bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA10: Improving existing cancer therapy by targeting the tumor microenvironment
Authors: Pallasch Christian , Gilbert Luke , Hemann Michael 
Published: May 2015

Abstract
Many human cancers fail to respond to chemotherapy, and cancers that initially respond frequently acquire drug resistance and relapse. This process of tumor relapse is particularly confounding, as patients can be in remission for years following treatment prior to the reemergence of a cancer. Additionally, tumors that relapse have generally acquired resistance to the initial treatment. While conventional anti-cancer therapies have been in clinical use for decades, little is known about the mechanisms by which a tumor cell can survive treatment and persist in a patient for extended period of time. In fact, a major cause of cancer deaths is the inability to eradicate small sets of surviving tumor cells, termed “minimal residual disease” or “MRD”. Work from our laboratory has found that chemotherapy paradoxically elicits a pro-survival response in certain anatomical cites. Specifically, normal cells proximal to tumor cells secrete factors that counter the effects of the chemotherapy. This survival response likely serves to protect normal progenitor and stem cells to allow for tissue regeneration following damage, but it is coopted by tumor cells that find themselves in these specialized sites. Thus, effective cancer therapy may not only involve targeting cancer cells but also may require inhibiting survival signals emanating from surrounding cells. We have developed multiple models of MRD that have not only identified mechanisms of tumor cell persistence, but also strategies to sensitize chemorefractory tumors to front-line chemotherapy.
Citation Format: Christian Pallasch, Luke Gilbert, Michael Hemann. Improving existing cancer therapy by targeting the tumor microenvironment. [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 IA10.
Abstract IA11: Understanding drug responses and resistance mechanisms using imaging in live mice
Authors: Egeblad Mikala , Nakasone Elizabeth , Askautrud Hanne , Wysocki Robert , Fein Miriam , Kees Tim , Park Juwon , Park Jae-Hyun 
Published: May 2015

Abstract
It is well appreciated that factors intrinsic to the cancer cells, such as specific mutations, regulate response to chemotherapy. However, there is limited knowledge on the dynamics of cancer cell death in response to therapy in the naturally developing tumor microenvironment. Using intravital microscopy (microscopy in live mice) of tumors, we show that factors within the microenvironment, extrinsic to the cancer cells, support the development of chemoresistance by regulating drug distribution and the inflammatory response. Specifically, intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to the chemotherapeutic drug doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. These results have clinical implications, as myeloid cell infiltration is increased in human breast tumors after chemotherapy and the cellular composition of the immune infiltrate is a strong predictor of overall survival. Our data further suggest that the response to classical chemotherapeutic drugs can be improved by changing the tumor microenvironment with agents that modify matrix metalloproteinase activity and chemokine signaling. Thus, intravital imaging can be used to gain insights into drug responses in situ.
Citation Format: Mikala Egeblad, Elizabeth Nakasone, Hanne Askautrud, Robert Wysocki, Miriam Fein, Tim Kees, Juwon Park, Jae-Hyun Park. Understanding drug responses and resistance mechanisms using imaging in live mice. [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 IA11.
Abstract IA12: The use of forward genetics for drug target discovery and the identification of mediators of therapy resistance
Authors: Adams David J. 
Published: May 2015

Abstract
In this talk I will outline how we've been using the extensive collection of cancer genomes generated by the TCGA and ICGC together with forward genetic screens in the mouse to discover new cancer genes. I will also discuss how further insights into the function of these genes, and importantly candidate therapies and combination treatments, have been derived using mouse model systems. Specifically, I will describe the identification of CUX1 as an important new driver of tumorigenesis, and a new mechanism of resistance to Braf-inhibitor treatment. Both of these stories illustrate the power of model systems to discover new cancer genes that were not immediately obvious from the human cancer genome alone, and how the mouse may be deployed to gain important insights into the function of these new cancer genes.
Citation Format: David J. Adams. The use of forward genetics for drug target discovery and the identification of mediators of therapy resistance. [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 IA12.
Abstract IA5: Using cross-species analysis of genome-wide regulatory networks to identify drivers of cancer malignancy
Authors: Abate-Shen Cory 
Published: May 2015

Abstract
We have been interested in using systems biology approaches for cross-species interrogations of cancer phenotypes. To identify regulatory drivers of prostate cancer malignancy, we have performed cross-species analysis of complementary human and mouse gene regulatory networks (interactomes) assembled from molecular profiles of human tumors and genetically engineered prostate cancer mouse models, respectively. Genome-wide analysis of these interactomes reveals extensive conservation of their transcriptional programs, particularly those known to be essential for prostate tumorigenesis. Cross-species interactome interrogation and subsequent experimental validation have elucidated a synergistic interaction of FOXM1 and CENPF that drives prostate cancer malignancy. Silencing of both FOXM1 and CENPF, but not either individually, abrogates prostate tumor growth in vivo via cooperative regulation of key signaling pathways in prostate cancer progression. Furthermore, co-expression of FOXM1 and CENPF is a highly robust prognostic indicator of disease outcome. Taken together, these analyses suggest that genome-wide cross-species interrogation of regulatory networks represents a valuable new strategy to identify causal mechanisms of human cancer.
Citation Format: Cory Abate-Shen. Using cross-species analysis of genome-wide regulatory networks to identify drivers of cancer malignancy. [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 IA5.
Abstract IA8: A new class of drugs active in T-ALL is revealed in a zebrafish screen
Authors: Gutierrez Alejandro , Pan Li , Groen Richard , Baleydier Frederic , Kentsis Alex , Marineau Jason , Grebliunaite Ruta , Kozakewich Elena , Reed Casie , Pflumio Francoise , Poglio Sandrine , Uzan Benjamin , Clemons Paul , Verplank Lynn , An Frank , Burbank Jason , Norton Stephanie , Tolliday Nicola , Steen Hanno , Weng Andrew P. , Yuan Huipin , Bradner James E. , Mitsiades Constantine , Look A. Thomas , Aster Jon C. 
Published: May 2015

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer frequently associated with activating NOTCH1 mutations and dysregulation of MYC. We performed two complementary screens to identify novel agents with activity against T-ALL: i) a zebrafish screen for small molecules toxic to MYC-overexpressing thymocytes, and ii) a human T-ALL cell line screen for small molecules that synergize with Notch inhibitors. “Hits” common to both screens included perphenazine, a phenothiazine antipsychotic that induced apoptosis of fish, mouse, and human T-ALL cells. Using ligand-affinity chromatography coupled to mass spectrometry, we identified protein phosphatase 2A (PP2A) as the critical perphenazine target. In line with this finding, T-ALL cell lines treated with perphenazine underwent apoptosis associated with rapid dephosphorylation of multiple PP2A substrates, indicating that perphenazine binds and activates the PP2A tumor supressor. Moreover, shRNA knockdown of the scaffolding or catalytic subunits of PP2A attenuated the activity of perphenazine, indicating that PP2A is required for its antileukemic activity. Finally, treatment of primary human T-ALLs with pherphenazine suppressed cell growth and caused dephosphorylated of PP2A targets in vitro and in vivo. Our findings provide a mechanistic explanation for the recurrent “rediscovery” of phenothiazines as a class of drugs with anti-cancer effects and highlight the therapeutic potential of pharmacologic PP2A activation in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates.
Citation Format: Alejandro Gutierrez, Li Pan, Richard Groen, Frederic Baleydier, Alex Kentsis, Jason Marineau, Ruta Grebliunaite, Elena Kozakewich, Casie Reed, Francoise Pflumio, Sandrine Poglio, Benjamin Uzan, Paul Clemons, Lynn Verplank, Frank An, Jason Burbank, Stephanie Norton, Nicola Tolliday, Hanno Steen, Andrew P. Weng, Huipin Yuan, James E. Bradner, Constantine Mitsiades, A. Thomas Look, Jon C. Aster. A new class of drugs active in T-ALL is revealed in a zebrafish screen. [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 IA8.
Abstract PR02: Targeting NOTCH1 and C-MYC in humanized models of relapsed and induction failure pediatric T-ALL
Authors: Roderick Justine E. , Tesell Jessica , Gutierrez Alejandro , Look Thomas , Qi Jun , Bradner James E. , Kelliher Michelle A. 
Published: May 2015

Abstract
Although prognosis has improved for children with T cell acute lymphoblastic leukemia (T-ALL), 20-30% of patients undergo induction failure (IF) or relapse. Leukemia-initiating cells (L-ICs) are hypothesized to be resistant to chemotherapy and to mediate relapse. We and others have shown that Notch1 directly regulates c-Myc and c-Myc is a known regulator of quiescence in stem and progenitor populations, leading us to examine whether c-Myc inhibition results in efficient targeting of T-ALL-initiating cells. We demonstrate that c-Myc suppression by shRNA or pharmacological approaches prevents leukemia initiation in mice by reducing the L-IC population. Consistent with its anti-L-IC activity in mice, treatment with the BET bromodomain BRD4 inhibitor JQ1 reduces C-MYC expression and inhibits the growth of relapsed and induction failure (IF) pediatric T-ALL samples in vitro. Although treatment of relapsed T-ALL cells with gamma secretase inhibitors (GSI) or JQ1 reduces, it does not abrogate C-MYC mRNA levels, indicating a role for dual NOTCH and MYC inhibition in relapsed disease. To test this possibility, we engrafted immunodeficient NSG mice with relapsed pediatric T-ALL cells and treated them with vehicle, GSI, JQ1 or with GSI and JQ1 and monitored survival. Although JQ1 or GSI treatment alone significantly prolonged survival, the combination therapy was more effective at extending survival. These findings reveal a requirement for MYC in mouse and human L-IC maintenance and provide evidence that NOTCH1 and MYC inhibition may be an effective therapy for relapsed/IF T-ALL patients.
This abstract is also presented as Poster A48.
Citation Format: Justine E. Roderick, Jessica Tesell, Alejandro Gutierrez, Thomas Look, Jun Qi, James E. Bradner, Michelle A. Kelliher. Targeting NOTCH1 and C-MYC in humanized models of relapsed and induction failure pediatric T-ALL. [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 PR02.
Abstract PR06: Clonal evolution enhances leukemia propagating cell activity in T-cell acutelymphoblastic leukemia through AKT/mTORC1 pathway activation
Authors: Blackburn Jessica , Liu Sali , Dobrinski Kimberly , Martinez Sarah , Moore Finola , Lobbardi Riadh , Langenau David 
Published: May 2015

Abstract
Leukemia progression and relapse are driven by molecularly distinct and often-rare cancer cells called leukemia-propagating cells (LPCs). If LPCs are retained following treatment, they will ultimately initiate relapse disease. Despite the substantial number of genetic lesions that have been identified in relapse samples and the contention that these mutations likely modulate response to therapy, acquired mutations that increase the overall frequency of tumor propagating cells following continued clonal evolution have not been reported in any cancer to date. Here, we have developed a transgenic zebrafish model where single fluorescently-labeled T-cell acute lymphoblastic leukemia (T-ALL) cells are transplanted into genetically identical recipient fish and functionally assessed for differences in leukemia propagating cell frequency, growth, and dexamethasone resistance. While subclonal variation was observed within single cells from the same primary leukemia, a subset of clones continued to evolve genetic lesions and epigenetic modifications to enhance growth and overall LPC frequency. A majority of evolved clones acquired activated AKT signaling, which simultaneously increased the number of leukemia propagating cells through activating the mTORC1 pathway, enhanced growth by stabilizing Myc protein levels, and rendered T-ALL cells resistant to dexamethasone, which was reversed by combined treatment with an AKT inhibitor. These results were confirmed using large-scale transgenic epistasis experiments and limiting-dilution cell transplantation studies. In total, our data suggest that diagnosis clones can stochastically acquire mutations necessary to survive treatment and drive relapse even before a patient begins treatment, with acquired mutations being independently selected based on important cancer phenotypes including elevated growth rate and leukemia propagating potential. Moreover, our work also identifies combination therapies that utilize dexamethasone and AKT inhibitor can kill LPCs in a subset of refractory T-ALL. Finally, these are the first studies performed in any model to follow single cell evolution as it relates to relapse, utilizing in excess of 6,000 transplant recipient animals and opening new and exciting avenues of study to uncover genetic pathways that drive cancer malignancy.
This abstract is also presented as Poster A08.
Citation Format: Jessica Blackburn, Sali Liu, Kimberly Dobrinski, Sarah Martinez, Finola Moore, Riadh Lobbardi, David Langenau. Clonal evolution enhances leukemia propagating cell activity in T-cell acutelymphoblastic leukemia through AKT/mTORC1 pathway activation. [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 PR06.
Abstract PR10: From melanocyte to melanoma: Identifying key molecular events at the onset of cancer
Authors: Kaufman Charles K. , Mosimann Christian , White Richard , Matos Dominic , Zon Leonard I. 
Published: May 2015

Abstract
A fundamental challenge in cancer biology is understanding the earliest events that switch a premalignant or premetastatic cell into a fully competent cancer cell. Driven by this question, we focused on the zebrafish gene crestin that marks the embryonic neural crest from the onset of somitogenesis through 72 hpf when it normally turns off; surprisingly, our lab previously discovered that crestin mRNA is reexpressed in melanoma tumors in adult zebrafish. We have developed a fluorescent reporter gene using the crestin promoter that recapitulates the embryonic expression pattern of crestin, and when bred into our BRAFV600E/p53 mutant melanoma zebrafish model, marks grossly visible melanoma tumors. Remarkably, we found that crestin:EGFP becomes active when lesions are only a few cells in number, potentially in the first cell of the melanoma. We are able to isolate crestin (+) patches at the few to single cell level. Using a crestin:CreERt2 inducible recombinase together with a lox-dependent fluorescent lineage tracer line ubi:switch, multiple neural crest descendant lineages including melanocytes can be traced. Further by expressing the melanocyte lineage master transcription factor mitf under the control of the crestin promoter, we can rescue melanocyte formation in mitf null embryos, and in the Na/BRAFV600E/p53 melanoma-prone mutant background, some adult fish develop darkly pigmented patches and melanoma tumors. These data support a model in which BRAFV600E/p53 mutated melanocytes stochastically reactivate an early melanocyte or neural crest progenitor program as read out by crestin reactivation at the onset of melanoma formation. Using our novel reporter, we are able to analyze in vivo the earliest steps of cancer formation as well as the neural crest lineage program.
This abstract is also presented as Poster A47.
Citation Format: Charles K. Kaufman, Christian Mosimann, Richard White, Dominic Matos, Leonard I. Zon. From melanocyte to melanoma: Identifying key molecular events at the onset of 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 PR10.
Abstract A05: The control of nuclear ERK activity by the DUSP phosphatases in colorectal cancer
Authors: Cagnol Sebastien , Rivard Nathalie 
Published: May 2015

Abstract
The RAS/RAF/MEK/ERK pathway is suspected to be strongly implicated in malignant transformation of colorectal epithelial cells since KRAS and BRAF genes are mutated in up to 60% of human colorectal cancers (CRCs). Despite intensive efforts made in the understanding of KRAS and BRAF functions in colorectal carcinogenesis, little is known about the oncogenic regulation of ERK activity in CRC cells, especially by the ERK-specific nuclear DUSP phosphatases. We have recently demonstrated in CRC cells that ERK1/2 activity is confined to the cytoplasm because of a pervanadate-dependent phosphatase activity. Accordingly, DUSP4 mRNA was found to be highly expressed, in a MEK-dependent manner, in CRC cells. Thus, DUSP4 and other nuclear DUSPs may function as part of a negative feedback mechanism in the control of the duration and magnitude of nuclear ERK activation during colorectal carcinogenesis. We thus speculate that the modification of nuclear ERK activity might strongly impact on the oncogenic properties of CRC.
Methods: Expression of DUSPs was analyzed by PCR in CRC cells and qPCR in human colorectal tumors from different stages. To elucidate the role of nuclear DUSPs, RNA interference was used to specifically silence their expression in human HT29 CRC cell line, a cell line exhibiting BRafV600E mutation. Inducible expression of a DUSP4 inactivated mutant (DUSP4C284S) was done in a model of IEC-6 cells that express an inducible form of BRaf oncogene (BRafV600E:ER).
Results: 1- DUSP2, DUSP4 and DUSP5 mRNAs were found to be highly expressed, in a MEK-dependent manner, in CRC cells. 2- DUSP4 and DUSP5 mRNA levels were markedly increased in colorectal tumors in comparison to healthy matched adjacent tissues. 3- Silencing of DUSP 2, 4 or 5 in HT29 cells increased ERK phosphorylation levels and markedly reduced colony formation in soft agar. 4- Furthermore, expression of DUSP4C284S in BRafV600E-expressing IEC-6 cells increased ERK phosphorylation into the nucleus and markedly reduced colony formation in soft agar.
Conclusion: We are currently searching by which mechanisms sustained nuclear ERK activity reduces colorectal tumor cell growth. Therefore, targeting nuclear DUSP activity could become a new strategy to treat CRC.
Citation Format: Sebastien Cagnol, Nathalie Rivard. The control of nuclear ERK activity by the DUSP phosphatases in colorectal 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 A05. doi: 10.1158/1557-3125.RASONC14-A05
Abstract A15: Megakaryocyte differentiation is regulated by p21-activated kinase 2
Authors: Kosoff Rachelle E. , Chernoff Jonathan 
Published: May 2015

Abstract
Megakaryocytes (MKs) mature and differentiate into multi-nucleated cells in the bone marrow, and migrate from the osteoblastic niche to the vascular niche by means of an SDF-1a gradient, culminating in the release of platelets into circulation. Failure to do so results in myeloproliferative disorders, which can manifest with extremely reduced platelet counts. Regulation of this process is controlled by MAPK signaling, cytoskeletal and microtubule-associated proteins and GTPases. p21-activated kinase 2 (Pak2) regulates the cytoskeleton through the MAPK and RhoA signaling pathways, both required for MK differentiation and cytokinesis. In our study, we demonstrate that Pak2 is essential for proper MK differentiation and polyploidization, in vitro and in vivo. Pak2 deletion, upon cre induction specifically in hematopoietic tissues (Mx1-cre), reduces peripheral blood platelet counts (thrombocytopenia) by 50%. Bone marrow histology demonstrates hyperplastic MKs coinciding with reduced platelet counts. Analysis of bone marrow by flow cytometry demonstrates altered MK differentiation, observed by elevated MK stem cell precursors in the bone marrow (CD150+CD41+). Increased stem cell potential of MKs deficient for Pak2 results in increased colony forming units (CFU-Mks). Additionally, Pak2-null MKs have increased levels of polyploidization. Signaling to MLC2 and GEF-H1 are altered in Pak2-deficient MKs, both previously shown to regulate MK differentiation and polyploidization, respectively. In summary, Pak2 is a negative regulator of MK stem cell differentiation as well as polyploidization. Since Pak2 negatively regulates polyploidization, this leads to therapeutic uses for Pak family inhibitors in the treatment for acute megakaryoblastic leukemia, a fatal disorder which presents with an accumulation of immature MKs, due to a failure to differentiate into mature MKs.
Citation Format: Rachelle E. Kosoff, Jonathan Chernoff. Megakaryocyte differentiation is regulated by p21-activated kinase 2. [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 A15. doi: 10.1158/1557-3125.RASONC14-A15