bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 30: Intermittent treatment with the PARP inhibitor olaparib delays tumor development in BRCA1-deficient mice
Authors: Liby Karen T. , To Ciric 
Published: May 2015

Abstract
Women with inherited BRCA gene mutations are at extremely high risk for developing breast cancer. Although these high risk patients are ideal candidates for an effective chemoprevention regimen, “watchful waiting” or bilateral prophylactic mastectomy are the only currently available options. BRCA proteins are required for repairing double strand DNA breaks through homologous recombination. In BRCA-deficient cells, DNA is repaired by base excision repair, which requires a PARP protein. PARP inhibitors can selectively induce apoptosis in BRCA-deficient cells, without affecting normal cells, by blocking the only DNA repair pathway available to these cells. Various PARP inhibitors are being tested in the clinic in women with BRCA mutations, and if effective, these drugs might also be useful for chemoprevention. When fed continuously in diet, the PARP inhibitor olaparib (200 mg/kg diet) significantly delayed tumor development by 6.5 weeks in the aggressive Brca1Co/Co;MMTV-Cre;p53+/- mouse model. An intermittent schedule was then tested; olaparib was given for 2 week cycles in order to induce apoptosis in premalignant cells followed by 4 week rest periods in an attempt to reduce drug toxicity. Intermittent therapy with olaparib was nearly as effective as the continuous feeding protocol and increased the age of initial tumor onset to 35.6 ± 1.0 wks compared to 29.9 ± 1.1 wks in the control group (P &lt; 0.001; n = 18-19 mice/group). Olaparib also decreased proliferation and induced apoptosis in the mammary glands of mice without palpable tumors. In summary, these studies demonstrate that the PARP inhibitor olaparib is effective for delaying tumor development in BRCA1-deficient mice and suggest that intermittent therapy with this drug might be useful for chemoprevention in high risk women with BRCA mutations.
Supported by Susan G. Komen for the Cure and the Breast Cancer Research Foundation
Citation Format: Karen T. Liby, Ciric To. Intermittent treatment with the PARP inhibitor olaparib delays tumor development in BRCA1-deficient mice. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 30. doi:10.1158/1538-7445.CANSUSC14-30
Abstract 44: Leukemia-associated DNMT3A R882 mutations and their role in anthracycline-induced DNA damage response and therapeutic resistance
Authors: Guryanova Olga A. , Shank Kaitlyn , Luciani Luisa , Loizou Evangelia , Keller Matthew D. , Weinstein Abby R. , Abdel-Wahab Omar , Mukherjee Siddhartha , Nimer Stephen S. , Levine Ross L. 
Published: May 2015

Abstract
Despite significant advances in cancer research and treatment, therapeutic resistance remains a major obstacle for achieving stable remission in cancer patients. Acute myeloid leukemia (AML) is no exception, and most AML patients develop resistance to chemotherapy/targeted therapies, which results in disease relapse and progression. Recurrent mutations in the DNA methyltransferase 3A (DNMT3A) gene have been identified in 20-30% of AML cases and are predictive of unfavorable prognosis in patients treated with standard anti-leukemic regimens. In addition, DNMT3A-mutant AMLs appear to be relatively refractory to anthracycline family chemotherapeutics, such as daunorubicin. Half of all DNMT3A mutations affect amino acid residue R882, and recent work has shown that these mutants display decreased enzymatic activity and aberrant binding properties. In addition, previous studies have shown that wild-type DNMT3A functions as a pro-apoptotic switch in response to genotoxic stress induced by another anthracycline doxorubicin. We propose that mutant DNMT3A protects cells from apoptosis in response to DNA damage by altering molecular machinery involved in DNA-damage sensing, response and/or repair, through DNA methylation-dependent or independent mechanisms. Specifically, our data show that mutant DNMT3A affects recruitment of DNA repair proteins to chromatin, including aberrant distribution of homologous recombination marker RAD51. We are currently investigating molecular changes in DNA damage response in DNMT3A-mutant cells in vitro and ex vivo, and leukemogenic potential of the mutant Dnmt3a allele in vivo, whether alone or in combination with other cooperating oncogenes.
Citation Format: Olga A. Guryanova, Kaitlyn Shank, Luisa Luciani, Evangelia Loizou, Matthew D. Keller, Abby R. Weinstein, Omar Abdel-Wahab, Siddhartha Mukherjee, Stephen S. Nimer, Ross L. Levine. Leukemia-associated DNMT3A R882 mutations and their role in anthracycline-induced DNA damage response and therapeutic resistance. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr 44. doi:10.1158/1538-7445.CANSUSC14-44
Abstract IA01: Gene regulatory network approaches to interpreting breast cancer GWAS results
Authors: Ponder Bruce A. J. , Meyer Kerstin , Fletcher Michael , Markowetz Florian , Santiago Ines de , Castro Mauro 
Published: May 2015

Abstract
Six years after the publication of the first breast cancer GWAS, skepticism is expressed about the usefulness of the results. The GWAS loci identified to date explain only a minority of the estimated genetic variance, and the risks conferred by even the strongest individual variants are small. Classical biochemical pathway approaches to elucidating mechanism have had modest success.
I will argue that an attempt to examine the combined effects by common and rare variants and their interactions through analysis based on gene regulatory networks may yield new and useful information. Although still speculative, I will present initial data that provide support for this approach.
Citation Format: Bruce A. J. Ponder, Kerstin Meyer, Michael Fletcher, Florian Markowetz, Ines de Santiago, Mauro Castro. Gene regulatory network approaches to interpreting breast cancer GWAS results. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA01. doi:10.1158/1538-7445.CANSUSC14-IA01
Abstract IA05: Fanconi's anemia: Emerging therapeutic opportunities
Authors: Grompe Markus , Postlethwait John , D'Andrea Alan , Olson Susan , Zhang Qingshuo , Bagby Grover 
Published: May 2015

Abstract
Fanconi's anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure, birth defects and cancer susceptibility. At the cellular level, FA features hypersensitivity to DNA cross-linking agents, cell cycle abnormalities and abnormal responses to cytokines. Therapy for the hematopoietic defects of FA has consisted of supportive care, stem cell transplantation and administration of androgens such as oxymetholone. Unfortunately, even successfully transplanted FA patients have a very high risk for subsequent solid tumors, especially squamous cell carcinomas of oropharyngeal and urogenital areas.
The pharmacological treatment of FA has been unchanged for several decades and for this reason our group has embarked on systematic search for small molecule therapeutics that could benefit FA patients. This effort has been made possible by the cloning of 16 FA genes and biochemical insights into the function of FA proteins. Mouse models, zebra fish models and FA patient cell lines, including IPSC are available for screening and validation.
The specific goals of small molecule interventions are to delay or prevent hematopoietic failure and also to delay or prevent carcinogenesis.
To date we have shown that the superoxide dismutase mimetic drug Tempol can significantly delay tumor formation in FA mice. Similarly, resveratrol clearly improved hematopoiesis in the same model.
Medium throughput screens have revealed numerous new molecules which ameliorate the FA phenotypes of cells, mice and zebrafish respectively. Using genetic approaches we also have identified the p53 pathway as a therapeutic target in FA.
These therapeutic opportunities and progress in FA small molecule screening will be discussed.
Citation Format: Markus Grompe, John Postlethwait, Alan D'Andrea, Susan Olson, Qingshuo Zhang, Grover Bagby. Fanconi's anemia: Emerging therapeutic opportunities. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA05. doi:10.1158/1538-7445.CANSUSC14-IA05
Abstract IA08: PTEN and PI3K signaling in brain development and disease
Authors: Baker Suzanne J. 
Published: May 2015

Abstract
Virtually all adult glioblastomas contain somatic mutations resulting in elevated activity of the receptor tyrosine kinase (RTK)/Ras/PI3K signaling axis, including common loss of function mutations in PTEN, activating mutations in PIK3CA encoding p110α, the catalytic subunit of PI3Kα, or mutations in PIK3R1, encoding p85α, the regulatory subunit of PI3K. Despite an important role in sporadic glioblastoma, germline PTEN mutations do not confer an increased genetic susceptibility to brain tumors. However, inherited mutation of PTEN is associated with macrocephaly and neurological abnormalities including seizures, ataxia, autism and Lhermitte-Duclos disease. Mouse models further demonstrate that PTEN plays an essential role in development, homeostasis, and tumor suppression in the mammalian brain. Recently, germline or somatic mutations in multiple components of the PI3K signaling pathway were identified in human megalencephaly syndromes without apparent association with cancer predisposition, including mutations in PIK3CA, AKT3, PIK3R2, and MTOR. Mouse models that demonstrate the varying contributions of PI3K pathway members in brain development or tumorigenesis, and show context-dependent roles for PI3K signaling will be discussed.
Citation Format: Suzanne J. Baker. PTEN and PI3K signaling in brain development and disease. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA08. doi:10.1158/1538-7445.CANSUSC14-IA08
Abstract IA10: Li-Fraumeni syndrome: p53 and beyond
Authors: Wasserman Jonathan , Villani Anita , Samuel Nardin , Merino Diana , Novokmet Ana , Pienkowska Margaret , IdSaid Badr , Malkin David 
Published: May 2015

Abstract
Germline TP53 mutations are observed in ∼80% of patients with Li-Fraumeni syndrome (LFS) and a lesser frequency of patients meeting the revised Chompret criteria. A variety of studies are being conducted exploring the role of genetic modifiers on p53 function and their impact in refining the genotype:phenotype correlation of the TP53:LFS relationship. In this presentation, four classical pediatric-onset LFS tumors (choroid plexus carcinoma, medulloblastoma, adrenocortical carcinoma and rhabdomyosarcoma) will be used as examples to demonstrate the molecular nuances of this complex relationship. A spectrum of findings will be outlined that support the notion that presence of a germline TP53 mutation in the context of different modifying effects of intragenic TP53 polymorphism as well as variants in genes and proteins that play important roles in the p53 network confers certain biological features to the presentation of these tumors. Biological mechanisms will be discussed and strategies for early cancer detection will be presented.
Citation Format: Jonathan Wasserman, Anita Villani, Nardin Samuel, Diana Merino, Ana Novokmet, Margaret Pienkowska, Badr IdSaid, David Malkin. Li-Fraumeni syndrome: p53 and beyond. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA10. doi:10.1158/1538-7445.CANSUSC14-IA10
Abstract IA19: Dyskeratosis congenita and related syndromes
Authors: Dokal Inderjeet 
Published: May 2015

Abstract
Dyskeratosis Congenita (DC) is a heterogeneous multi-system syndrome exhibiting marked clinical and genetic heterogeneity. In its classical form it is characterized by mucocutaneous abnormalities (abnormal skin pigmentation, nail dystrophy, leucoplakia), bone marrow failure and a high predisposition to malignancy (hematological and non-hematological). Bone marrow failure is the principal cause of mortality and patients display features of premature aging (including early dental loss, premature greying and osteoporosis).
Studies over the last 15 years have led to significant advances with ten DC genes (DKC1, TERC, TERT, NOP10, NHP2, TINF2, USB1, TCAB1, CTC1 and RTEL1) having been characterized. Nine of these are important in telomere maintenance. DC is therefore principally a disease of defective telomere maintenance and patients usually have very short/ and or abnormal telomeres.
The genetic advances have also led to the unification of DC with a number of other disorders. This includes the severe multi-system disorders Hoyeraal-Hreidarsson and Revesz syndromes as well as a subset of patients with aplastic anemia, myelodysplasia, leukemia, liver disease and idiopathic pulmonary fibrosis. This wide spectrum of diseases ranging from classical DC to aplastic anemia can be regarded as disorders of defective telomere maintenance - “the telomereopathies”.
These advances have increased our understanding of several human diseases (including genetic predisposition to subtypes of cancer) and highlighted the importance of telomere maintenance in human biology. They are also facilitating diagnosis (especially when presentation is atypical) and management. Correct early diagnosis is important as bone marrow failure associated with this group of disorders is unlikely to respond to immunosuppressive agents and is more likely to respond to anabolic steroids such as oxymetholone. For patients who are unresponsive to anabolic steroids allogeneic hematopoietic stem cell transplantation using fludarabine based low intensity protocols is producing encouraging results.
Citation Format: Inderjeet Dokal. Dyskeratosis congenita and related syndromes. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA19. doi:10.1158/1538-7445.CANSUSC14-IA19
Abstract IA23: The BRCA1 tumor suppressor network
Authors: Greenberg Roger A. 
Published: May 2015

Abstract
BRCA1 is an essential component of multiple distinct protein complexes that are dedicated to DNA damage recognition and repair. Germline heterozygous mutations to genes encoding multiple BRCA associated proteins result in cancer susceptibility, while biallelic mutations lead to developmental abnormalities, cancer predisposition, and systemic hypersensitivity to chemotherapy. BRCA1 associates with the RAP80 complex to recognize lysine63-linked ubiquitin chains at DNA damage sites. Three members of the RAP80 complex are mutated in hereditary breast cancer, implicating ubiquitin recognition as a bona fide component of BRCA1 dependent tumor suppression. This presentation will describe in vivo interactions between BRCA1 associated DNA damage site ubiquitin recognition and other protein complexes that are dedicated to homologous recombination mediated DNA repair to S-phase. Relevance to cancer etiology and response to therapy will be discussed.
Citation Format: Roger A. Greenberg. The BRCA1 tumor suppressor network. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA23. doi:10.1158/1538-7445.CANSUSC14-IA23
Abstract A03: Effectiveness of melatonin on the epithelial mesenchymal transition after induction with transforming growth factor beta (TGF-β)
Authors: Gonçalves Naiane do Nascimento , Ferreira Lívia Carvalho , Lopes Juliana Ramos , Maschio Larissa Bazela , Moschetta Marina Gobbe , Gelaleti Gabriela Bottaro , Martins Gustavo Rodrigues , Zuccari Debora Aparecida Pires de Campos 
Published: May 2015

Abstract
Background: The mammary tumors are the most frequent in women in Brazil and worldwide. The high mortality rate in breast cancer is mainly due to invasiveness and metastatic. The metastatic process involves a mechanism called epithelial-mesenchymal transition (EMT). The EMT mechanism can be induced by growth factors such as transforming growth factor beta (TGF-β), which alters the epithelial phenotype (E-cadherin) to a mesenchymal phenotype (n-caderina/vimentina). Studies have shown significant importance of the epithelial mesenchymal transition in breast cancer, which makes the study of new therapeutic agents that act in the process, very important. Melatonin, a hormone naturally secreted by the pineal gland, has shown oncostatic properties. For these reasons, the aim of this study was to evaluate the anti-metastatic potential of melatonin by the epithelial mesenchymal transition induced by TGF-β in breast cancer cell line. Methods: The breast cancer cell line MCF-7 was cultured at 37 ° C and 5% CO2 in DMEM High Glucose culture medium. Once established, the best concentration of TGF-β (0.5 ng / mL) to induce epithelial mesenchymal transition the cells were divided into four groups (Group I - Control, Group II - TGF-β, Group III - Melatonin and Group IV - TGF- β + Melatonin) to evaluate the protein expression of E-cadherin, N-cadherin and vimentin by immunocytochemistry. Quantitation of immunoreactivity was performed by densitometry (ImageJ software). The results were compared by ANOVA followed by Bonferroni. Results: The results showed that there were statistically significant increased protein e-cadherin in cells treated with melatonin (P &lt; 0.05) when compared to cells treated with TGF-β. Furthermore, immunostaining of proteins N-cadherin and vimentin was lower in cells treated with TGF-B + melatonin (P &lt; 0.05) compared to cells treated only with TGF-β. Conclusion: Melatonin interfered in the expression of proteins related to epithelial mesenchymal transition after induction with TGF-B which may suggested a possible anti-metastatic role of this hormone.
Citation Format: Naiane do Nascimento Gonçalves, Lívia Carvalho Ferreira, Juliana Ramos Lopes, Larissa Bazela Maschio, Marina Gobbe Moschetta, Gabriela Bottaro Gelaleti, Gustavo Rodrigues Martins, Debora Aparecida Pires de Campos Zuccari. Effectiveness of melatonin on the epithelial mesenchymal transition after induction with transforming growth factor beta (TGF-β). [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A03. doi:10.1158/1538-7445.CHTME14-A03
Abstract A04: Endothelial FAK activity controls vascular permeability and tumor metastasis
Authors: Jean Christine , Chen Xiao Lei , Tancioni Isabelle , Uryu Sean , Lawson Christine , Miller Nichol , Turowski Patric , Dejana Elisabetta , Weis Sara , Cheresh David , Schlaepfer David D. 
Published: May 2015

Abstract
Tumor spread remains a primary cause of cancer mortality. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase co-activated by integrin and growth factor receptors in the control of vascular permeability. As FAK inhibitors are being tested in clinical trials, it is important to determine whether FAK signaling plays distinct roles in tumor versus stromal cell biology. Herein, we elucidate a new mechanism for endothelial cell (EC) FAK activity in the regulation of blood vessel barrier integrity and the passage of tumor cells through an EC barrier. We show that vascular endothelial cadherin (VEC) tyrosine (Y) 658 is phosphorylated by FAK in tumor-associated ECs. Conditional kinase-dead FAK knockin within ECs inhibited recombinant vascular endothelial growth factor (VEGF-A) and tumor-induced VEC Y658 phosphorylation in vivo. Adherence of VEGF-expressing tumor cells to ECs triggered FAK-dependent VEC Y658 phosphorylation. Both FAK inhibition and VEC Y658F mutation within ECs prevented VEGF-initiated paracellular permeability and tumor cell transmigration across EC barriers. In mice, EC FAK inhibition prevented VEGF-dependent tumor cell extravasation and melanoma dermal to lung metastasis without affecting primary tumor growth. Although it is known that Src tyrosine kinase activity is important in controlling VEC tyrosine phosphorylation downstream of VEGF, we find that pharmacological Src inhibition prevents FAK activation. Moreover, FAK inhibition prevents both Src and FAK translocation to EC adherens junctions, but does not alter Src activation. Together, these results identify EC FAK as a key intermediate between Src and the regulation of EC barrier function controlling tumor metastasis.
Citation Format: Christine Jean, Xiao Lei Chen, Isabelle Tancioni, Sean Uryu, Christine Lawson, Nichol Miller, Patric Turowski, Elisabetta Dejana, Sara Weis, David Cheresh, David D. Schlaepfer. Endothelial FAK activity controls vascular permeability and tumor metastasis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A04. doi:10.1158/1538-7445.CHTME14-A04
Abstract A23: ALK activity in macrophages drives metastasis in murine models of breast cancer
Authors: Lynn Kristi D. , Brekken Rolf A. 
Published: May 2015

Abstract
VEGF-induced angiogenesis and macrophages contribute directly to metastasis, the leading cause of breast cancer related mortality. VEGF is a major driver of angiogenesis, yet its targeted inhibition is often ineffective at controlling metastases. In contrast, pathways that contribute to a pro-metastatic macrophage phenotype are unclear and pharmacological strategies to inhibit pro-metastatic activity are lacking. In this study, we illustrate that anti-VEGF therapy modulates PTN expression in multiple mouse models of breast cancer. Once expressed, PTN induces the expression of VEGFR2 on macrophages and promotes an anti-inflammatory, pro-metastatic macrophage phenotype. This phenomenon is dependent on ALK signaling, as inhibition with the small molecule receptor tyrosine kinase inhibitor crizotinib (Xalkori, Pfizer), which targets ALK, or ALK siRNA is sufficient to reverse PTN-induced VEGFR2 and anti-inflammatory macrophage marker expression. Importantly, phosphorylated ALK and VEGFR2 positive macrophages were detected in tumor but not normal breast tissue from patients. Furthermore, inhibition of ALK signaling in macrophages blunted metastasis but had no effect on primary MMTV-PyMT tumors; while blockade of VEGF slowed primary tumor growth without effect on metastatic burden. Combined inhibition of ALK and VEGF activity showed potent anti-tumor and anti-metastatic activity in animals with disseminated disease. Collectively, our data document novel markers of pro-metastatic macrophages and reveal how macrophage phenotype can be manipulated to suppress breast cancer progression.
Citation Format: Kristi D. Lynn, Rolf A. Brekken. ALK activity in macrophages drives metastasis in murine models of breast cancer. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr A23. doi:10.1158/1538-7445.CHTME14-A23