification, number, and types of alterations found in human tumors and are increasingly being applied prospectively to patient samples in the clinic. At the same time, complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes involved in cancer initiation and progression. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. The ability to systematically manipulate gene expression at genome scale now provides opportunities to investigate the function of genes involved in cancer initiation and maintenance, which will provide a framework for therapeutic strategies.
Citation Format: William C. Hahn. Functional genomics and cancer vulnerabilities. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA14.
Abstract IA15: Accelerating translational research using ESC-GEMM models and inducible RNAi
Authors: Lowe Scott W. 
Published: May 2015

Abstract
Cancer arises through an evolutionary process whereby normal cells acquire mutations that erode growth controls, leading to the expansion of aberrantly proliferating cells. Such mutations activate oncogenes or inactivate tumor suppressors, each bestowing new capabilities to developing leukemic cells. Our research is based on the premise that the path of cancer evolution dictates a tumor's subsequent response to therapy and creates unique vulnerabilities that represent therapeutic opportunities. Hence, we in use cancer genomics and functional studies in a coordinated manner to identify cancer drivers and dependencies, the then study their role of key genes in therapy response. To facilitate our research, we frequently employ mouse cancer models based on the genetic manipulation of stem and progenitor cells ex vivo followed by transplantation of the altered cells into the appropriate organ of syngeneic recipient mice. This approach allows us to rapidly study the impact of many genes and gene combinations on tumorigenesis and distinguish driver and passenger events from many candidates. Furthermore, we have developed powerful methods for using RNA interference to suppress gene function in vivo in either a stable and reversible manner, enabling us to study the gene function in established disease. Recently, we have combined these approaches to identify and validate candidate driver genes, and then used the animal models obtained from these studies as preclinical model to test novel therapeutic approaches. In addition, we have used inducible RNAi to study the role of tumor suppressor genes and cancer targets in normal and neoplastic tissues.
Citation Format: Scott W. Lowe. Accelerating translational research using ESC-GEMM models and inducible RNAi. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA15.
Abstract IA18: Pathogenesis of gastric cancer: Lessons and therapeutic targets from mouse models
Authors: Wang Timothy C. 
Published: May 2015

Abstract
Many if not most gastrointestinal cancers arise in the setting of chronic inflammation, and a prime example is H. pylori-associated gastric cancer. We have utilized murine models of both proximal and distal gastric neoplasia to investigate the role of chronic inflammation in the development of malignancy. The development of gastric cancer in the mouse is dependent upon commensal flora and activation of both immature myeloid cells and cancer-associated fibroblasts. Gastric cancer arises in highly innervated portions of the stomach, and can be suppressed by surgical or chemical denervation of the stomach. Neurons and neurotransmitters promote the growth of gastric stem cells in organoid culture in vitro. Carcinogenesis of the stomach is associated with activation and early activation and amplification of epithelial stem or progenitor cells appears to be a requirement for the development of neoplasia. Further, conditional loss in gastric stem cells of tumor suppressor genes in vivo may not be sufficient for tumorigenesis but instead may require inflammatory signals in order to maintain self-renewal. In summary, the early stages of tumor development are often niche-dependent, and targeting the cancer niche represents an attractive strategy for cancer prevention and cancer therapy.
Citation Format: Timothy C. Wang. Pathogenesis of gastric cancer: Lessons and therapeutic targets from mouse models. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA18.
Abstract IA3: The Co-Clinical Trial Project
Authors: Pandolfi Pier Paolo 
Published: May 2015

Abstract
Herein we report the first application of a “Co-Clinical” approach, and assess the effectiveness of this integrated platform to investigate the genetic basis of resistance to androgen deprivation therapy (ADT) in prostate cancer (CaP). Surprisingly, we find that physical castration counteracts tumour progression in a Pten-loss driven mouse model of CaP through the induction of a potent apoptotic response and proliferation block. We took advantage of these findings to identify “co-clinically” new determinants of ADT resistance. We show that the tumour suppressive response to ADT is completely bypassed as a consequence of concomitant deletion of either Trp53 or Lrf together with Pten, leading to the development of castration resistant prostate cancer (CRPC). Mechanistically, we find that compound loss of Pten with Lrf or Trp53 triggers the down-regulation of the pro-apoptotic factor Xaf1, along with the up-regulation of the steroid 5-alpha-reductase enzyme Srd5a1, hence promoting CaP cell survival in low androgen conditions. Integrated acquisition of data from mouse and human CaP identifies p53/LRF/XAF1/SRD5A1 as a novel predictive signature for castration resistance. Importantly, we further show both in vitro and in vivo that combined inhibition of XAF1/XIAP and AR pathways overcomes castration resistance. Thus these results provide a proof of principle for the “Co-Clinical” approach as a means to facilitate the stratification of human patients and the development of tailored therapeutic treatments.
Citation Format: Pier Paolo Pandolfi. The Co-Clinical Trial Project. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA3.
Abstract IA7: Drosophila cancer models identify complex therapeutics
Authors: Cagan Ross 
Published: May 2015

Abstract
The complex genomic nature of human tumors presents a challenge for cancer research. To capture this genetic complexity, we generated multigenic models of several cancer types in Drosophila based on patient sequencing data, including thyroid, colorectal, and lung tumors. As we increased in genetic and metabolic complexity, the models prove increasingly resistant to targeted cancer therapies. We have mapped this emergent resistance to specific cancer gene combinations, and have found that drug combinations can “break” this resistance. To establish single compound candidate therapeutics, we collaborated with Kevan Shokat's group to combine fly genetics and medicinal chemistry to develop single agents that suppress multiple targets, while rationally avoiding ‘anti-targets’ that promote toxicity. Finally, I will discuss our efforts to bring these Drosophila tools to individual patients through our new Center for Personalized Cancer Therapeutics.
Citation Format: Ross Cagan. Drosophila cancer models identify complex therapeutics. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr IA7.
Abstract PR13: Using a hypoxia-induced CSC tumor initiation model to improve predictive potential for patients with metastatic breast cancer
Authors: Patel Purvi , Ma Yupo , Zhai Haiyan , Ju Jingfeng , Chen Emily 
Published: May 2015

Abstract
About 10-20% of breast cancers are found to be triple-negative. TNBCs have a relapse pattern that is very different from hormone-positive breast cancers: the risk of relapse is much higher for the first 3-5 years but drops substantially below that of hormone-positive breast cancers after that. Therefore, preventing tumor recurrence and metastasis in high-risk TNBC patients within 3-5 years of diagnosis will dramatically improve the long-term survival of these patients. Currently, most of preclinical animal models have limited predictive clinical potential for advanced metastatic diseases. One possible explanation is that most of the pre-clinical studies focus on the therapeutic benefit of eradicating bulk tumor cells. Using a stem-like subpopulation from triple negative breast cancer (TNBC) cell lines enriched by exposing the cells to cycles of hypoxia and reoxygenation, we showed that mammary tumors initiated from this subpopulation have a high recurrence rate (100%) after the taxol treatment compared to no recurrence from taxol treated tumors initiated from the bulk cancer cells. Our model mimics the progression of recurrence-prone breast tumors with a period of dormancy before the recurrence of local and distal tumors. Molecular analysis of the treatment naïve and recurrent tumors revealed increased expression of chemoresistance-associated miRNAs in the recurred xenograft tumors. In addition, we identified new markers in the recurred xenograft tumors that are also increased in drug resistant human breast tumors compared to the treatment naïve breast tumors. Ultimately, we propose that cancer stem cell based tumor model can be used to improve the predictive potential of pre-clinical models for patients with metastatic breast tumors.
This abstract is also presented as Poster A12.
Citation Format: Purvi Patel, Yupo Ma, Haiyan Zhai, Jingfeng Ju, Emily Chen. Using a hypoxia-induced CSC tumor initiation model to improve predictive potential for patients with metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr PR13.
Abstract A01: The role of EphA2 in KRAS mutant non-small cell lung cancer
Authors: Amato Katherine , Wang Shan , Hastings Andrew , Chen Haiying , Colvin Daniel , Ye Fei , Chen Jin 
Published: May 2015

Abstract
Lung cancer is the leading cause of cancer-related deaths in the United States accounting for approximately 160,000 deaths per year. Emerging data from sequencing efforts has emphasized the importance of identifying molecular subtypes of non-small cell lung cancer (NSCLC) and matching patients with appropriate targeted therapies for the most effective treatment of this disease. Although significant progress has been made to develop novel, molecularly-targeted therapeutics, challenges still remain in targeting commonly occurring mutations in NSCLC, such as KRAS. Overcoming these challenges will require strategies to identify and inhibit novel targets required for the suppression of cell viability in these subtypes of lung cancer. To this end, we have shown that the EphA2 receptor tyrosine kinase plays a unique role in the maintenance of cell viability in NSCLC, especially those with activating KRAS mutations. EphA2 is generally overexpressed in NSCLC and even further overexpressed in KRAS mutant NSCLC. Preliminary data from our lab has shown that silencing of EphA2 expression dramatically inhibits cell viability in human NSCLC cell lines bearing KRAS mutations. To further understand this phenotype, we are working to define the molecular mechanism downstream of EphA2 that is critical for maintaining cell viability in KRAS mutant NSCLC. Additionally, we have created a transgenic mouse model of KRAS mutant NSCLC with EphA2 depletion to study the role of EphA2 in KRAS driven lung tumorigenesis . Based on our preliminary data, we propose that EphA2 provides a novel target for modulating cell viability in lung cancers with KRAS mutations which are currently associated with limited therapeutic options.
Citation Format: Katherine Amato, Shan Wang, Andrew Hastings, Haiying Chen, Daniel Colvin, Fei Ye, Jin Chen. The role of EphA2 in KRAS mutant non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A01. doi: 10.1158/1557-3125.RASONC14-A01
Abstract A09: Notch signaling couples with Kras or PI3K to drive EGFR independent pancreatic acinar to ductal metaplasia
Authors: Halbrook Christopher J. , Crawford Howard C. 
Published: May 2015

Abstract
Almost all reported cases of pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer, harbor an oncogenic Kras mutation. Recently, targeting oncogenic Kras to specific cell types in the adult pancreas has shown the acinar compartment to be more susceptible to neoplastic transformation than ductal cells. Acinar to ductal metaplasia (ADM) is a phenomenon where acinar cells undergo a morphological change and begin expressing markers normally found only in ductal cells while losing markers typical of acinar cells. ADM is highly proliferative with the potential to develop into pancreatic intraepithelial neoplasias, a precursor lesion to pancreatic cancer. Acinar cells harvested from mice expressing mutant Kras undergo spontaneous ADM when embedded in 3D collagen cultures, however, we and others have found the epidermal growth factor receptor (EGFR) is required for ADM induced by mutant Kras expression in vitro. Activation of EGFR by treatment of WT collagen embedded acinar cell explants with the EGFR ligand TGF-α has also been shown to induce ADM in a manner requiring Notch pathway activation. Furthermore, it has been demonstrated that expression of Notch2 intracellular domain (N2ICD) is sufficient to induce ADM in WT acinar cells. To directly investigate the relationship of the EGFR, Kras, and Notch signaling pathways in ADM, we examined the effect of Notch signaling in acinar cells harvested from EGFRf/f; Ptf1a+/Cre (EKO) mice, which harbor a pancreas specific deletion of EGFR. Surprisingly, we found that expression of N2ICD failed to induce ADM in acinar cells from EKO mice. We also observed that co-expression of a constitutively active p110α mutant or mutant Kras with N2ICD was able to rescue ADM in acinar cells from EKO mice, though neither was sufficient to drive ADM in the absence of N2ICD. Additionally, treatment of acinar cells from WT mice with either the p110α inhibitor Pik75 or the expression of a dominant negative mutant of the PI3K downstream target Rac1 reduced Erk1/2 phosphorylation, whereas expression of constitutively active p110α increased the level of Erk1/2 phosphorylation. These results demonstrate the importance of EGFR signaling in ADM, and identify the need to determine the mechanism of crosstalk between the PI3K and MAPK pathways in acinar cells.
Citation Format: Christopher J. Halbrook, Howard C. Crawford. Notch signaling couples with Kras or PI3K to drive EGFR independent pancreatic acinar to ductal metaplasia. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A09. doi: 10.1158/1557-3125.RASONC14-A09