bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2400: Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for targeted sequencing in a prospective randomized trial for personalized treatment in all tumor type: The SHIVA study
Authors: Pierga Jean-Yves , Decraene Charles , Bernard Virginie , Kamal Maud , Blin Anthony , Leroy Quentin , Rio Frio Thomas , Pierron Gaëlle , Callens Céline , Bieche Ivan , Saliou Adrien , Madic Jordan , Rouleau Etienne , Bidard François-Clément , Lantz Olivier , Stern Marc-Henri , Lebofsky Ronald , Le Tourneau Christophe 
Published: August 2015

Abstract
Rationale: The noninvasive biomarker circulating cell-free tumor DNA (ctDNA) has the potential to enable noninvasive diagnostic tests for personalized medicine in providing similar molecular information as that derived from invasive tumor biopsies. The ongoing large multicentric randomized histology-independent phase II trial (SHIVA, NCT01771458) compares molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with any type of refractory cancer. The screening phase consists of the invasive biopsy of metastatic tumor tissue and downstream analysis using Ion Torrent's Ampliseq hotspot cancer panel. We evaluated whether ctDNA analysis would identify the same mutations as those obtained through invasive biopsy.
Patients and methods: de novo detection of somatic mutations using ctDNA in 34 patients covering 18 different tumor types, scanning ∼50 genes and more than 2500 mutations with a multiplexed next generation sequencing panel.
Results: In 27 patients, 27 of 28 actionable mutations identified in metastasis biopsies (96%) were detected in matched ctDNA. Among these 27 patients, two additional mutations were found in ctDNA only. In the seven other patients, mutation detection from metastasis biopsy failed due to inadequate biopsy material, but was successful in all plasma DNA samples providing three more potential actionable mutations. Conclusion; These results suggest that ctDNA analysis is a cheaper, safer and quicker alternative to invasive biopsy of metastasis, irrespective of cancer type and metastatic site, for multiplexed mutation detection in selecting personalized therapies based on the patient's tumor genetic content.
Citation Format: Jean-Yves Pierga, Charles Decraene, Virginie Bernard, Maud Kamal, Anthony Blin, Quentin Leroy, Thomas Rio Frio, Gaëlle Pierron, Céline Callens, Ivan Bieche, Adrien Saliou, Jordan Madic, Etienne Rouleau, François-Clément Bidard, Olivier Lantz, Marc-Henri Stern, Ronald Lebofsky, Christophe Le Tourneau. Circulating tumor DNA as a non-invasive substitute to metastasis biopsy for targeted sequencing in a prospective randomized trial for personalized treatment in all tumor type: The SHIVA study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2400. doi:10.1158/1538-7445.AM2015-2400
Abstract 2408: A novel multiplex droplet digital PCR approach to KRAS mutation detection in circulating tumor DNA
Authors: Pender Alexandra , Garcia-Murillas Isaac , Rana Sareena , de Castro David Gonzalez , Turner Nicholas , Popat Sanjay , Downward Julian 
Published: August 2015

Abstract
Microdroplet digital PCR can be used to detect low frequency mutations in oncogene-driven lung cancer. Detection of circulating tumour DNA in plasma can be limited by paucity of material, particularly during response to anti-cancer therapy. The range of KRAS point mutations observed in NSCLC necessitates a multiplex approach for efficient mutation detection in circulating DNA.
We designed and optimised 3 droplet digital PCR multiplex assays investigating 9 different KRAS mutations using PrimePCR™ ddPCR™ Mutation Assays and the Bio-Rad QX100 system. DNA was extracted from FFPE tissue and plasma from patients with advanced lung adenocarcinoma and was analysed to assess for the presence of these KRAS activating mutations.
Multiple sub-clonal KRAS mutant populations were detectable in both tissue and circulating tumour DNA at low frequency (up to 0.1%). Similar KRAS allele frequency was observed using multiplex or duplex assays (r2 = 0.99). Sub-clonal population representation varied over the disease course.
Multiplex microdroplet digital PCR assays can be adapted to be used to efficiently identify tissue and circulating KRAS mutations in advanced lung adenocarcinoma. Variation in sub-clonal populations between tissue and plasma, and at different time points over the disease course, illustrates the potential use of circulating DNA analysis as a more readily accessible, non-invasive and accurate representation of the molecular profile of NSCLC throughout treatment.
Citation Format: Alexandra Pender, Isaac Garcia-Murillas, Sareena Rana, David Gonzalez de Castro, Nicholas Turner, Sanjay Popat, Julian Downward. A novel multiplex droplet digital PCR approach to KRAS mutation detection in circulating tumor DNA. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2408. doi:10.1158/1538-7445.AM2015-2408
Abstract 2415: Development of a clinical cell-free DNA assay for cancer molecular profiling
Authors: Clark Travis , Kennedy Mark , Young Geneva , Young Lauren , He Jie , Yelensky Roman , Ali Siraj , Otto Geoff , Lipson Doron , Miller Vince , Stephens Phil 
Published: August 2015

Abstract
Background:
Profiling cell-free circulating tumor DNA (ctDNA) for the genomic alterations which drive oncogenesis in patients with cancer promises to provide information important for understanding cancer biology, informing therapy selection when conventional biopsies are unobtainable and monitoring response to therapy. Facile collection of ctDNA samples could enable recurrent molecular profiling of an individual patient's disease with lower cost, discomfort and risk as compared to conventional biopsies. To assess the clinical validity of profiling cancer genomics in ctDNA, a highly accurate targeted NGS-based assay was developed and ctDNA results were compared to patient-matched FFPE tumor biopsies characterized by comprehensive genomic profiling using the FoundationOne assay from over 150 patients with lung, breast and other cancer types.
Methods:
To ensure robust performance, the ctDNA assay was developed as part of an integrated workflow including primary sample collection, storage and transport, and ctDNA purification, followed by optimized construction of adaptor-ligated sequencing libraries and enrichment by solution hybridization and then sequencing to high depth (Illumina HiSeq). Computational methodologies were developed to enable sensitive and specific detection of base substitutions, indels, genomic rearrangements and high-level amplificagtions from ctDNA. Accuracy and reproducibility was assessed using cell-line mixtures designed to simulate the limited DNA inputs and low tumor purity expected in routine clinical samples.
Results:
The ctDNA assay enabled accurate detection of most genomic alterations in cell-line mixtures. Short variants (base substitutions and indels) and genomic rearrangements in ALK and RET were detected with high sensitivity and specificity at &lt;1% tumor. Comparative results from patient-matched ctDNA isolated from plasma and FFPE biopsies across more than 150 lung, breast and other cancer samples will be presented.
Conclusions:
Accurate profiling of ctDNA can enable detection of biologically and clinically relevant genomic alterations in clinical plasma samples. These results demonstrate the potential utility of ctDNA molecular profiling for the management of patients with cancer, but prior to integration into routine practice, extensive rigorous tumor-type specific studies of patient-matched ctDNA and solid biopsy specimens are required.
Citation Format: Travis Clark, Mark Kennedy, Geneva Young, Lauren Young, Jie He, Roman Yelensky, Siraj Ali, Geoff Otto, Doron Lipson, Vince Miller, Phil Stephens. Development of a clinical cell-free DNA assay for cancer molecular profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2415. doi:10.1158/1538-7445.AM2015-2415
Abstract 2419: Predicting clinical response based on ex vivo drug response in renal cell carcinoma using kinase activity profiling
Authors: Ruijtenbeek Rob , Houkes-van Kerkhoff Liesbeth , Hilhorst Maria , Mulders Peter , Oosterwijk-Wakka Jeannette , Kiemeney Lambertus , Oosterwijk Egbert 
Published: August 2015

Abstract
Introduction: Sunitinib, a potent multitargeted receptor tyrosine kinase inhibitor, is the first line treatment for metastatic renal cell carcinoma (mRCC). Because sunitinib responses and toxicity are highly variable, there is a need for biomarkers predicting sunitinib response or predicting the optimal sequence preference when using alternative tyrosine kinase inhibitors. The aim of this study was to investigate the correlation between ex vivo drug response and clinical response in renal cell carcinoma (RCC) and to explore alternative treatment options. This study has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement no 259939.
Methods: Protein tyrosine kinase activity profiles were generated on PamChip® peptide microarrays of lysed tumor resection tissues (1-5mm3) from 22 mRCC patients. The ex vivo effect of kinase inhibitors (sunitinib, axitinib, sorafenib, pazopanib, erlotinib and crenolanib) was determined and analyzed with Bionavigator software. A two-group (sunitinib responders versus non-responders) comparison applied on the inhibition ratios identified the significantly different peptide phosphorylations. Peptides were clustered according to their correlation with clinical response.
Results: As little as 5 μg protein input (0.05 mm3 tissue) was used per kinase activity profile. The ex vivo sunitinib effect positively correlated with clinical responses especially in the subgroup which received sunitinib as 1st line treatment (4 responders vs. 4 non-responders). 18 of the 105 peptides were significantly (p&lt;0.05) less phosphorylated upon ex vivo sunitinib treatment in 4 responders compared to 4 non-responders. Pathway analysis of the peptide phosphorylation patterns revealed sunitinib target involvement. Ex vivo erlotinib, axitinib or crenolanib showed reversed inhibition patterns i.e. more inhibition in the non-responder than in the responder group.
In summary, we have shown that predicting clinical response to sunitinib based on the ex vivo response to sunitinib is feasible. This requires further investigation with a larger sample set. Furthermore, the ex vivo response to a drug panel suggests that identification of novel treatment options for non-responders might be feasible.
Citation Format: Rob Ruijtenbeek, Liesbeth Houkes-van Kerkhoff, Maria Hilhorst, Peter Mulders, Jeannette Oosterwijk-Wakka, Lambertus Kiemeney, Egbert Oosterwijk. Predicting clinical response based on ex vivo drug response in renal cell carcinoma using kinase activity profiling. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2015-2419
Abstract 2432: A technology platform for personalized medicine in melanoma
Authors: Girotti Maria R. , Rothwell Dominic , Viros Amaya , Mandal Amit Kumar , Lim Kok Haw J. , Gremel Gabriela , Furney Simon , Pedersen Malin , Rogan Jane , Swan Jacqueline , Fusi Alberto , Brady Ged , Lorigan Paul , Dive Caroline , Marais Richard 
Published: August 2015

Abstract
We developed patient derived xenografts (PDX), performed whole exome sequencing (WES) and analyzed circulating tumor DNA (ctDNA) to complement clinical management of four melanoma patients. Synchronous treatment of patients and mice showed that PDX responses mirrored those of the patients’ tumor to BRAF inhibitors. PDXs were used to test second-line treatments in relapsed patients and to validate WES-based therapies in tumors that did not have a BRAF mutation. Longitudinal analysis of ctDNA was predictive of responses to targeted and immunotherapies, and to determine mechanisms of resistance. Thus, we describe a powerful combination of techniques for personalized medicine in melanoma and discuss the challenges and limitations of implementing these novel technologies in patient management.
Citation Format: Maria R. Girotti, Dominic Rothwell, Amaya Viros, Amit Kumar Mandal, Kok Haw J. Lim, Gabriela Gremel, Simon Furney, Malin Pedersen, Jane Rogan, Jacqueline Swan, Alberto Fusi, Ged Brady, Paul Lorigan, Caroline Dive, Richard Marais. A technology platform for personalized medicine in melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2432. doi:10.1158/1538-7445.AM2015-2432
Abstract 2437: Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates
Authors: Boriack-Sjodin Ann , Jin Lei , Jacques Suzanne L. , Drew Allison , Porter Scott Margaret , Ribich Scott , Moradei Oscar 
Published: August 2015

Abstract
Co-activator-associated arginine methyltransferase 1 (CARM1) is a protein arginine N-methyltransferase (PRMT) enzyme that has been implicated in a variety of cancers including AML (1) and breast (2), prostate (3), lung (4) and colorectal (5) carcinomas. CARM1 is known to methylate H3 histones and non-histone substrates including p300/CBP, AIB1/SRC-3 and PABP1 (6). To date, several crystal structures of CARM1 have been solved, including structures with small molecule inhibitors (7), but no ternary structures with nucleotide and peptide substrate have been reported. Here, the crystal structures of human CARM1 with the SAM mimic sinefungin (SFG) and three different peptide sequences from histone H3 and PAPB1 are presented, and both non-methylated and singly-methylated arginine residues are exemplified. Extensive interactions are seen with residues Glu266, Glu257, and His414 and the substrate arginine side chain. Two key hydrogen bonds are made by the side chain of Asn161 with the backbone carbonyl of the P’1 peptide residue and the backbone NH of the P’3 peptide residue. The carbonyl of the P1 peptide residue engages the protein through water mediated hydrogen bonds. These structures show how the CARM1 binding site is capable of accommodating a variety of peptide sequences. Comparisons to known CARM1 complexes with small molecules provide additional insights into inhibitor design.
1. Vu, L. P. et al, PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Rep 2013, 5 (6), 1625-38.
2. Al-Dhaheri, M. et al, CARM1 is an important determinant of ERalpha-dependent breast cancer cell differentiation and proliferation in breast cancer cells. Cancer Res 2011, 71 (6), 2118-28.
3. Kim, Y. R. et al, Differential CARM1 expression in prostate and colorectal cancers. BMC Cancer 2010, 10, 197.
4. Elakoum, R. et al, CARM1 and PRMT1 are dysregulated in lung cancer without hierarchical features. Biochimie 2014, 97, 210-8.
5. Ou, C. Y. et al, A coactivator role of CARM1 in the dysregulation of beta-catenin activity in colorectal cancer cell growth and gene expression. Mol Cancer Res 2011, 9 (5), 660-70.
6. Bedford M.T.; Clarke S.G. Protein arginine methylation in mammals: who, what, and why. Mol Cell 2009, 33, 1-13.
7. Sack, J.S et al, Structural basis for CARM1 inhibition by indole and pyrazole inhibitors. Biochem J 2011, 436, 331-9.
Citation Format: Ann Boriack-Sjodin, Lei Jin, Suzanne L. Jacques, Allison Drew, Margaret Porter Scott, Scott Ribich, Oscar Moradei. Crystal structures of CARM1 bound to sinefungin and diverse peptide substrates. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2437. doi:10.1158/1538-7445.AM2015-2437
Abstract 2443: Optides (optimized peptides), a new knottin-based cancer drug discovery platform
Authors: Olson James M. , Strong Roland , Mehlin Christopher , Correnti Colin 
Published: August 2015

Abstract
Some of the highest value targets in cancer therapeutics involve protein:protein interactions that are difficult to inhibit with small molecule therapeutics. Peptide drug candidates offer an alternative, but many peptide drugs have poor pharmacokinetic properties and some are immunogenic. Knottin peptides have long been promoted as scaffolds for human drug discovery efforts because the exquisitely tight knot formed by disulfide bridges creates resistance to proteolytic and other forms of degradation. Furthermore, some knottins cross the blood brain barrier, the gut wall, or cell membranes which is ideal for certain targets. Unfortunately, creating knottins synthetically or in bacteria results in a large number of disulfide isomers, which has hampered research. We have created a mammalian expression system that enables production of most knottin scaffolds and variants of native knottins encoded in plant and animal genomes. The platform routinely produces approximately 10 mg/liter of near pure naked peptide, which is sufficient to conduct in vivo studies without major scale-up. The system is endotoxin free. In addition to building the platform, we identified over 200,000 new potential knottin peptides in various genomes, creating a rich collection of scaffolds from which to establish diversity libraries of native and optimized variants. These candidates have potential for targeting therapeutics to cancer cells as a solid tumor penetrating alternative to antibody drug conjugates. Optides also have potential to be developed as anti-cancer drugs themselves. The fact that knottin peptides are not substrates for resistance mechanisms such as p-glycoprotein pumps underscores the potential importance of this class of drugs for those with previously treated cancer.
Citation Format: James M. Olson, Roland Strong, Christopher Mehlin, Colin Correnti. Optides (optimized peptides), a new knottin-based cancer drug discovery platform. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2443. doi:10.1158/1538-7445.AM2015-2443
Abstract 2447: Development of Hsp90 paralog specific inhibitors with mitochondrial drug delivery system
Authors: Kang Byoung Heon 
Published: August 2015

Abstract
The mitochondrial pool of Hsp90 and its mitochondrial paralog, TRAP1, suppresses cell death and reprograms energy metabolism in cancer cells; therefore, Hsp90 and TRAP1 have been suggested as target proteins for anticancer drug development. Here, we report that the actual target protein in cancer cell mitochondria is TRAP1, not Hsp90, and current Hsp90 inhibitors cannot effectively inactivate TRAP1 due to insufficient accumulation in the mitochondria. To develop mitochondrial TRAP1 inhibitors, we determined the crystal structures of human TRAP1 complexed with Hsp90 inhibitors. The isopropyl amine of the Hsp90 inhibitor PU-H71 was replaced with the mitochondria-targeting moiety triphenylphosphonium to produce SMTIN-P01. SMTIN-P01 showed a different mode of action from the non-targeted PU-H71, as well as much improved cytotoxicity to cancer cells. In addition, we determined the structure of a TRAP1-adenylyl-imidodiphosphate (AMP-PNP) complex. Based on comparative analysis of TRAP1 structures, we propose a molecular mechanism of ATP hydrolysis that is crucial for chaperone function.
Citation Format: Byoung Heon Kang. Development of Hsp90 paralog specific inhibitors with mitochondrial drug delivery system. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2447. doi:10.1158/1538-7445.AM2015-2447
Abstract 2451: The nuclear-targeted gold nanoparticles inhibit the tumor growth in mouse model as potential anticancer agents
Authors: Peng Xianghong , Macke Megan A. , Shin Hyung Ju C , Nannapaneni Sreenivas , Chen Nelson , Kim Sungjin , Chen Zhuo (Georgia) , El-Sayed Mostafa A , Shin Dong 
Published: August 2015

Abstract
The use of gold nanoparticles (AuNPs) as chemotherapeutic agents, based on their intrinsic antineoplastic properties is becoming an increasingly exciting possibility for the treatment of cancer. The specific targeting of AuNPs to the nucleus of malignant cells can be achieved via peptide functionalization of the nanoparticle surface, resulting in DNA damage and subsequent apoptosis. Here, we utilized these novel AuNPs for systemic delivery in vivo and determined their efficacy as chemotherapeutic agents. In addition, we assessed their effects on overall health in order to characterize their systemic toxicity. AuNPs (30 nm in diameter) were functionalized with an Arg-Gly-Asp (RGD) peptide sequence, providing tumor cell specific targeting, as well as a Lys-Lys-Lys-Arg-Lys nuclear localization sequence (NLS) peptide. These novel nuclear-targeting AuNPs were delivered via tail vein injection in nude mice bearing Tu212 tumors. Their in vivo therapeutic efficacy was evaluated, along with assessing their systemic toxicity. The AuNPs, specifically targeted to the tumor cell nucleus, exhibit circulation half-life of 4.1 h, which is exceptionally greater than common chemotherapeutic agents and, although they exhibit uptake by organs of the reticuloendothelial system (RES) (e.g. liver and spleen), they also accumulate in the tumor. In addition, when systemically delivered at low doses (5 nM AuNPs) these novel targeted AuNPs show significant tumor regression (via DNA damage and subsequent apoptosis) when compared to their non-targeting counterparts (P = 0.004), with no observed toxicity in terms of hepatic function, renal function, or body weight. In conclusion, by delivering AuNPs to the nucleus of tumor cells, at low doses in vivo, high therapeutic efficacy is achieved with minimal side effects, indicating the potential for the use of these novel nuclear-targeted AuNPs as chemotherapeutic agents.
Citation Format: Xianghong Peng, Megan A. Macke, Hyung Ju C Shin, Sreenivas Nannapaneni, Nelson Chen, Sungjin Kim, Zhuo (Georgia) Chen, Mostafa A El-Sayed, Dong Shin. The nuclear-targeted gold nanoparticles inhibit the tumor growth in mouse model as potential anticancer agents. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2451. doi:10.1158/1538-7445.AM2015-2451