bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1194: MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer
Authors: Apfel Athena M. , Merrill Nathan M. , Vandecan Nathalie M. , Bao Liwei , Cheng Xu , Lopez-Barcons Lluis A. , Day Kathleen C. , Palmbos Phillip L. , Day Mark L. , Udager Aaron M. , Soellner Matthew B. , Merajver Sofia D. 
Published: July 2021

Abstract
There are diverse resources available for data relevant to the drug screening of bladder cancer cell lines in 2D culture, such as the Cancer Cell Line Encyclopedia (CCLE) and Genomics of Drug Sensitivity in Cancer (GDSC) databases; however, 3D culture is more representative of in vivo response in patients. Moreover, drug screens in 3D reveal differential drug response and expression of genes and proteins that indicate the potential of more effective selection of drugs for specific patients: the basic tenet of personalized oncology. Therefore, we screened bladder cancer cell lines in 3D culture using a library of curated small-molecule inhibitors to identify compounds and classes of compounds with efficacy in bladder cancer. Genomic and transcriptomic data for these bladder cancer cell lines were used to correlate genomic molecular parameters with drug response with the aim of discerning biomarkers of response or to suggest plausible drug combinations. This allowed us to identify groups of tumors that are vulnerable to specific drugs or classes of drugs. We found that MEK inhibitors were a promising target among basal bladder cancers, an RNA-based molecular subtype of bladder cancer, especially aggressive and exhibiting poor prognosis. Furthermore, trametinib was found to be a “very active” MEK inhibitor in basal cancers, classified using drug sensitivity 3 (DSS3) scoring. PI3K/AKT/MTOR inhibitors target a parallel signaling pathway to MEK inhibition; therefore, we tested PI3K/AKT/MTOR combinations with trametinib in basal bladder cancer to query for synergistic properties. Additionally, we tested PI3K/AKT/MTOR combinations with trametinib using ex vivo organoids of bladder cancer patient samples collected directly at operation. Taken together, MEK inhibition is a promising therapeutic strategy in the basal subtype of bladder cancer, particularly in combination with parallel pathway inhibition. Moving forward, we plan to test PI3K/AKT/MTOR combinations with trametinib in trametinib-resistant basal bladder cancer cell lines to investigate how this affects signaling and re-sensitization to trametinib.
Citation Format: Athena M. Apfel, Nathan M. Merrill, Nathalie M. Vandecan, Liwei Bao, Xu Cheng, Lluis A. Lopez-Barcons, Kathleen C. Day, Phillip L. Palmbos, Mark L. Day, Aaron M. Udager, Matthew B. Soellner, Sofia D. Merajver. MEK inhibition in combination with PI3K/AKT/MTOR is a promising therapeutic in basal bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1194.
Abstract 1196: BALF liquid biopsy provides a novel platform for speedy and accurate EGFR mutation testing in advanced NSCLC patients
Authors: Kim In Ae , Hur Jae Young , Kim Hee Joung , Kim Wan Seop , Lee Kye Young 
Published: July 2021

Abstract
Background
EGFR mutation testing is an essential step for the therapeutic decision in newly diagnosed advanced NSCLC patients and usually performed by using DNA extracted from biopsied tumor tissue with a turnaround time(TAT) of 2-3 weeks. Plasma liquid biopsy using ctDNA is minimally invasive and less time-consuming, but shows limited usefulness due to low sensitivity. We conducted a prospective study to demonstrate clinical usefulness of bronchoalveolar lavage fluid (BALF) liquid biopsy using extracellular vesicle(EV)-derived DNA in advanced NSCLC patients by comparing the sensitivity and TAT with conventional tissue biopsy and plasma liquid biopsy
Methods
The analysis set for liquid EGFR genotyping is 224 BALF samples and 110 plasma samples obtained from newly diagnosed 224 advanced non-squamous NSCLC patients. EGFR genotyping was done through peptide nucleic acid(PNA)-mediated real-time PCR after extracting BALF EV DNA and plasma cfDNA separately. The sensitivity, specificity, and concordance rate of BALF liquid biopsy were calculated in comparison to matched tissue genotyping and plasma liquid biopsy. In addition, TAT was compared between BALF liquid biopsy and tissue genotyping.
Results
Tissue genotyping revealed 93 EGFR mutant cases (41.5%) and 131 wild-type cases (58.5%). The sensitivity, specificity, positive predictive value, negative predictive value, and concordance rate of BALF liquid biopsy to tissue genotyping were 97.8%, 96.9%, 96.8%, 98.4%, and 97.7%, respectively. BALF liquid biopsy showed almost identical performance with standard tissue genotyping, while only 5 cases were mismatched each other. On the other hand, plasma liquid biopsy using cfDNA (n=110) revealed 48.5% sensitivity, 86.3% specificity, and 63.6% concordance rate in comparison to tissue genotyping. The mean turnaround times of BALF liquid biopsy was significantly shortened to 2.6±2.0 days in contrast to 13.9±12.4 days of tissue genotyping. (p&lt;0.001).
Conclusion
BALF liquid biopsy can be developed as a novel platform for EGFR mutation testing in advanced NSCLC with almost identical performance with conventional tissue genotyping and significantly shorten TAT to 1-2 days.
Citation Format: In Ae Kim, Jae Young Hur, Hee Joung Kim, Wan Seop Kim, Kye Young Lee. BALF liquid biopsy provides a novel platform for speedy and accurate EGFR mutation testing in advanced NSCLC patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1196.
Abstract 1204: SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels
Authors: Sadilkova Lenka Kyrych , Valentova Iva , Hoskova Simona , Vopalensky Pavel , Bammert Lukas , Beerli Roger , Moebius Ulrich , Spisek Radek 
Published: July 2021

Abstract
Claudin (CLDN) 18.2, a member of a large family of transmembrane proteins with distinct functions, has been shown to have a high prevalence, predominantly in gastric and pancreatic cancer. In addition, ectopic expression of CLDN18.2 was described for other cancer types including ovarian, lung, liver and colon, whereas healthy tissue expression is restricted to the stomach. SO-N102 represents a CLDN18.2 targeting antibody-drug conjugate based on a novel proprietary highly specific monoclonal antibody conjugated to a derivative of PNU-159682 using SMACTM technology for the therapy of patients with various CLDN18.2-positive solid tumors, mainly of gastric and pancreatic origin. The CLDN18.2 protein sequence is highly conserved in mammalians with 100% identity in the targeted extracellular loop among rodents, cynomolgus monkey and human. SO-N102 showed excellent specificity for CLDN18.2, strong binding to the target followed by efficient tumor cell killing. Preferential binding to selected patient-derived tumor tissues was observed ex vivo when compared to healthy stomach tissues from mice and cynomolgus monkey. Single-agent therapeutic activity of SO-N102 was demonstrated in 10 patient-derived mouse xenografts models (gastric, pancreatic, liver, colon and lung adenocarcinomas). Complete responses were observed in all models, independent of CLDN18.2 expression levels, ranging from low (IHC1+) to high (IHC3+), with minimum efficacious doses between 0.2 mg/kg and 0.6 mg/kg. An acceptable tolerability profile was observed in preliminary toxicity studies at 10 mg/kg (mouse), 6 mg/kg (rat) and 1 mg/kg (cynomolgus monkey). SO-N102 demonstrated favorable pharmacokinetic properties with half-lives in the range of 8 days and 13 days in cynomolgus monkey and rat, respectively. Stability of SO-N102 without any significant loss of the payload was demonstrated in vitro and in animals. Further toxicology studies in rats and cynomolgus monkeys were initiated, paralleled by process development and manufacturing activities with the plan to initiate the first clinical study with SO-N102 in patients in the first half of 2022.
Citation Format: Lenka Kyrych Sadilkova, Iva Valentova, Simona Hoskova, Pavel Vopalensky, Lukas Bammert, Roger Beerli, Ulrich Moebius, Radek Spisek. SO-N102, a novel CLDN18.2-targeting antibody-drug conjugate with strong anti-tumor effect in various solid tumors expressing low target levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1204.
Abstract 1214: Identification of URST1 as a prognostic biomarker and therapeutic target for lung cancer
Authors: Takano Atsushi , Miyagi Yohei , Daigo Yataro 
Published: July 2021

Abstract
This study aims to identify novel biomarkers and therapeutic targets for lung cancer. Our strategies are as follows: i) Identification of up-regulated genes in lung cancers by gene expression profile analysis, ii) Validation of clinicopathological importance of their protein expression using tissue microarray, iii) Examination of their effect on cancer cell proliferation/survival by siRNAs and/or small molecules. During this process, we identified up-regulated in solid tumor 1 (URST1). Immunohistochemical analysis of URST1 expression revealed that URST1 expression was observed in the majority of non-small cell lung cancers (NSCLCs) and SCLCs. Strong positivity of URST1 staining was correlated with tumor size and lymph node metastasis and it was significantly associated with poor prognosis for NSCLC patients. Multivariate analysis showed that strong expression of URST1 was an independent prognostic factor for NSCLCs that had undergone curative surgery. Inhibition of URST1 expression by siRNAs for URST1 suppressed the growth and invasive ability of lung cancer cells. Treatment of lung cancer cells with selective inhibitors for URST1 significantly suppressed the cell growth partly through G2/M arrest and subsequent cell death. Downstream targets of URST1 were identified by microarray analysis using lung cancer cells transfected with siRNAs for URST1. Targeting URST1 is likely to be an effective diagnostic and therapeutic approach for lung cancer.
Citation Format: Atsushi Takano, Yohei Miyagi, Yataro Daigo. Identification of URST1 as a prognostic biomarker and therapeutic target for lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1214.
Abstract 1244: Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action
Authors: Zaher Dana , Ramadan Wafaa , El-Awady Raafat , Omar Hany , Hersi Fatema , Srinivasulu Vunnam , Al-Tel Taleb 
Published: July 2021

Abstract
Introduction: Cancer is a leading cause of death worldwide, as about 1 in 6 deaths is due to cancer. Despite the advances in cancer treatment, the success rate of cancer cure is very low, due to the low therapeutic index and many off target side effects of the available anticancer drugs. This highlight the urgent need for the development of novel anticancer compounds with high efficacy and wide safety margin.
Methods: Phenotypic screening of a skeletally diverse library of benzopyrane yielded a unique chemotype with novel anticancer mechanism. Cell viability assays were performed against a panel of cancer cell lines followed by various assays to verify the effect of our compound on inducing apoptosis, DNA damage, cell cycle arrest. For further explore the compound's mechanism of action, a proteomic study was conducted along with western blot analysis, metabolism studies and other enzymes specific mechanistic assays. In addition, mouse tumor model was developed to assess the safety and the activity of the compound in vivo.
Results: The novel compound possesses a potent anticancer effect against multiple cancer cell lines, induces apoptosis, DNA damage and perturbs the cell cycle progression. Interestingly, it inhibits the activity of essential enzymes involved in the cell's redox balance including Thioredoxin and Glutathione reductases. Moreover, it inactivates vital cancer survival pathways. Lastly, the compound safely reduces tumor proliferation in vivo.
Conclusion: Due to the achieved safety profile, potency and efficacy of this novel benzopyrane derived agent as well as its unique mechanism of action, the compound is a potential candidate for further testing in preclinical and clinical settings.
Keywords: Multitarget, apoptosis, DNA damage, cell cycle, thioredoxin reductase, glutathione reductase
Citation Format: Dana Zaher, Wafaa Ramadan, Raafat El-Awady, Hany Omar, Fatema Hersi, Vunnam Srinivasulu, Taleb Al-Tel. Discovery of a novel anticancer benzopyrane derivative with an effective multitarget mechanism of action [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1244.
Abstract 1251: Dithiocarb-copper complex, CuET, demonstrates anti-neoplastic activity in mouse model of prostate cancer and prevents recurrence of tumors
Authors: Dumut Daciana Catalina , DeSanctis Juan B. , Mistrik Martin , Skrott Zdenek , Dzubak Petr , Bartek Jiri , Hajduch Marian , Radzioch Danuta 
Published: July 2021

Abstract
INTRODUCTION Prostate cancer (PCa) is the most common cancer in the North-American man. It was responsible for about 192,000 new cases and 33,000 deaths in the USA in 2020. Surgical resection and systemic androgen deprivation therapy are standard approaches to treat both localized and metastatic PCa (mPCa). The five-year survival from prostate cancer (PCa) without bone metastasis is 56% versus 3% with metastasis There is no cure for the metastatic prostate cancer (mPCa) which often spreads to the hip, spine, and pelvis bones. Therefore, new approaches and combination therapy need to be developed to improve patients's survival. Disulfiram's anti-cancer activity was previously explored and its metabolite ditiocarb-copper complex (CuET) was found to have high anti-cancer activity. The mechanism of action of CuET involves NPL4 aggregation and activation of ER stress, leading to preferential apoptosis of cancer cells. Since altered protein degradation is targeted by CuET, it might display high efficacy in highly mutated PCa. Consequently, we want to propose CuET for the treatment of mPCa.
METHODS Survival curve and colony-formation assays in murine dKO cell line harboring PTEN and Rb driver mutations as well as in the human metastatic PC3 cell line, were performed. Anti-metastatic effect of CuET in vitro was assessed through Boyden chamber. In vivo efficacy of systemic treatment with CuET, was studied in dKO model of C57BL/6 mice.
RESULTS Our results demonstrate that CuET displays cytotoxicity in dKO and PC3 cells at very low concentrations with respective IC50 of 46.2nM and 90.5nM. In vitro, CuET significantly reduced both the clonogenicity and migration ability of cells. In vivo, systemic treatment with CuET significantly reduced growth of dKO tumor and prevented recurrence of tumors.
CONCLUSION Given these positive pre-clinical results, CuET should be investigated for its antineoplastic activity in clinical setting as an adjuvant therapy for mPCa.
Citation Format: Daciana Catalina Dumut, Juan B. DeSanctis, Martin Mistrik, Zdenek Skrott, Petr Dzubak, Jiri Bartek, Marian Hajduch, Danuta Radzioch. Dithiocarb-copper complex, CuET, demonstrates anti-neoplastic activity in mouse model of prostate cancer and prevents recurrence of tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1251.
Abstract 1279: Development of a selective CDK2-E inhibitor in CCNE driven cancers
Authors: Choi Yoon J. , Wenglowsky Steve , Brown Victoria , Bifulco Neil , Choi Yeon S. , Guo Jian , Hatlen Megan , Kim Joseph , LaBranche Tim , Lobbardi Riadh , Perola Emanuele , Rozsahegyi Emily , Maynard Michelle , Ramsden Phil , Silva Grace , Stevison Faith , Vargas Richard , Wang Ruduan , Wilson Doug , Woessner Rich , Zhang Dean , Meissner Rob , Hoeflich Klaus , Dorsch Marion 
Published: July 2021

Abstract
Background: Cyclin dependent kinases (CDK) comprise a family of proteins which are activated upon cyclin binding to promote cell cycle progression. Historically, CDK family inhibitors have had limited utility in the clinic due to 1) toxicities associated with broad spectrum CDK inhibition; and 2) varied and unpredictable efficacy due to lack of a patient selection strategy. The recent approval of three selective CDK4/6 drugs (palbociclib, ribociclib and abemaciclib) has revived the pursuit of therapies against a related interphase kinase, CDK2. Cyclin E gene (CCNE) alterations are prevalent in cancers with high unmet medical need and are emerging as a potential mechanism of clinical resistance to targeted therapies (e.g. CDK4/6 therapies).
Methods: Here we report preclinical validation leading to the development of a selective CDK2 inhibitor for the treatment of cancers harboring CCNE alterations. We highlight advanced, orally bioavailable compounds exhibiting single-digit low nanomolar biochemical and cellular potency (pRB), exquisite CDK family selectivity (CDK1, 4, 6, 7 and 9), and whole kinome selectivity. We have characterized the phenotypic and mechanistic consequences of targeting CDK2, employing both genetic and pharmacologic methods across cell lines and xenograft models (e.g. OVCAR-3, MKN-1, HCC1569).
Results: In a panel of cell lines, CCNE1-amplified lines exhibited profound sensitivity to selective CDK2 inhibition by halting cells at the G1/S phase of the cell cycle. Upon further inspection, CDK2 inhibition induced multiple markers of senescence, e.g. SA-b-gal and IL-6, in CCNE1-amplified but not in CCNE non-amplified cell lines. Consistent with this, these compounds exhibit robust anti-tumor activity in multiple CCNE1-amplified xenograft models, which was sustained after removal of treatment with these compounds.
Conclusions: These data provide a strong rationale for advancing this class of compounds toward clinical development in CCNE-altered cancers.
Citation Format: Yoon J. Choi, Steve Wenglowsky, Victoria Brown, Neil Bifulco, Yeon S. Choi, Jian Guo, Megan Hatlen, Joseph Kim, Tim LaBranche, Riadh Lobbardi, Emanuele Perola, Emily Rozsahegyi, Michelle Maynard, Phil Ramsden, Grace Silva, Faith Stevison, Richard Vargas, Ruduan Wang, Doug Wilson, Rich Woessner, Dean Zhang, Rob Meissner, Klaus Hoeflich, Marion Dorsch. Development of a selective CDK2-E inhibitor in CCNE driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1279.
Abstract 1394: Poly ADP-ribose polymerase inhibitor promotes the immunoradiotherapeutical efficacy in small cell lung cancer
Authors: Zhang Nannan , Gao Yanping , Zeng Zihang , Luo Yuan , Jiang Xueping , Zhang Jianguo , Li Jiali , Huang Zhengrong , Gong Yan , Xie Conghua 
Published: July 2021

Abstract
This study aimed to investigate the safety and efficacy of radiotherapy combined with poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors in small cell lung cancer (SCLC). Tumor-bearing xenograft mouse model was used to examine the safety and anti-tumor effects of radiotherapy plus niraparib and PD-1 antibodies. SCLC cell lines were used to explore the underlying mechanisms in this combination. PARP inhibitor suppressed SCLC cell proliferation, induced cell apoptosis, and increased cell cycle arrest at G2/M phase. Niraparib treatment augmented radiation-induced double-strand DNA breaks, which subsequently activated the cGAS/STING pathway to increase the expression levels of CXCL10, CCL5 and PD-L1 in SCLC cells. Moreover, the combination of radiation, niraparib and PD-1 antibodies significantly inhibited SCLC tumor growth and prolonged the survival of immunocompetent C57BL/6 mice. The induced CCL5 and CXCL10 activated CD8+ T cells in vivo. Our study indicated that niraparib combined with radiation promoted immune checkpoint inhibitor functions via inducing PD-L1 expression, and activated CD8+ T cells via increasing CXCL10 and CCL5 levels through cGAS/STING pathway. The combination treatment of PARP inhibitors, radiotherapy and immunotherapy were safe in vivo, effectively suppressed SCLC tumor progression, increased survival and decreased the adverse events via lowering the dose of individual treatment.
Citation Format: Nannan Zhang, Yanping Gao, Zihang Zeng, Yuan Luo, Xueping Jiang, Jianguo Zhang, Jiali Li, Zhengrong Huang, Yan Gong, Conghua Xie. Poly ADP-ribose polymerase inhibitor promotes the immunoradiotherapeutical efficacy in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1394.