bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B177: Synthetic lethal approach identifies potent and selective TTK and CLK inhibitor with preclinical anticancer activity in triple-negative breast cancer model
Authors: Zhu Dan , Deyanat-Yazdi Gordafaried , Mikolon David , Narla Rama K. , Peng Sophie X. , Ning Yuhong , Riggs Jennifer R. , Boylan John F. 
Published: August 2018

Abstract
Historically, synthetic lethal-based drug discovery has yielded a high percentage of novel, first-in-class drugs while uncovering new tumor biology. Using a synthetic lethal approach, we identified one compound that preferentially induced apoptosis in triple-negative breast cancer (TNBC) cell lines while sparing luminal breast cancer cell lines. The synthetic lethal approach evolved into a targeted approach following the identification of the two kinases that were selectively inhibited by CC-671 in enzyme assays: human protein kinase monopolar spindle 1 (hMps1), also known as TTK, and CDC2-like kinase (CLK2). Detailed CC-671 cellular mechanism of action studies showed phosphorylation inhibition of the direct substrates of TTK and CLK2. The CC-671 IC50 concentration that inhibited phosphorylation of the CLK2 substrate SR protein ranged between 530 and 553 nM in CAL51 cells. Gene Set Enrichment Analyses (GSEA) of RNAseq data suggest that CC-671 CLK2 inhibition induces apoptosis by reducing expression of antiapoptotic isoforms via splicing modification. Cellular CC-671 TTK inhibition was demonstrated by significant reduction of TTK autophosphorylation at T686 and phosphorylation of KNL1, one of the well-characterized TTK substrates. CC-671 treatment also led to a decrease of cyclin B and securin protein level. As a result, the percentage of mitotic cells in nocodazole-arrested CAL51 cells was substantially reduced by CC-671. Furthermore, data from time-lapse video microscopy experiments confirmed the mitotic phase length was reduced by approximately half upon CC-671 treatment. Inhibition of phospho-Histone H3 (Ser 10) following a single CC-671 administration was observed in TNBC in vivo tumor model. More importantly, significant CC-671 in vivo efficacy was demonstrated in a cell line-derived TNBC xenograft model with weekly dosing. The data described here suggest that dual inhibition of TTK and CLK2 represents an attractive therapeutic approach for triple-negative breast cancer. CC-671 presents a unique profile for an anticancer kinase inhibitor.
Citation Format: Dan Zhu, Gordafaried Deyanat-Yazdi, David Mikolon, Rama K. Narla, Sophie X. Peng, Yuhong Ning, Jennifer R. Riggs, John F. Boylan. Synthetic lethal approach identifies potent and selective TTK and CLK inhibitor with preclinical anticancer activity in triple-negative breast cancer model [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 B177.
Abstract B181: The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including low-dose gemcitabine, in preclinical models of cancer
Authors: Hansen Ryan J. , Strouse Bryan , Anderes Kenna , Smith Gregg , Hassig Christian 
Published: August 2018

Abstract
Depending on genetic and other factors, tumor cells exhibit replication stress (RS) to various extents. Low levels of RS contribute to genomic instability, an enabling hallmark of cancer, whereas high levels may be cytotoxic. The DNA damage response (DDR) checkpoint kinase 1, Chk1, is essential for managing RS by stabilizing replication forks, abrogating origin firing, pausing the cell cycle, and fostering homologous recombination DNA repair. Consequently, tumor cells become highly reliant on Chk1 to manage RS and maintain proliferation and survival. Certain chemotherapeutic drugs, including nucleoside analogs, DNA cross-linkers, and topoisomerase inhibitors, are effective extrinsic inducers of RS. Here we demonstrate that the potent, selective oral Chk1 inhibitor, SRA737, strongly synergizes with a range of extrinsic inducers of RS to kill tumor cells in vitro and in vivo. We find that clinically used drugs including the DNA crosslinking agents mitomycin C and cisplatin, as well as the nucleoside analog gemcitabine, exacerbate cellular RS markers (e.g. γ-H2A.X and p-RPA) and synergize with SRA737 to increase tumor cell death in vitro. Combination indices (CI) at various doses across a cell line panel were 0.46, 0.54, and 0.25 for mitomycin C, cisplatin, and gemcitabine, respectively. Similar results were observed with both type I and type II topoisomerase inhibitors (SN-38 and etoposide). Notably, gemcitabine potentiates SRA737 in several bladder cancer cell lines including 5637, TCCSUP, and J82 cells, as well as in human primary bladder cancer patient 3D organoids. Consistent with the observed cytotoxicity, the combination of SRA737 and gemcitabine induces γ-H2A.X and p-RPA 3- to 5-fold over gemcitabine alone in tumor xenografts. Moreover, the combination inhibits tumor growth by 64% following administration of both agents at 100 mg/kg in a gemcitabine-insensitive patient-derived xenograft (PDX) model of bladder cancer. Importantly, SRA737 also synergizes with subtherapeutic doses of gemcitabine (40 mg/kg) in xenograft models of colorectal adenocarcinoma and osteosarcoma, indications where gemcitabine is not standard of care. These findings support the clinical development of SRA737 in combination with gemcitabine in bladder cancer, as well as the broader application of SRA737 in combination with extrinsic inducers of RS.
Citation Format: Ryan J. Hansen, Bryan Strouse, Kenna Anderes, Gregg Smith, Christian Hassig. The Chk1 inhibitor, SRA737, demonstrates chemical synthetic lethality with replication stress-inducing agents, including low-dose gemcitabine, in preclinical models of 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 B181.
Abstract B189: New class of TOP1 inhibitors selective for HR deficiencies and SLFN11 expression
Authors: Marzi Laetitia , Pommier Yves G. 
Published: August 2018

Abstract
To relax DNA supercoiling, topoisomerase I (TOP1) induces DNA cleavage complexes (TOP1cc). These TOP1cc can be trapped by camptothecin, leading to replication-induced DNA double-strand breaks (DSB). Widely used, camptothecin derivatives are plagued by limitations. It is now possible to overcome these limitations with the non-camptothecin indenoisoquinolines currently in clinical trials (the LMPs: LMP400, LMP776, and LMP744). Homologous recombination (HR) and its key components BRCA1, BRCA2, and PALB2 are needed to repair DSB induced by TOP1 inhibitors. It has been shown that BRCA1 is a determinant of response to camptothecins in addition to olaparib. Also, Schlafen11 (SLFN11) expression has been demonstrated to be a highly penetrant determinant of response to camptothecin derivatives. To rationally select patients for phase 2 clinical trials based on cancer-specific genomic alterations, we have determined whether HR components deficiency or SLFN11 expression are determinants of LMPs response. Using isogenic cell lines, we assessed the survival and cell cycle modifications after treatment with the LMPs. We found that SLFN11-negative cells are 10 times hypersensitive to LMPs compared to WT cells. Also, BRCA1-, BRCA2-, and PALB2-deficient cells are 3 to 5 times hypersensitive to the LMPs. Adding olaparib led to a greater cell death, especially in HR-deficient cells. Our results show that the indenoisoquinolines are active at nanomolar concentrations and that HR deficiency and SLFN11 expression are strong drug response determinants. They also demonstrate that the LMPs synergize with olaparib. These findings provide a rationale for personalized treatment and further clinical trials with the indenoisoquinolines in HR-deficient cancers.
Citation Format: Laetitia Marzi, Yves G. Pommier. New class of TOP1 inhibitors selective for HR deficiencies and SLFN11 expression [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 B189.
Abstract B191: Synergistic anticancer activity of eribulin plus palbociclib in patient-derived xenograft (PDX) models of ER+/Her2- human breast cancer
Authors: Nomoto Kenichi , de Boisferon Marc H. , Littlefield Bruce A. 
Published: August 2018

Abstract
Eribulin is a synthetic analog of the marine sponge natural product halichondrin B. Its clinical formulation is currently approved in numerous countries for treating certain patients with advanced breast cancer or advanced liposarcoma. Eribulin’s anticancer mechanisms include relatively fast antimitotic effects that lead to cell death by apoptosis, and slower complex effects on the tumor microenvironment that include increased vascular perfusion, reduced hypoxia, and changes in phenotype associated with decreased migration and invasiveness in vitro. Such changes in tumor phenotype led us to ask whether eribulin could be successfully combined with inhibitors of cyclin dependent kinases 4 and 6 (cdk 4/6), which work at the G1/S cell cycle checkpoint where phenotypic changes are typically regulated. It is now recognized that patient-derived xenograft (PDX) tumor models more faithfully recapitulate human tumor biology and drug responsiveness than standard xenograft models derived from established human cancer cell lines. Accordingly, in the current study, we used two ER+/PR+/Her2- PDX models developed from patients with luminal B breast cancers, OD-BRE-0192 and OD-BRE-0745, to test in vivo combinations of eribulin and the cdk 4/6 inhibitor palbociclib. Eribulin and palbociclib dose levels were chosen that led to only minimal effects when given alone, and were administered on Q7Dx3 and Q1Dx5[x3] schedules, respectively, with palbociclib withheld the day before and the day of weekly eribulin dosing to avoid cell cycle-based antagonism that could occur between mitotic and G1/S blockers. In the OD-BRE-0745 model only, a fourth cycle of eribulin followed by 5 days of palbociclib was administered starting 13 days after the third eribulin dose. Under these conditions, combining eribulin and palbociclib led to markedly superior anticancer activity in both models (minimum T/C values of 29% and 41%) compared to either agent alone (T/C: 55-67% and 88-98%, respectively). These preclinical PDX results support clinical exploration of eribulin and palbociclib combinations for appropriate patients with ER+/Her2- breast cancers.
Citation Format: Kenichi Nomoto, Marc H. de Boisferon, Bruce A. Littlefield. Synergistic anticancer activity of eribulin plus palbociclib in patient-derived xenograft (PDX) models of ER+/Her2- human breast 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 B191.
Abstract CN01-02: Chromosomal instability as a driver of tumor metastasis
Authors: Bakhoum Samuel F. 
Published: August 2018

Abstract
Chromosomal instability (CIN) is a hallmark of cancer, and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of rupture-prone micronuclei that expose their DNA content to the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. Using single-cell RNA sequencing, we uncover a CIN-induced transcriptional switch from a proliferative and metabolically active state to a mesenchymal phenotype associated with inflammatory pathways, offering an opportunity to target chromosome segregation errors for therapeutic benefit.
Citation Format: Samuel F. Bakhoum. Chromosomal instability as a driver of tumor metastasis [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 CN01-02.
Abstract LB-A09: Predicting PARPi sensitivity in patient derived ex vivo 3D tumor cultures
Authors: Basten Sander , Herpers Bram , Yan Kuan , Vader Willemijn , Price Leo 
Published: August 2018

Abstract
Ex vivo culture of patient derived tumor material has broad applications including functional testing to support treatment decisions, as well as testing drugs in development. Because average therapeutic response rates are low, there is a need for clinical tools to predict treatment response. Such tools may also reduce overtreatment and provide alternatives when treatment options are exhausted. Here we present data for 3D tumor cultures focusing on standard chemotherapy in combinations with targeted therapy, namely PARPi.
By embedding and optimizing growth for small amounts of heterogeneous tumor material in extracellular matrix protein hydrogels, we have generated 3D tumor cultures from various cancer indications. Initiated from both fresh and cryopreserved material, tumor cultures are seeded into 384 well plates and exposed to standard-of-care therapies, targeted therapies and drug combinations. An automated high content screening platform measures cell and tissue morphology, and reports responses such as tumor cell killing, growth arrest and local invasion. Depending on the tumor type and drug mechanism of action, morphological features are selected as standard read-outs for the response.
We will present results of proof-of-concept experiments that aim to compare drug sensitivity of tumor cultures with treatment responses in the clinic. Tumor material of gastric, endometrial, cervical, and ovarian cancer patients was used to generate 3D cultures, which were subsequently tested for drug sensitivity. Patient-dependent responses are identified for treatment schedules including platinum-based drugs, taxanes, anthracyclines and 5-FU. In addition, responses to drugs that are not (yet) considered standard of care (PARP inhibitors) were measured.
In conclusion, our technology can determine drug sensitivities of 3D cultured tumor tissues. This allows patient-specific treatment responses to standard-of-care drugs to be determined. In addition, this material can be used to test experimental drugs currently in development and in clinical studies. Ongoing proof-of-concept trials will reveal the correlation of our in vitro test with treatment responses in the clinic.
Keywords; in vitro diagnostic; organoids; tumor cultures; drug sensitivity testing.
Citation Format: Sander Basten, Bram Herpers, Kuan Yan, Willemijn Vader, Leo Price. Predicting PARPi sensitivity in patient derived ex vivo 3D tumor cultures [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 LB-A09.
Abstract LB-A17: Identification and Characterization of Cyclic Peptide Inhibitors for Ras/PI3K and Ras/Raf Protein Complexes
Authors: Ismail Mohamed S. , Downward Julian 
Published: August 2018

Abstract
Ras oncogenic mutations are present in almost 25% of human cancers - indicative of their involvement in important signalling pathways that regulate many cellular functions such as: cell growth, proliferation, differentiation and survival. PI3K and Raf Kinases control two of the main effector signalling pathways that are activated by Ras proteins. There have been long efforts in discovering drugs for Ras mutants however these drugs either lacked strong binding affinity or specificity to Ras mutants. Here, in collaboration with Ali Tavassoli’s lab at Southampton University, we apply a new approach for discovering inhibitors that can block the Ras/Raf and Ras/PI3K interactions. The technique gives a great advantage of the possibility to discover inhibitors against Ras, Raf or PI3K proteins at the same time, rather than following the traditional route of screening drugs against Ras in isolation. In addition, because the effector-binding site of Ras is negatively charged and both of the binding sites of Raf and PI3K with Ras are positively charged - this opens up the opportunity for both negatively and positively charged inhibitors to compete with both interactions. The technique we are applying combines two methodologies: The “split-intein cyclisation of peptides and proteins” (SICLOPPS), for producing random cyclic peptides in vivo; and a bacterial reverse two-hybrid system (RTHS), can be used for high throughput screening (HTS). SICLOPPS has the capacity to produce millions of random cyclic peptides, which significantly increases the chances of finding suitable inhibitors, to interrupt protein complexes. Alongside this the RTHS provides a time efficient and effective technique to screen such a high number of peptides. We have developed a robotic HTS process that allows the screening of thousands of peptides per day. Initial characterisation of positive peptides that disrupt the interaction of the Ras/p110 α complex is currently in progress.
Citation Format: Mohamed S. Ismail, Julian Downward. Identification and Characterization of Cyclic Peptide Inhibitors for Ras/PI3K and Ras/Raf Protein Complexes [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 LB-A17.
Abstract LB-A19: Targeting ERBB2 pathway in ovarian cancer
Authors: Kovtun Irina V. , Piyan Zhang , Harris Faye R. , Hou Xiaonan , Weroha Saravut J. , Vasmatzis George 
Published: August 2018

Abstract
Ovarian cancer (OC) is most lethal gynecologic malignancy. About 75% of OC patients relapse and/or develop chemo-resistant disease after initial response to standard-of-care treatment with platinum-based therapies. HER2 amplifications and overexpression in OC are reported to vary and responses to HER2 inhibitors have been feeble.
Next generation sequencing technologies in conjunction with testing using patient-derived xenografts (PDX) allow validation of personalized treatments. Using whole-genome mate-pair next generation sequencing protocol we profiled a set of serous OC to identify copy number changes and gene fusions. Specific focus was on DNA alterations which were therapeutically targetable. The efficiency of anti-Her2 therapy was tested in three different PDX lines with alterations at genes of ERBB pathway and various levels of HER2 protein expression. Tumor in one line harbored a duplication of ERBB2 and high expression of HER2 protein. Second PDX model had a fusion at NRG1 gene, a ligand for HER4 and HER4 receptors, that was highly expressed on protein level. Third line harbored an amplification of NRG3 gene, a known ligand for HER4 receptor. Treatment responses to pertzumab/trastuzumab were compared in each PDX line to standard carboplatin and paclitaxel combination treatment. In all three PDX models HER2-targeted therapy resulted in significant inhibition of tumor growth compared to untreated control. However, the responses in each were inferior to chemotherapy, even in chemo-resistant case. There was an extra benefit when chemotherapy and HER-2 targeted therapy were administered together, as a significant regression of tumor was observed after 6 weeks of treatment using this regiment compared to chemotherapy alone. Post-treatment analysis of the tissues, nevertheless, revealed inhibition of ERBB2 pathway on the level of phosphorylation and expression of downstream targets. In conclusion, targeting of presumably activated ERBB2 pathway alone in OC results in a modest treatment benefit. A combination therapy including both chemo drugs and Her2 inhibitors provides far better response. Further studies are needed to address development of recurrence and sensitivity of recurrent disease to Her2 targeted therapy.
Citation Format: Irina V. Kovtun, Zhang Piyan, Faye R. Harris, Xiaonan Hou, Saravut J. Weroha, George Vasmatzis. Targeting ERBB2 pathway in ovarian 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 LB-A19.
Abstract PL05-01: Personal regulome navigation
Authors: Chang Howard Y. 
Published: August 2018

Abstract
In every human cell, two meters of DNA are packed into a ~10-micron nucleus. The genome is extensively compacted, except for the active regulatory DNA elements that remain accessible. We have developed an Assay of Transpose Accessible Chromatin by sequencing (ATAC-seq) as a facile and sensitive method to map the landscape of gene regulation. The landscape of accessible chromatin from primary cells and tissues is uniquely informative for cell types, cell states, and the molecular basis of genetic variants associated with human diseases. Single-cell chromatin accessibility reveals DNA elements and trans-acting factors that mediate cell-to-cell variation, which directly impacts cancer heterogeneity. Real-time monitoring of gene regulation landscape in patients can provide prognostic prediction for response to cancer therapy. New technologies that incorporate 3-dimensional chromosome conformation, in situ imaging, and single-cell multi-omics provide new levels of precision and insights into human diseases.
Citation Format: Howard Y. Chang. Personal regulome navigation [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 PL05-01.