bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B184: TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R
Authors: Cui J. Jean , Zhai Dayong , Deng Wei , Rogers Evan , Huang Zhongdong , Whitten Jeffrey , lim John , Li Yishan 
Published: August 2018

Abstract
The tropomyosin receptor kinases (TRKs), including TRKA/B/C encoded by NTRK1/2/3 genes, are high-affinity receptors for neurotrophins. Oncogenic rearrangement of NTRK1, NTRK2, and NTRK3 have been identified in many solid malignancies. The use of TRK inhibitors entrectinib and larotrectinib has led to clinical benefit in patients with solid malignancies harboring oncogenic NTRK fusions. Similar to ALK and ROS1 inhibitor treatment, the solvent front mutations TRKA G595R and TRKC G623R (both analog to ALK G1202R) were reported in clinic from treatment-resistant patients. A new generation of TRK inhibitors targeting both wild type and mutated TRKs is highly needed for effectively treating patients harboring fusion TRKs. TPX-0005, a novel three-dimensional macrocycle with a much smaller size than current TRK inhibitors in the clinic, was designed to overcome clinical resistance mutations systematically. TPX-0005 potently inhibited both wild type and mutant TRKs including solvent front mutations. TPX-0005 showed pico-molar activity against TRK kinases (IC50s 0.83 nM, 0.05 nM, and 0.10 nM for TRKA/B/C, respectively) in Reaction Biology kinase assay. TPX-0005 is the most potent TRK inhibitor in clinic and effectively overcomes clinical resistance TRK mutations as shown in the table in cell proliferation assays. It was recently reported that LOXO-195 inhibited the phosphorylation of TRKA and ERK kinases in NIH3T3 cell line expressing ΔTRKA G595R or ETV6-TRKC G623R with IC50s of 7 nM and 45.5 nM, respectively. TPX-0005 is more than 10-fold more potent than LOXO-195. In the xenograft tumor model studies including human PDX model, TPX-0005 dramatically caused tumor regression in the tumors carrying WT or solvent-front mutated TRK fusion gene. Overall, TPX-0005 demonstrated desired drug-like properties, good safety profile, and is a supreme TRK inhibitor against WT and mutated TRKs. A phase 1/2 clinical trial of TPX-0005 is actively being pursued (NCT03093116). KM-12 IC50 (nM)Ba/F3 Cell Proliferation Assay IC50 (nM)InhibitorTPM3-TRKAWTLMNA-TRKA WTLMNA-TRKA G595RETV6-TRKB WTETV6-TRKB G639RETV6-TRKC WTETV6-TRKC G623RTPX-0005&lt;0.2&lt;0.20.4&lt;0.20.6&lt;0.23Entrectinib9.20.3705&lt;0.513840.61000Larotrectinib12.33.5102410.9300010.21500
Citation Format: J. Jean Cui, Dayong Zhai, Wei Deng, Evan Rogers, Zhongdong Huang, Jeffrey Whitten, John lim, Yishan Li. TPX-0005, a highly potent TRK inhibitor, effectively overcomes clinical-resistance TRK mutations including solvent front mutants TRKA G595R, TRKB G639R, and TRKC G623R [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B184.
Abstract B193: Characterization of selective active-site targeted covalent inhibitors of usp7
Authors: Wang Feng , Wu Jian , Wang Liqing , Sokirniy Ivan , Wang Hui , Chen Lee , Cunnion Brigid , Sterner David , Grove Charles , Bregnard Thomas , Weinstock Joseph , Mattern Michael , Bezsonova Irina , Hancock Wayne W. , Kumar Suresh 
Published: August 2018

Abstract
The ubiquitin-specific protease 7 (USP7) has emerged as an attractive oncology/immune-oncology target owing to its critical roles in several cancer-related signaling pathways as well as its essential role in maintaining functions of Foxp3+ T-regulatory cells (Tregs), the key players in tumor immune evasion. Progenra has developed a series of compounds that inhibit purified USP7 selectively and attenuate USP7 activity in cells and in vivo; these inhibitors exert antitumor activity directly and also facilitate immune-mediated antitumor activity by suppressing Treg functions. However, the precise mechanism of action of these compounds remains unclear. In this study, using a combination of NMR spectroscopy, mass spectrometry, and single amino-acid substitution approaches, we have now demonstrated that our USP7 inhibitors specifically target the catalytic pocket of USP7 and modify its active site cysteine (Cys223) by forming a covalent adduct. Consistent with the covalent binding mechanism, pharmacokinetic studies revealed long-lasting, irreversible USP7 inhibition after a short pulse treatment with inhibitor, accompanied by changes in the level and ubiquitylation of various pharmacodynamic markers, including the Treg lineage-specific transcription factor Foxp3. Detailed knowledge of the mechanism of USP7 inhibition will permit the rational design of improved inhibitors as a new class of anticancer agent.
Citation Format: Feng Wang, Jian Wu, Liqing Wang, Ivan Sokirniy, Hui Wang, Lee Chen, Brigid Cunnion, David Sterner, Charles Grove, Thomas Bregnard, Joseph Weinstock, Michael Mattern, Irina Bezsonova, Wayne W. Hancock, Suresh Kumar. Characterization of selective active-site targeted covalent inhibitors of usp7 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B193.
Abstract B198: Targeting CSK kinase activity to enhance antitumor immunity
Authors: Wang Cindy , Cao Carolyn , Berman-Booty Lisa , Swanson Jesse , Eraslan Rukiye , Sanjuan Miguel , Vite Gregory , Qin Lan-Ying , Hunt John , Fink Brian , Wee Susan 
Published: August 2018

Abstract
To mount an effective immune response, a T-cell receptor (TCR) must first recognize a cognate antigen presented by malignant cells. Successful effector T-cell activation initiates an intracellular signaling cascade that results in the release of cytotoxins and proinflammatory cytokines that ultimately result in the elimination of antigen-presenting diseased cells. A key regulator of this signaling cascade is the C-terminal Src (CSK) kinase. In lymphocytes CSK inhibits T-cell activation by phosphorylating the SRC kinase family member LCK at tyrosine 505 and thereby terminates the signaling cascade. To assess whether relieving an intracellular blockade of TCR signaling will lead to a more robust T-cell response, and hence improved tumor immunity, we developed both genetic and pharmacologic approaches to inhibit CSK activity. A tamoxifen-inducible transgenic CSK knockout mouse was engineered to bypass the embryonic lethality observed with constitutive systemic CSK depletion. As expected, loss of CSK enhanced cytokine production and increased antitumor immune response in the MC38 syngeneic tumor mouse model. Potent and selective CSK small-molecule inhibitors, in the presence of TCR stimulation, similarly activated the proximal TCR signaling pathway and increased cytokine production and proliferation. In an in vivo efficacy study, however, the CSK inhibitor as monotherapy or in combination with aPD1 did not improve antitumor immune response at the dose levels tested. This seemingly discrepant finding in tumor response observed in the tamoxifen-inducible KO mice and mice treated with the CSK inhibitor may reflect the need for a more optimized dosing regimen and target coverage. In this poster, we will present our findings on the role of CSK inhibition in tumor immunity.
Citation Format: Cindy Wang, Carolyn Cao, Lisa Berman-Booty, Jesse Swanson, Rukiye Eraslan, Miguel Sanjuan, Gregory Vite, Lan-Ying Qin, John Hunt, Brian Fink, Susan Wee. Targeting CSK kinase activity to enhance antitumor immunity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B198.
Abstract B204: Integrin β1 plays a crucial role in vasculogenic mimicry formation
Authors: Kawahara Ryota , Niwa Yuki , Simizu Siro 
Published: August 2018

Abstract
Tumor metastasis is caused by multiple processes, such as epithelial-mesenchymal transition, lymph node metastasis, and angiogenesis. In recent years, vasculogenic mimicry (VM) is focused on the association with tumor malignancy. VM is a unique phenomenon, a blood vessel-like network structure formed only by cancer cells without vascular endothelial cells, and is observed in extracellular matrix (ECM) rich region. Although previous studies suggested that VM plays a crucial role in tumor metastasis, a detailed mechanism of VM formation has not been fully understood. Latest studies indicate that cell surface proteins such as integrins and cadherins contribute to VM formation. In this study, we focused on transmembrane cell surface receptor, integrin β1. Integrin β1 is an important factor for interactions between cell-cell and cell-ECM, and mediates several cell signalings. Therefore, we investigated the importance of integrin β1 in VM formation. We assessed VM formation capability as network structure formed by cancer cells on matrigel. Since previous studies revealed that Ca2+ regulates integrin activities, we treated with EGTA and CaCl2 to assess whether Ca2+ is necessary for VM formation. We performed integrin β1 gene knockout (KO) by using CRISPR/Cas9 system in human fibrosarcoma HT1080 cells, and assessed VM formation capability of the KO cells. In addition, we established integrin β1-rescued HT1080 cells by reintroduction of Cas9-resistant integrin β1-expressing vector to integrin β1-KO HT1080 cells to confirm the importance of integrin β1 in VM formation. Furthermore, we also established integrin β1-KO human breast cancer MDA-MB-231 cells to verify that integrin β1 is necessary for VM formation in other human cancer cell lines. As a result, chelation of Ca2+ by treatment with EGTA inhibited network formation in HT1080 cells, and cotreatment with CaCl2 rescued this effect, suggesting that integrins might be important for VM formation. In integrin β1-KO HT1080 cells, which is confirmed the completely knockout of integrin β1 by Western blot, network formation was abrogated. Additionally, integrin β1-rescued HT1080 cells exhibited network formation as well as parental HT1080 cells. These results suggested that integrin β1 is a critical factor in VM formation. Furthermore, integrin β1-KO MDA-MB-231 cells also did not form network structure, suggesting that integrin β1 plays a crucial role in VM formation in general human cancer cell lines. Taken together, our study provides new knowledge of the association between VM and integrin β1, and inhibition of integrin β1 may be a novel therapeutic approach for metastatic cancer.
Citation Format: Ryota Kawahara, Yuki Niwa, Siro Simizu. Integrin β1 plays a crucial role in vasculogenic mimicry formation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B204.
Abstract B210: BET inhibitors show superior ability to suppress the progression of tumors containing the Pro47Ser single-nucleotide polymorphism of p53
Authors: Barnoud Thibaut , Basu Subhasree , Kung Che-Pei , Reiss Matthew , Zhang Rugang , Murphy Maureen 
Published: August 2018

Abstract
The tumor suppressor TP53 is the most frequently mutated gene in human cancer and serves to restrict both tumor initiation and progression. Single-nucleotide polymorphisms (SNPs) in the p53 pathway can have a marked impact on p53 tumor suppressor function, and several have been associated with increased cancer risk. We have reported that a naturally occurring SNP affects codon 47 of TP53 (rs1800371, G/A). In most individuals, codon 47 encodes a proline (P47). However, approximately 2.5% of African-Americans express a p53 allele with a serine residue (S47) at this position. In order to compare the ability of the WT and S47 variants of p53 to suppress tumor development, we isolated mouse embryonic fibroblasts (MEFs) from WT and S47 mice and transformed them with the oncogenes E1A and Ras, in order to generate a facile model that would allow us to study responses to therapy. WT and S47 cells grew similarly in 10% serum. However, transformed S47 cells grew significantly better under nutrient-deprived conditions. S47 transformed cells also grew with increased dynamics in a xenograft mouse model and in a tail vein model of metastasis. These data support the premise that the S47 variant of p53 is significantly impaired as a tumor suppressor. We found that, for the majority of conventional genotoxic drugs, S47 tumor cells are resistant, compared to tumor cells with WT p53. In order to identify novel compounds that preferentially target S47 tumor cells, we performed a drug screen on WT and S47 transformed MEFs, using a library of over 200 conventional and experimental chemotherapeutic drugs. We found that S47 cells are far more sensitive to the class of bromodomain inhibitors, specifically BET inhibitors. Using short-term (96 hrs, Alamar Blue) cell viability assays, we found that S47 transformed cells were approximately 5-fold more sensitive to OTX-015, a BET inhibitor currently in clinical trials. We also found that S47 cells were significantly impaired in their ability to form colonies when pretreated for 24 hours with OTX-015. These data highlight the relevance of targeted therapy for patients harboring the S47 variant of p53, and suggest that BET inhibitors may preferentially target S47 tumors.
Citation Format: Thibaut Barnoud, Subhasree Basu, Che-Pei Kung, Matthew Reiss, Rugang Zhang, Maureen Murphy. BET inhibitors show superior ability to suppress the progression of tumors containing the Pro47Ser single-nucleotide polymorphism of p53 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B210.
Abstract CN05-01: DNA damage signatures and practical use
Authors: Nik-Zainal Serena 
Published: August 2018

Abstract
A cancer genome is a historical account of the mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation matters. While driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically informative (1-5). We previously outlined the methods for identifying and quantifying base substitution mutational signatures present in primary human cancers (1-5). Recently, the intellectual framework of mutational signatures was extended to include six novel rearrangement signatures (6). Exploring this in &gt;2,500 whole genome-sequenced tumors of multiple tumor types reveals how our early (and rather simplistic) thinking of mutational signatures requires critical reevaluation. There are more nuances than previously appreciated. Diving into the detail of individual mutational signatures (7), we reveal intriguing mechanistic insights into the DNA damage and repair processes that mark the landscape of cancer genomes. In some instances, our findings invite more thoughtful consideration of that relatively binary distinction between drivers and passengers. Furthermore, we demonstrate why our whole-genome profiling methods could assist in taking things to a clinical level (6-8), with mutational signatures forming an additional weapon in the arsenal of cancer diagnostics and therapeutic stratification, in the modern war against cancer.References: 1. Nik-Zainal S et al. Mutational processes molding the genomes of 21 breast cancers. Cell 2012;149:979-93 .2. Nik-Zainal S et al. The life history of 21 breast cancers. Cell 2012;149: 994-1007. 3. Helleday T, Eshtad S, Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers. Nat Rev Genet 2014;15:585-98. 4. Alexandrov LB et al. Signatures of mutational processes in human cancer. Nature 2013;500:415-21. 5. Alexandrov LB, Nik-Zainal S, Wedge DC, Campbell PJ, Stratton MR. Deciphering signatures of mutational processes operative in human cancer. Cell Rep 2013;3:246-59. 6. Nik-Zainal S et al. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 2016;534:47-54. 7. Glodzik D et al. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers. Nat Genet 2017;49:341-48. 8. Davies H et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017;23:517-25.
Citation Format: Serena Nik-Zainal. DNA damage signatures and practical use [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN05-01.
Abstract CN05-02: Novel mechanisms of PARP inhibitor resistance
Authors: D'Andrea Alan D. 
Published: August 2018

Abstract
Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi anemia genes including FANCN/PALB2, FANCO/RAD51, FANCJ/BRIP, and FANCA. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to platinum analogues, topoisomerase inhibitors, and PARP inhibitors (PARPi). The synthetic lethal interaction with PARPi is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer where multiple PARPi have been FDA approved. PARP inhibitor resistance has already emerged as a vexing clinical problem for the treatment of BRCA1/2-deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HRR proficiency via disruption of multiple proteins, such as PTIP or CHD4, that leads to replication fork (RF) stabilization. Importantly, this latter mechanism–namely, the restoration of RF stability–appears to be a highly prevalent mechanism of PARPi resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARPi resistance by limiting the nucleolytic degradation of their stalled replication forks. We have recently made the surprising observation that BRCA2-deficient tumors can become resistant to PARPi by downregulating the expression of the polycomb repressive complex PRC2, a methyltransferase complex containing EZH2, SUZ12, EED, and RbAp48. Importantly, downregulation of PRC2 results in the reduced recruitment of the nuclease MUS81 to the RF, thereby providing a novel mechanism of RF protection and PARPi resistance. A molecular understanding of PARPi resistance mechanisms may allow the generation of a new class of drugs or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARPi to more tumor types.
Citation Format: Alan D. D'Andrea. Novel mechanisms of PARP inhibitor resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN05-02.
Abstract CN07-02: Epigenetics: A gatekeeper to DNA amplification
Authors: Whetstine Johnathan R. 
Published: August 2018

Abstract
DNA copy gains and amplifications are often associated with tumorigenesis, poor prognosis, and drug resistance. However, little is known about how these regions of the genome are selected for amplification. Our group discovered that modulation of epigenetic factors and their associated chromatin states controls DNA copy gains of drug-resistant regions. In fact, transient site-specific copy number gains occur in both normal and cancer cells upon manipulation of a histone H3 lysine 9/36 (H3K9/36) tri-demethylase KDM4A. However, the mechanism by which KDM4A is targeted to specific genomic regions and whether additional chromatin regulators are involved in this process were unknown. To begin addressing these questions, we performed a series of unbiased genetic screens against all the histone lysine-modifying enzymes and followed their ability to generate copy gains of regions using DNA fluorescence in situ hybridization. Our screen uncovered insights about how KDM4A targeting influences DNA amplification in the human genome. We also demonstrated that specific epigenetic factors are working as a network to modulate DNA amplification of drug-resistant regions of the genome. Furthermore, we uncovered KDM4A-independent DNA amplifications, which established that additional regions are undergoing epigenetic control for amplification. These data will be discussed at the meeting.
Citation Format: Johnathan R. Whetstine. Epigenetics: A gatekeeper to DNA amplification [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN07-02.
Abstract KN02: Keynote Lecture: T-cell recognition of human cancer
Authors: Schumacher Ton 
Published: August 2018

Abstract
Many human tumors contain large numbers of mutations, of which many hundreds can be present within expressed genes. As the resulting altered protein sequences are foreign to the immune system, immune recognition of such "neoantigens" has been proposed as a major factor in the activity of clinically used immunotherapeutics such as anti-CTLA-4 and anti-PD-1.
In support of this hypothesis, work by others and us over the past years has demonstrated that CD4 and CD8 T-cell recognition of the consequences of DNA damage is a common feature in, e.g., human melanoma, and can also be boosted by immunotherapy.
These data establish "tumor foreignness," as determined by neoantigen formation, as one of the determinants of effective cancer immunotherapies. However, it is evident that the outcome of cancer-immune interaction is also critically dependent on a number of other factors. With the ultimate aim to describe a "cancer immunogram" that depicts the state of cancer-immune interactions for individual patients, we are developing and exploiting genetic screens and (functional) assays of human tumor material. A detailed understanding of the specific bottleneck(s) in immune-mediated tumor control in individual patients should be of value for both patient selection and for the development of novel clinical interventions.
Citation Format: Ton Schumacher. Keynote Lecture: T-cell recognition of human cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr KN02.