bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 89: Development of preclinical lung adenocarcinoma model
Authors: Suh Young-Ah , Kim Minsuh , Lee Sun-Hye , Jung Chae Lim , Mun Hye-Min , Oh Ju-Hee , Choi Eun Kyung , Jang Se Jin 
Published: May 2015

Abstract
Lung cancer is a leading cause of cancer death in worldwide. 85% of lung cancers are classified as non-small cell lung cancers (NSCLC), and adenocarcinoma (ADC) type is the most prevalent cancer in NSCLC. Approximately 50% of non-small cell lung cancer (NSCLC) patients have mutations in some oncogenes. The K-ras activation due to the mutant is notorious in many kinds of cancer types, including pancreatic cancer and lung adenocarcinoma, as is generally accepted as driving mutation for lung malignancy of lung adenocarcinoma. Another predominantly alternated gene in lung cancer is the EGFR that would hit the similar signaling with K-ras activation, to which small molecules and antibodies target to halt the tumor progression. The tumor suppressor p53 is also often altered in almost all kinds of cancers and lung cancer. In this reason, K-ras activated mouse is utilized as lung cancer mouse model. K-ras activated mouse eventually develops lung adenocarcinoma, which can be accelerated with mutated p53. Due to the gain-of-function, mutant p53 protein contributes to tumor metastasis and shortening the latency of tumor progression. Thereby activated K-ras/mutant p53 mouse is preferentially used as lung adenocarcinoma preclinical model. Here, we have used mouse tumor cells derived from activated K-ras/mutant p53 mouse to establish syngeneic lung cancer mouse model, allowing in vivo imaging. We asked whether the gain-of-function metastatic phenotype observed in the mouse is responsible for the formation of lung tumors when inoculated intravenously. Tumor cells from the mice could efficiently develop tumors in four weeks at the same genetic background. Tumors from the mice were histologically identical with original lung adenocarcinoma, suggesting that these cells are the efficient tools to generate preclinical lung tumor mouse model. We have examined this model for evaluating the efficiency of chemotherapeutics and signaling pathways involved in tumor growth regulation.
Citation Format: Young-Ah Suh, Minsuh Kim, Sun-Hye Lee, Chae Lim Jung, Hye-Min Mun, Ju-Hee Oh, Eun Kyung Choi, Se Jin Jang. Development of preclinical lung adenocarcinoma model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 89. doi:10.1158/1538-7445.AM2014-89
Abstract 899: Combination of PI3K and MEK inhibitor chemosensitivity in human tumor explants and cell lines using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry
Authors: Dauffenbach Lisa M. , Sia Gela C. , Cash Patricia A. , Girees Sherif K. , Lim Ryan S. , Zheng Jianping , Olsen Eric P. , Kerfoot Christopher A. 
Published: May 2015

Abstract
The PI3K and MEK pathways promote tumor cell survival through a variety of downstream signals and are commonly explored in cancer research. Many agents are in clinical development and new evidence suggests that a combination of these inhibitors may be required to achieve optimal anti-tumor activity. Twenty-one viable colorectal and non-small cell lung cancer tissue explants with matched formalin-fixed, paraffin embedded (FFPE) tissue and 8 cell lines (A431, AGS, HCT-116, HT-29, MCF-7, MDA-MB-468, MKN45, and T47D) were used for this study. Fresh tissues were disaggregated into single cells and exposed to GDC-0941, a PI3K inhibitor, and AZD6244, a MEK inhibitor, both as single agents and in combination in the Mosaic Blue assay. Combination results were compared to single agent results. Samples were classified as resistant or sensitive. Matched FFPE tissues and cells were stained with the following biomarkers to identify predictive relationships: pAKT, p4EBP1, pPRAS40, ppS6 kinase, pS6 ribosomal protein, pERK, PTEN, cMET, EGFR, HER3, Ki-67, and p53. To assess pharmacodynamics changes, the 8 cell lines were also exposed to 1 concentration of each inhibitor both as single agents and in combination. The cells were fixed and paraffin embedded for IHC staining of the following biomarkers to identify pharmacodynamic relationships: pAKT, p4EBP1, pPRAS40, ppS6 kinase, pS6 ribosomal protein, pEGFR, pHER3, pMET, pERK, and Ki-67. The combination of inhibitors demonstrated additive growth inhibition in the explants and cell lines. The average combination IC50 was more potent than single agents, with greater additivity demonstrated in colorectal cancer compared to lung cancer. Predictive and pharmacodynamic biomarkers were identified with both single agent and combination treatments, and differences were observed between the two inhibitors. In summary, this study demonstrated that the Mosaic Blue assay is a useful tool for classifying sensitive and resistant tumor explants and cell lines and also confirmed that dual targeting of PI3K and MEK pathways is a valuable approach to achieving higher therapeutic activity in vitro. Evaluation of biomarker profiles revealed predictive and pharmacodynamic relationships in this setting.
Citation Format: Lisa M. Dauffenbach, Gela C. Sia, Patricia A. Cash, Sherif K. Girees, Ryan S. Lim, Jianping Zheng, Eric P. Olsen, Christopher A. Kerfoot. Combination of PI3K and MEK inhibitor chemosensitivity in human tumor explants and cell lines using the Mosaic Blue assay and relationship to biomarkers by immunohistochemistry. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 899. doi:10.1158/1538-7445.AM2014-899
Abstract 910: NOTCH3 expression is predictive of efficacy in pancreas tumor models treated with OMP-59R5, a monoclonal antibody targeting the NOTCH2 and NOTCH3 receptors
Authors: Cancilla Belinda , Yen Wan-Ching , Zhang Chun , Fischer Marcus M. , Ji May , Tang Tracy , Liu Yu-Wang , Tam Raymond S. , Wang Min , Gurney Austin , Hoey Timothy , Lewicki John , Kapoun Ann M. 
Published: May 2015

Abstract
The Notch signaling pathway regulates key functions during embryonic development, stem cell maintenance and differentiation in adult tissues, and is implicated in many human cancers. OMP-59R5 is a ligand-blocking antibody targeting both the NOTCH2 and NOTCH3 receptors. We have developed a series of primary human xenograft models from patients with pancreatic cancer and used these models to examine efficacy response to OMP-59R5. We found that anti-NOTCH2/3, either as a single agent or in combination with chemotherapeutic agents, was efficacious in pancreatic tumor models. Expression of NOTCH3 mRNA by next-generation sequencing in ten baseline pancreatic tumors correlates with response to OMP-59R5, where growth of tumors with moderate to high expression of NOTCH3 was significantly reduced compared to tumors with low expression. We developed a Research-Use-Only (RUO) qPCR assay for measuring NOTCH3 mRNA expression using Formalin-Fixed, Paraffin-Embedded (FFPE) samples. This assay shows consistent NOTCH3 expression data with the next-generation sequencing data in the ten pancreatic xenograft tumors. Expression levels of NOTCH3 were also examined in ∼120 human metastatic pancreatic specimens to determine the reportable range of the assay and to identify association with clinical factors. This analysis showed that NOTCH3 gene expression maintained the same distribution across different specimen types, such as biopsy, surgical biopsy and surgical resection, etc. Samples with clinically relevant sites of recurrence also showed a similar range in NOTCH3 gene expression. Moreover, we developed an immunohistochemistry (IHC) assay for NOTCH3 protein expression. The correlation between the IHC assay and the qPCR assay was examined in both the metastatic pancreatic human specimens and the primary human pancreatic xenograft models. A significant correlation was found between the gene and protein levels, suggesting that both NOTCH3 gene expression and protein expression may predict the response to OMP-59R5 in pancreatic cancer. We are evaluating NOTCH3 levels and patient response in ALPINE, a Ph1b/2 Anti-NOTCH2/3 trial in first-line advanced pancreatic cancer patients.
Citation Format: Belinda Cancilla, Wan-Ching Yen, Chun Zhang, Marcus M. Fischer, May Ji, Tracy Tang, Yu-Wang Liu, Raymond S. Tam, Min Wang, Austin Gurney, Timothy Hoey, John Lewicki, Ann M. Kapoun. NOTCH3 expression is predictive of efficacy in pancreas tumor models treated with OMP-59R5, a monoclonal antibody targeting the NOTCH2 and NOTCH3 receptors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2014-910
Abstract 911: Prostate-specific membrane antigen (PSMA) expression as a potential patient selection marker in patients with refractory solid tumors administered BIND-014, a PSMA-targeted nanoparticle containing docetaxel
Authors: Low Susan , Hoff Daniel Von , Mita Monica , Burris Howard , Eisenberg Peter , Hart Lowell , LoRusso Patricia , Weiss Glen , Sachdev Jasgit , Mita Alain , Ramanathan Ramesh , Hrkach Jeff , Summa Jason , Berk Gregory 
Published: May 2015

Abstract
Background: Prostate-specific membrane antigen (PSMA) is a transmembrane protein that is overexpressed in prostate adenocarcinomas and in non-prostatic tumor neovasculature. As a novel target for therapeutic approaches, the distribution pattern of PSMA in primary and metastatic tumors is of significant interest. In this study we addressed the cellular distribution and heterogeneity of PSMA expression in solid tumors from patients on a phase 1 study of BIND-014, a PSMA-targeted nanoparticle containing docetaxel.Methods: Paraffin-embedded sections of surgical specimens from 1 patient (pt) with prostate carcinoma and 4 pts with non-prostatic tumors (cervical, NSCLC, breast and hepatobiliary) were evaluated. Immunohistochemistry by platelet endothelial cell adhesion molecule (CD31) for the detection of endothelial cells and monoclonal mouse anti-human PSMA (Clone 3E6) for detection of PSMA were used to determine the cellular localization and staining intensity for each tumor type. Results: All pts evaluated experienced some clinical benefit from BIND-014 (including complete response, partial response or stable disease) which is targeted to PSMA. We demonstrated differences in staining intensity and localization of PSMA in neoplastic epithelium and neoplastic tissue-associated blood vessels. PSMA was detected in the epithelium of prostate tissue and in neoplastic tissue-associated vessels of cervical, anal, NSCLC, and hepatobiliary cancers. PSMA was not detected in benign tissue of any specimens evaluated. Conclusions: Our findings support the feasibility of developing this assay as a companion diagnostic to potentially select patients who may benefit from PSMA-directed targeted therapy. Ongoing Phase 2 studies with BIND-014 include further PSMA expression analysis.
Citation Format: Susan Low, Daniel Von Hoff, Monica Mita, Howard Burris, Peter Eisenberg, Lowell Hart, Patricia LoRusso, Glen Weiss, Jasgit Sachdev, Alain Mita, Ramesh Ramanathan, Jeff Hrkach, Jason Summa, Gregory Berk. Prostate-specific membrane antigen (PSMA) expression as a potential patient selection marker in patients with refractory solid tumors administered BIND-014, a PSMA-targeted nanoparticle containing docetaxel. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 911. doi:10.1158/1538-7445.AM2014-911
Abstract 939: Serial monitoring of EGFR mutations in plasma and matched tissue from EGFR mutant non-small cell lung cancer patients on erlotinib
Authors: Paweletz Cloud P. , Oxnard Geoffrey R. , Kuang Yanan , O'Connell Allison , Yanagita Masahiko , Messineo Melissa M. , Kirschmeier Paul , English Jessie M. , Jackman David M. , Jänne Pasi A. 
Published: May 2015

Abstract
Tumor genotyping has become standard in the care of non-small cell lung cancer (NSCLC), colorectal cancer, and melanoma because of its power in guiding the personalization of treatment with molecularly targeted therapies. A major limitation of cancer genotyping is the availability of pre- and post-treatment tumor biopsy specimens for accurate assessment of cancer biology. In addition, serial tumor biopsies from NSCLC patients at time of disease response or progression are not always desirable from the patient perspective and feasibility can be limited due to accessible tumor tissue and cost. The analysis of circulating cell-free DNA (cfDNA) has demonstrated potential to be a non-invasive means of interrogating the biology underlying response and resistance.
Here we report the detection, quantification and monitoring of EGFR mutations by droplet digital PCR in cfDNA on a prospective clinical trial of EGFR-mutant NSCLC patients on erlotinib. Droplet digital PCR, a novel technology that emulsifies DNA input into ∼20,000 consistently sized droplets, each individually genotyped, represents a promising approach for non-invasive quantification of specific tumor mutations. EGFR L858R, Del(19) and T790M were serially measured in over 300 samples from 40 lung cancer patients treated on erlotinib. Complete plasma response was seen in 8 cases; in 6, rising levels of inhibitor sensitizing EGFR Del(19) and L858R and acquired EGFR T790M mutations were detected up to 4 months prior to objective radiographic progression. An analysis of patients that progressed showed that 53% had tumor-genotype-confirmed EGFR sensitizing mutations in their plasma at diagnosis. Four of these patients had a tumor rebiopsy adequate for EGFR genotyping at progression, and EGFR T790M was confirmed in each. This contrasts to the same analysis on circulating tumor cells (CTC), collected simultaneously: No CTCs were identified at diagnosis and only 22% of patients had any detectable CTCs at progression. Our results strongly suggest that cfDNA genotyping has clinical utility in the molecular assessment of patients at diagnosis, and providing molecular understanding of patient's tumor evolution, in real time, by serial monitoring for resistance mutations.
Citation Format: Cloud P. Paweletz, Geoffrey R. Oxnard, Yanan Kuang, Allison O'Connell, Masahiko Yanagita, Melissa M. Messineo, Paul Kirschmeier, Jessie M. English, David M. Jackman, Pasi A. Jänne. Serial monitoring of EGFR mutations in plasma and matched tissue from EGFR mutant non-small cell lung cancer patients on erlotinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2014-939
Abstract 948: Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia
Authors: Cherian Joseph , Nacro Kassoum , Poh Zhi Ying , Guo Samantha , Ho Melvyn , Yang Haiyan , Lim Sharon , Choong Meng Ling , Ding Jun L. , Joy Joma Kanikadu , Kwek Zekui Perlyn , Liu Boping , Ong Hongqian Esther , Pendharkar Vishal , Poulsen Anders , Lee May Ann , Sangthongpitag Kanda , Chuah Charles , Ong Tiong S. , Hill Jeffrey , Keller Thomas H. , Matter Alex 
Published: May 2015

Abstract
Although targeting the BCR-ABL kinase with tyrosine kinase inhibitors (TKI) is effective in chronic phase (CP) CML, targeting BCR-ABL alone is not sufficient to treat late-stage or blast crisis (BC) CML. In BC CML, granulocyte macrophage progenitors (GMPs) acquire the ability to function as leukemic stem cells (LSCs), and are thought to act as a reservoir for TKI resistance. While long-term remission in BC CML is possible with allogeneic stem cell transplantation, only a minority of patients are eligible for transplantation, and may experience high morbidity and mortality. Safe and effective BC CML therapy will likely have to target the BC LSC population to ensure long-term disease control.
Recent studies have shown the importance of the MAP kinase interacting serine/threonine kinase (MNK1/2)-eukaryotic translation initiation factor 4E (eIF4E) axis in sustaining BC LSC self renewal. Thus, a single agent which inhibits both BCR-ABL and MNK1/2 kinase simultaneously represents a rational approach to target BC LSCs. Such an agent should be able to distinguish between normal hematopoietic stem cells (HSC) and LSCs.
Here, we report the discovery, structure activity relationships, pharmacokinetic properties, and biochemical characteristics of dual MNK1/2 and BCR-ABL inhibitors, ETC-027 and ETC-219. These compounds are able to prevent eIF4E phosphorylation, BCR-ABL-driven growth and proliferation of BC CML cells, as well as inhibit the MNK-eIF4E-dependent self-renewal function of BC LSCs, while leaving normal HSCs untouched.
Citation Format: Joseph Cherian, Kassoum Nacro, Zhi Ying Poh, Samantha Guo, Melvyn Ho, Haiyan Yang, Sharon Lim, Meng Ling Choong, Jun Li Ding, Joma Kanikadu Joy, Zekui Perlyn Kwek, Boping Liu, Hongqian Esther Ong, Vishal Pendharkar, Anders Poulsen, May Ann Lee, Kanda Sangthongpitag, Charles Chuah, Tiong S. Ong, Jeffrey Hill, Thomas H. Keller, Alex Matter. Discovery of dual MNK 1 and 2 and BCR-ABL kinase inhibitors for the treatment of blast crisis chronic myeloid leukemia. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 948. doi:10.1158/1538-7445.AM2014-948
Abstract 955: Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors
Authors: Niederst Matthew J. , Sequist Lecia V. , Lockerman Elizabeth L. , Garcia Angel R. , Costa Carlotta , Mohamoud Farhiya , Borger Darrell R. , Shioda Toshi , Getz Gad , Iafrate Anthony J. , Mino-Kenudson Mari , Engelman Jeffrey A. 
Published: May 2015

Abstract
Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers (NSCLCs) are sensitive to the EGFR inhibitors erlotinib and gefitinib. In the majority of patients with this type of cancer, EFGR inhibition leads to a dramatic reduction in tumor size coupled with an abatement of symptoms. These responses are temporary, and in most cases the cancers become resistant after an average of one year. Recently, we and others have found that a subset of these cancers transform from NSCLC to SCLC as they acquire resistance to EGFR TKI. Details underlying this novel resistance mechanism are largely undiscovered. To assess the genetic changes associated with NSCLC to SCLC transformation, we carried out next generation sequencing analysis on NSCLC and SCLC resistant tumors. The sequencing results revealed that Rb, along with p53 and PIK3CA were specifically altered in the SCLC transformed tumors. An IHC assay to detect Rb indicated that while 10 out of 10 SCLC transformed cases have loss of Rb, resistant cancers that maintained an NSCLC histology largely retained Rb. To address the mechanism underlying the resistance to EGFR inhibition in these tumors, we demonstrated that upon the transformation to SCLC there is a marked reduction in EGFR expression, suggesting that in transforming to SCLC these cells become a cell type that no longer requires EGFR for their survival. Finally, utilizing cell lines generated from biopsies taken from resistant cancers, we identify the Bcl-2/Bcl-XL inhibitor Abt-263 as a potential therapeutic approach to treat these resistant patients. Together, our results provide details underlying this novel mechanism of resistance to targeted therapy.
Citation Format: Matthew J. Niederst, Lecia V. Sequist, Elizabeth L. Lockerman, Angel R. Garcia, Carlotta Costa, Farhiya Mohamoud, Darrell R. Borger, Toshi Shioda, Gad Getz, Anthony J. Iafrate, Mari Mino-Kenudson, Jeffrey A. Engelman. Transformation from NSCLC to SCLC in EGFR mutant lung cancers with acquired resistance to EGFR inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 955. doi:10.1158/1538-7445.AM2014-955
Abstract 957: The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer
Authors: Friboulet Luc , Li Nanxin , Katayama Ryohei , Lee Christian C. , Gainor Justin F. , Crystal Adam S. , Michellys Pierre-Yves , Awad Mark M. , Yanagitani Noriko , Kim Sungjoon , Pferdekamper AnneMarie , Li Jie , Kasibhatla Shailaja , Sun Frank , Sun Xiuying , Hua Su , McNamara Peter , Mahmood Sidra , Lockerman Elizabeth L. , Fujita Naoya , Nishio Makoto , Harris Jennifer L. , Shaw Alice T. , Engelman Jeffrey A. 
Published: May 2015

Abstract
Non-small cell lung cancers (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangements are sensitive to the ALK tyrosine kinase inhibitor (TKI) crizotinib. However, these cancers invariably relapse due to the development of resistance, and approximately 1/3 of such cancers develop resistance mutations within the ALK tyrosine kinase domain. Here we report the preclinical evaluation of the next-generation ALK TKI, LDK378 in the setting of crizotinib resistance. Using EML4-ALK mutant Ba/F3 cellular models, in vivo models of acquired resistance to crizotinib, and novel cell lines established from biopsies of crizotinib-resistant NSCLC patients, we have examined the efficacy of LDK378 in crizotinib-naïve and -resistant ALK-positive cancers. These studies reveal that LDK378 is more potent than crizotinib and effectively overcomes resistance in vitro and in vivo. In particular, LDK378 inhibits ALK harboring crizotinib resistance mutations, including L1196M, G1269A, I1171T and S1206Y. Cell lines derived from crizotinib-resistant biopsies were sensitive to LDK378, including one that did not harbor an ALK resistance mutation and was also sensitive to crizotinib, suggesting that some crizotinib-resistant cancers with wildtype ALK are still sensitive to complete ALK inhibition. We observed that LDK378 did not effectively overcome two crizotinib-resistant ALK mutations, G1202R and F1174C
ALK, and mutations in one of these residues was identified in 5 out of 11 biopsies from patients with acquired resistance to LDK378. Altogether our results demonstrate that LDK378 can overcome many mechanisms of crizotinib resistance, consistent with emerging clinical data showing marked efficacy of LDK378 in patients with crizotinib-resistant disease.
Citation Format: Luc Friboulet, Nanxin Li, Ryohei Katayama, Christian C. Lee, Justin F. Gainor, Adam S. Crystal, Pierre-Yves Michellys, Mark M. Awad, Noriko Yanagitani, Sungjoon Kim, AnneMarie Pferdekamper, Jie Li, Shailaja Kasibhatla, Frank Sun, Xiuying Sun, Su Hua, Peter McNamara, Sidra Mahmood, Elizabeth L. Lockerman, Naoya Fujita, Makoto Nishio, Jennifer L. Harris, Alice T. Shaw, Jeffrey A. Engelman. The ALK inhibitor LDK378 overcomes crizotinib resistance in non-small cell lung cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 957. doi:10.1158/1538-7445.AM2014-957