bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A134: Therapeutic targeting of Hdm2/HdmX E3 ligase with bioactive cyclotides
Authors: Camarero Julio A 
Published: March 2020

Abstract
Reactivation of tumor-suppressor p53 for targeted cancer therapy is an attractive strategy for cancers bearing wild-type (WT) p53. Targeting the Hdm2-p53 interface or HdmX-p53 interface or both has been a focus in the field. However, targeting the E3 ligase activity of Hdm2–HdmX which is mediated by RING–RING interaction has recently appeared as a promising novel anticancer approach. Targeting the E3 ligase of Hdm2-HdmX should overcome HdmX-driven resistance, which is found in many cancers overexpressing HdmX, to p53-Hdm2 antagonists such a nutlins. Cyclotides are a novel class of micro-proteins (≈30-40 residues long) with a unique topology containing a head-to-tail cyclized backbone structure further stabilized by three disulfide bonds that form a cystine knot. This unique molecular framework makes them exceptionally stable to physical, chemical, and biological degradation compared to linear peptides of similar size. The cyclotides are also highly tolerant to sequence variability, aside from the conserved residues forming the cystine knot, orally bioavailable and able to cross cellular membranes to modulate intracellular protein-protein interactions (PPIs) both in vitro and in vivo. These unique properties make them ideal scaffolds for many biotechnological applications, including drug discovery. We report the discovery of a novel cyclotide, MCo-52-2, able to antagonize efficiently the interaction between the RING domains of Hdm2 and HdmX and show p53-specific anticancer activity in several cancer cell lines both in vitro and in vivo. We will also present different strategies to improve the cellular uptake and pharmacokinetic profiles of bioactive cyclotides.
Citation Format: Julio A Camarero. Therapeutic targeting of Hdm2/HdmX E3 ligase with bioactive cyclotides [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A134. doi:10.1158/1535-7163.TARG-19-A134
Abstract A136: Small molecule covalent drug discovery by IMTACTM
Authors: Ha Heather , Stanley Robert , Cai Qian , Zhou Wendy , Chen Hang , Yuan Irene , Cao Ping 
Published: March 2020

Abstract
There is currently a resurgence of interest in developing covalent drugs due to the high potency, good selectivity, and prolonged effects which may results in less-frequent drug dosing and wider therapeutic windows for patients. BridGene Biosciences established a novel IMTACTM (Isobaric Mass Tagged Affinity Characterization) platform for covalent drug discovery. Using IMTACTM platform, an intelligently designed drug-like probe with alkyne tag is able to “fish out” and identify proteins covalently bound to probes from live cells which enables us to discover druggable opportunities across the entire proteome. There are several advantages of IMTACTM : 1. Discover ligands for unliganded or undruggable targets; 2. Reduce the time and cost of lead discovery; 3. Identify additional targets of drugs or clinical candidates; 4. Build ligand-target interaction database and guide drug design. Using IMTACTM platform, our covalent library is screened in various live cells including cancer immune, and neuronal cell lines. The hit rate of IMTAC screening is about 20%, and the targets discovered by IMTACTM includes GMPS, Rictor, BTK, FABP5, ALDH, FUS, MIF and etc. Given the drug-like probe design, the probes can have nanomolar potency on the targets. And the drug like probe design minimizes the SAR efforts of developing a hit to a drug. IMTACTM platform allows us to expand the therapeutic applications of small molecule drugs to a new horizon.
Citation Format: Heather Ha, Robert Stanley, Qian Cai, Wendy Zhou, Hang Chen, Irene Yuan, Ping Cao. Small molecule covalent drug discovery by IMTACTM [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A136. doi:10.1158/1535-7163.TARG-19-A136
Abstract B003: Combinatorial therapies of neratinib for HER2-amplified cancer
Authors: Zhao Ming , Scott Stephen , Evans Kurt , Yuca Erkan , Saridogan Turcin , Demirhan Mehmet E , Kirby Bryce P , Kopetz Scott , Diala Irmina , Lalani Alshad S , Piha-Paul Sarina A , Meric-Bernstam Funda 
Published: March 2020

Abstract
Activation of HER2 signaling by amplification or overexpression of ERBB2 (HER2) is associated with the development and progression of breast cancer. Neratinib is an irreversible, pan-HER tyrosine kinase inhibitor which selectively inhibits EGFR, HER2 and HER4. In this preclinical study, we explored the therapeutic efficacy of neratinib in combination with other clinically relevant targeted agents for HER2-amplified breast cancer in in vitro and in vivo models. HER2-amplified cell lines BT-474, SK-BR-3, and HCC-1954 were sensitive to neratinib with low nanomolar IC50s. Cell viability and colony formation assays demonstrated synergistic anti-proliferative activity of neratinib in combination with multiple targeted agents, including the MEK inhibitor trametinib, the PI3Ka inhibitor alpelisib, the mTOR inhibitors everolimus and sapanisertib, and CDK4/6 inhibitor palbociclib. We tested combinatorial efficacy of neratinib with everolimus, trametinib, and palbociclib in vivo on five HER2-amplified PDXs (two breast, two colorectal and one gastric-esophageal junction cancer), four derived from patients with previous HER2-targeted therapy. The combination of neratinib with everolimus or trametinib led to at least a 100% increase in median time for tumor doubling in 25% (1 of 4) and 60% (3 of 5) models respectively and was associated with decreased tumor volumes in 50% (2 of 4) and 20% (1 of 5) of the models respectively. The combination of neratinib with palbociclib significantly enhanced antitumor efficacy compared to single agent treatment in all five PDX models. The combination achieved treatment/control volume ratios of 0.03-0.16 and increased time for tumor doubling more than 100% in all five models. Taken together, our results provide solid preclinical evidence for targeting combinatorial therapies of neratinib for HER2-amplified cancer.
Citation Format: Ming Zhao, Stephen Scott, Kurt Evans, Erkan Yuca, Turcin Saridogan, Mehmet E Demirhan, Bryce P Kirby, Scott Kopetz, Irmina Diala, Alshad S Lalani, Sarina A Piha-Paul, Funda Meric-Bernstam. Combinatorial therapies of neratinib for HER2-amplified cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B003. doi:10.1158/1535-7163.TARG-19-B003
Abstract B016: CDK7 inhibition suppresses AR addicted Castration-Resistant Prostate Cancer through MED1 inactivation
Authors: Rasool Reyaz , Natesan Ramakrishnan , deng qu , Aras Shweta , Lal Priti , Posimo Jessica , Palanisamy Nallasivam , Narla Goutham , Den Robert , Freedman Matthew , brady donita , asangani irfan a 
Published: March 2020

Abstract
Metastatic castration-resistant prostate cancer (CRPC) is an aggressive disease with high mortality rate, primarily resulting from the transcriptional addiction driven by Androgen Receptor (AR). First-line CRPC treatments typically target AR-signaling, but are rapidly bypassed, resulting in only a modest survival benefit with the FDA approved anti-androgen therapies such abiraterone or enzalutamide. Therefore, molecular approaches that more effectively block the AR-transcriptional program are urgently needed. Here, we present evidence demonstrating that AR transcriptional signaling is activated through a “phosphoswitch” catalyzed by cyclin-dependent-kinase 7 (CDK7). Specifically, CDK7 phosphorylates (in vitro and in vivo) the transcriptional co-activator MED1, a key subunit of Mediator complex, at Threonine 1457 to promote the formation of the AR-transcriptional complex at enhancers and super-enhancer (SE) sites. Furthermore, knockdown or inhibition of CDK7 with the recently developed covalent inhibitor THZ1 abolished T1457 phosphorylation that led to MED1 decruitment from the chromatin, attenuated AR-signaling and eliminated AR-addicted naïve or enzalutamide refractory prostate cancer cells. Interestingly, the reduced AR transcriptional output and cellular phenotypes associated with CDK7 knockdown or inhibition was reversed by T1457D phosphomimic suggesting MED1 as a major effector substrate of CDK7 transcription kinase. Finally, THZ1 demonstrated tumor regression in CRPC xenograft models in vivo. In summary, our identification of MED1 T1457 as a novel CDK7 substrate, which is essential for driving AR-mediated transcription, makes CDK7 a potential “non-oncogene dependency” in AR addicted advanced prostate cancer. Taken together, we will present data that strongly support the clinical evaluation of CDK7 specific inhibitors as a monotherapy or in combination with second generation anti-androgens in refractory castration-resistant prostate cancer. Conflict of Interest: None (P.S. This work is undergoing final revision for publication in Cancer Discovery)
Citation Format: Reyaz Rasool, Ramakrishnan Natesan, qu deng, Shweta Aras, Priti Lal, Jessica Posimo, Nallasivam Palanisamy, Goutham Narla, Robert Den, Matthew Freedman, donita brady, irfan a asangani. CDK7 inhibition suppresses AR addicted Castration-Resistant Prostate Cancer through MED1 inactivation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B016. doi:10.1158/1535-7163.TARG-19-B016
Abstract B052: ATR inhibition potentiates ionizing radiation-induced innate immune response via sensing cytosolic RNAs
Authors: Chen Junjie 
Published: March 2020

Abstract
Radiation therapy, widely used for cancer treatment for decades, is being revitalized through its ability to induce systemic anti-tumor immune response via activating type I interferon signaling, especially when it is combined with immune checkpoint blockade therapy. Mechanistic understanding of how ionizing radiation induces type I interferon signaling and how to amplify this signaling module will be highly instructive in maximizing the efficacy of radiation therapy. Here we found that ATR inhibitors, which are currently being developed as anti-cancer agents, significantly potentiate ionizing radiation-induced antiviral innate immune response. Using a series of knockout cell lines we generated for components involved in cytosolic nucleic acid sensing pathways, we demonstrated that the MAVS-dependent cytosolic RNA sensing pathway is the major pathway responsible for ionizing radiation alone or radiation plus ATR inhibitor-induced type I interferon signaling in human cells. Mechanistically, ATR-CHK1-CDC25C axis dependent G2/M DNA damage checkpoint abrogation is required for ATR inhibitor plus ionizing radiation-induced type I interferon signaling. More importantly, we proposed DNA damage-elicited double stranded DNA breaks could release AT-rich DNA sequences, which initiate MAVS-dependent type I interferon signaling via RNA polymerase III-mediated transcription in human cells. Our studies suggest that ATR inhibition in combination with radiation therapy and immune checkpoint blockade is a promising new combination therapy for cancer treatment.
Citation Format: Junjie Chen. ATR inhibition potentiates ionizing radiation-induced innate immune response via sensing cytosolic RNAs [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B052. doi:10.1158/1535-7163.TARG-19-B052
Abstract B069: Cell Model Passports—a hub for clinical, genetic and functional datasets of preclinical cancer models
Authors: Meer Dieudonne van der , Barthorpe Syd , Yang Wanjuan , Lightfoot Howard , Hall Caitlin , Gilbert James , Francies Hayley , Garnett Mathew 
Published: March 2020

Abstract
In vitro cancer cell cultures are facile experimental models used widely for research and drug development. Many cancer cell lines are available and efforts are ongoing to derive new models representing the histopathological and molecular diversity of tumours. Cell models have been generated by multiple laboratories over decades and consequently their annotation is incomplete and inconsistent. Furthermore, the relationships between many patient-matched and derivative cell lines have been lost, and accessing information and datasets is time-consuming and difficult. Here, we describe the Cell Model Passports database (cellmodelpassports.sanger.ac.uk) which provides details of cell model relationships, patient and clinical information, as well as access to associated genetic and functional datasets. The Passports database currently contains curated details and standardized annotation for &gt;1600 cell models, including cancer organoid cultures. The Passports will be updated with newly derived cell models and datasets as they are generated. Users can navigate the database via tissue, cancer-type, genetic feature and data availability to select a model most suitable for specific applications. A flexible REST-API provides programmatic data access and exploration. The Cell Model Passports are a valuable tool enabling access to high-dimensional genomic and phenotypic cancer cell model datasets empowering diverse research applications.
Citation Format: Dieudonne van der Meer, Syd Barthorpe, Wanjuan Yang, Howard Lightfoot, Caitlin Hall, James Gilbert, Hayley Francies, Mathew Garnett. Cell Model Passports—a hub for clinical, genetic and functional datasets of preclinical cancer models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B069. doi:10.1158/1535-7163.TARG-19-B069
Abstract B084: PLOD2 is essential to functional activation of integrin beta1 for invasion/metastasis of cancer
Authors: Kondo Eisaku , Saito Ken 
Published: March 2020

Abstract
Identifying the specific functional regulator of integrin family molecules in cancer cells is critical because they are directly involved in tumor invasion and metastasis. Here we report high expression of PLOD2 in various cancer cells, and its critical role as a stabilizer of ITGB1, enabling ITGB1 to initiate tumor invasion/metastasis, which was demonstrated mainly using SCC cells as a representative example. ITGB1 stabilized by PLOD2-mediated hydroxylation was recruited to the plasma membrane, its functional site, and accelerated tumor cell motility, leading to tumor metastasis in vivo, whereas loss of PLOD2 expression abrogated it. In accordance with molecular analysis, examination of SCC tissues from patients corroborated PLOD2 expression associated with ITGB1 at the invasive front of tumor nests. PLOD2 is thus implicated as the key regulator of ITGB1 that prominently regulates tumor invasion and metastasis not only in SCCs but tumors of diverse origins, and it provides important clues engendering novel therapeutics for these intractable cancers.
Citation Format: Eisaku Kondo, Ken Saito. PLOD2 is essential to functional activation of integrin beta1 for invasion/metastasis of cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B084. doi:10.1158/1535-7163.TARG-19-B084
Abstract B097: Development of a mouse-human chimeric antibody against human CXADR having a potent antitumor activity in animal models
Authors: Kawada Manabu , Sakamoto Shuichi , Inoue Hiroyuki , Kaneko Mika , Ogasawara Satoshi , Kajikawa Masunori , Urano Sakiko , Ohba Shun-ichi , Kato Yukinari 
Published: March 2020

Abstract
Coxsackievirus and adenovirus receptor (CXADR) is a single-pass transmembrane protein that is expressed on some cancers including prostate, lung, and brain tumor tissues. We previously developed a mouse monoclonal antibody against human CXADR, mu6G10A, and found that mu6G10A significantly exerts an anti-tumor activity against various human cancer cell lines expressing CXADR through antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities. In this study, we have developed a mouse-human chimeric anti-CXADR antibody, ch6G10A, from mu6G10A, and evaluated its anti-tumor activity. As a result, in vitro experiments clearly showed that ch6G10A possesses binding, ADCC, and CDC activities against human prostate cancer DU-145 cells expressing CXADR like mu6G10A. In vivo xenograft models showed that ch6G10A exerts a significant anti-tumor activity against DU-145 cells when human NK cells were co-injected. These results indicate that a mouse-human chimeric anti-CXADR antibody, ch6G10A, has a therapeutic potential as a novel anti-tumor antibody drug.
Citation Format: Manabu Kawada, Shuichi Sakamoto, Hiroyuki Inoue, Mika Kaneko, Satoshi Ogasawara, Masunori Kajikawa, Sakiko Urano, Shun-ichi Ohba, Yukinari Kato. Development of a mouse-human chimeric antibody against human CXADR having a potent antitumor activity in animal models [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B097. doi:10.1158/1535-7163.TARG-19-B097
Abstract B122: The CD98hc oncoprotein as a target of new anticancer therapy
Authors: Lanzillotta Delia , Iaccino Enrico , Artese Anna , Mimmi Selena , D'Agostino Sabrina , Romeo Isabella , Cantafio Patrizia , Dattilo Vincenzo , Costa Giosuè , Brescia Carolina , Gaudio Eugenio , Alcaro Stefano , Trapasso Francesco 
Published: March 2020

Abstract
Among the proteins putatively interacting with PTPRJ, a tyrosine phosphatase with tumor suppressor activity, we focused on the oncoprotein CD98hc as a very interesting candidate for the development of innovative targeted drugs. In fact, CD98hc, representing the heavy chain of a transmembrane aminoacid transporter, is overexpressed in several human cancers. Furthermore, CD98hc higher expression is associated with poor prognosis in lung cancer patients. CD98hc is linked to light chains (LATs, xCT) by disulfide bridge, polar and hydrophobic interactions. The light chain confers substrate specificity, and ERK, AKT, FAK and mTOR pathways are involved in CD98hc-LATs/xCT downstream signals. Moreover, CD98hc is a coreceptor of b-integrins and it is involved in cell proliferation, migration and invasion. We identified two peptides and 15 small molecules (putatively targeting the disulfide bridge) as candidate CD98hc inhibitors by phage display and in silico screenings, respectively, and validated in vitro the binding between peptides and transmembrane fraction of CD98hc by cytofluorimetric assay. Then, we tested the capability of both types of compounds to affect cell viability and proliferation through MTT and CFSE assays, respectively. We observed that the targeting of CD98hc through both peptides and small molecules reduced cell proliferation in A549 human lung cancer cells, strongly encouraging a deeper characterization of these candidate anticancer molecules. Indeed, our next goals will be the assessment of biochemical activity of CD98hc following to its inhibition, as well as the evaluation of compounds toxicity, both in vitro and in vivo. The final aim is to identify lead compounds inhibiting CD98hc, in order to develop novel molecules to be translated in the clinical setting and to be used as monotherapy and/or in a combinatorial approaches for the treatment of cancer patients.
Citation Format: Delia Lanzillotta, Enrico Iaccino, Anna Artese, Selena Mimmi, Sabrina D'Agostino, Isabella Romeo, Patrizia Cantafio, Vincenzo Dattilo, Giosuè Costa, Carolina Brescia, Eugenio Gaudio, Stefano Alcaro, Francesco Trapasso. The CD98hc oncoprotein as a target of new anticancer therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B122. doi:10.1158/1535-7163.TARG-19-B122
Abstract C014: Development of an injectable water-soluble anticancer drug CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation
Authors: Kakeya Hideaki , Kishimoto Atsuhiro , Umeta Hitomi , Imaizumi Atsushi , Kanai Masashi 
Published: March 2020

Abstract
Recent well-designed preclinical studies have demonstrated that KRAS mutations can activate the canonical NF-κB signaling pathway, which is a pivotal role in tumor progression. Therefore, inhibition of this KRAS-NF-κB axis would be a promising target to develop a new molecular targeted anticancer agent. Curcumin, a naturally occurring polyphenol derived from the plant Curcuma longa, has been shown to block NF-κB signaling pathway via at least two mechanisms; inhibition of IkB phosphorylation and inhibition of ubiquitin-dependent degradation of IκB. Recently dual-specificity tyrosine-regulated kinase (DYRK2), a positive regulator of the 26S proteasome, has been reported as a direct molecular target of curcumin, which is consisted with the inhibition of NF-κB signaling pathway by curcumin. Several preclinical studies have clearly demonstrated that curcumin exhibits anticancer effects in colorectal cancer model through NF-κB inhibition. However, since curcumin is highly lipophilic and orally administrated curcumin has very low bioavailability, its clinical application in cancer patients has been hampered. Very recently we developed a synthetic water-soluble prodrug CMG, curcumin mono-β-D-glucuronide, to overcome these problems. In this study, we investigated the anticancer effect of CMG on oxaliplatin (L-OHP) -resistant colorectal cancer cells HCT116 with KRAS mutation and p53 deletion (KRAS+p53- cells). Curcumin, the active substance released from CMG in vivo, showed similar effects regardless of KRAS/p53 mutation status in vitro. In xenograft models using KRAS+p53- HCT116 cells, intraperitoneal administration of CMG significantly superior antitumor effects compared to L-OHP monotherapy. Notably, no adverse events were noted in the CMG group, whereas bodyweight loss, severe myelosuppression, and liver damage were observed in the L-OHP group. Combination of CMG and L-OHP showed additive antitumor effects with moderate suppression of liver damage by L-OHP. These results indicate that CMG could be a novel anticancer drug with minimal toxicities for colon cancer patients with KRAS and p53 mutations.
Citation Format: Hideaki Kakeya, Atsuhiro Kishimoto, Hitomi Umeta, Atsushi Imaizumi, Masashi Kanai. Development of an injectable water-soluble anticancer drug CMG for oxaliplatin-resistant colorectal cancer with KRAS mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C014. doi:10.1158/1535-7163.TARG-19-C014