bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6168: Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action
Authors: Oplustil O'Connor Lenka , Hamm Gregory , Udriste Maria , Ling Stephanie , Wilson Joanne , Durant Steve , Hughes Gareth , Cosulich Sabina , Shao Wenlin , Pass Martin , Jones Gemma , Pierce Andrew , Goodwin Richard , O'Connor Mark , Barrett Carl , Harrington Elizabeth 
Published: September 2020

Abstract
Ataxia telangiectasia mutated (ATM) kinase is a key factor in DNA double strand break response and is constitutively activated in glioblastoma, leading to marked radioresistance [Bartkova, Carruthers] and therefore an attractive radiosensitisation target in this disease. AZD1390, a potent ATM inhibitor optimized to cross the blood brain barrier, is being evaluated with radiotherapy in Phase 1 (NCT03423628). Positron emission tomography (PET) studies demonstrated AZD1390 brain exposure in healthy human subjects. This study characterises ATM inhibitor penetration and distribution in brain and GBM, as well as pharmacodynamic biomarker changes in human orthotopic GBM patient-derived explant (PDX) models. Radiation +/- AZD1390 treatment was evaluated for compound concentration in plasma and relative abundance in brain/ GBM regions by mass spectrometry imaging (MSI). Parallel samples were analysed by immunohistochemistry for biomarkers of DNA damage response and ATM signalling. We show AZD1390 penetrates brain tissue with preferential compound accumulation into tumour. Higher ratios of AZD1390 in GBM versus normal brain correlate with improved efficacy and greater levels of DNA damage. Moreover, AZD1390 in the GBM region was heterogeneously distributed with MSI characterized specific metabolic clusters having varied AZD1390 intensities. As expected, radiation treatment activated ATM signalling (indicated by increase in pRAD50 and γH2AX positive cells) which was effectively inhibited by AZD1390 co-treatment. Our work provides novel insights into ATM inhibitor pharmacokinetics in brain tumours and demonstrates the benefit of using MSI in conjunction with pharmacodynamic markers to provide a more complete picture of AZD1390 mechanism of action for future translational studies on clinical GBM samples.
Citation Format: Lenka Oplustil O'Connor, Gregory Hamm, Maria Udriste, Stephanie Ling, Joanne Wilson, Steve Durant, Gareth Hughes, Sabina Cosulich, Wenlin Shao, Martin Pass, Gemma Jones, Andrew Pierce, Richard Goodwin, Mark O'Connor, Carl Barrett, Elizabeth Harrington. Characterization of ATM inhibitor (AZD1390) distribution and pharmacodynamic changes in brain and glioblastoma in preclinical models to inform on mechanism of action [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6168.
Abstract 6223: Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models
Authors: Tao Ran , Wang Guangfeng , Fang Douglas D. , Zhai Guoqin , Li Yuanbao , Lv Jing , Wu Miaoyi , Ge Yangfeng , Zhang Feifei , Wen Danyi , Yang Dajun , Zhai Yifan 
Published: September 2020

Abstract
Osimertinib (AZD9291) is the first-line treatment for EGFR-mutated NSCLC; however, the majority of patients inevitably develop resistance due to de novo genomic abnormalities, such as C797S mutation, EGFR exon 20 insertion, MET amplification and other unknown mechanisms. Hence, effective therapies to overcome acquired resistance are urgently needed. Inhibition of BCL-2/BCL-xL has been reported to enhance apoptosis in EGFR-TKI resistant cells with low sensitivity to EGFR inhibition. In this study, we evaluated whether the combination of a dual BCL-2/BCL-xL inhibitor APG-1252 and chemotherapeutics could overcome osimertinib resistance in preclinical xenograft models.
First, EGFR C797S mutation was introduced to human NCI-H1975 NSCLC cells to construct an NCI-H1975-C797S resistant cell line using CRISPR technology. NCI-H1975-C797S derived-xenografts were treated with APG-1252, cisplatin/docetaxel or their combinations.
Combination therapy with APG-1252 and cisplatin or docetaxel exhibited synergistic antitumor activity. APG-1252 plus docetaxel combination achieved 100% tumor partial regression (PR). Similar results were demonstrated in a patient-derived xenograft (PDX) tumor model derived from an osimertinib-resistant NSCLC patient harboring 19del-T790M-C797S mutations. Furthermore, the combinations also exhibited enhanced antitumor activity in an osimertinib-resistant PDX model that the resistant mechanism remained unknown.
In summary, our results suggest that the combination treatment with APG-1252 and chemotherapeutics can overcome acquired resistance to osimertinib and the combination deserves further clinical evaluations.
Citation Format: Ran Tao, Guangfeng Wang, Douglas D. Fang, Guoqin Zhai, Yuanbao Li, Jing Lv, Miaoyi Wu, Yangfeng Ge, Feifei Zhang, Danyi Wen, Dajun Yang, Yifan Zhai. Combination of BCL-2/BCL-xL dual inhibitor APG-1252 and chemotherapeutics overcomes resistance to osimertinib in EGFR mutant NSCLC in preclinical models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6223.
Abstract 6252: Development and validation of an LC/MS/MS method for the determination of celastrol in rat plasma and its application to the pharmacokinetic evaluation of celastrol-encapsulated silk fibroin nanoparticles
Authors: Zhan Shuyu , Paik Amy , Onyeabor Felicia , Ding Baoyue , Prabhu Sunil , Wang Jeffrey 
Published: September 2020

Abstract
Celastrol (CL), a compound isolated from Tripterygium wilfordii, possesses various bioactivities such as anti-tumor, anti-inflammatory and anti-obesity effects. Many new drug delivery systems of CL have been designed to overcome its poor water solubility and low bioavailability. However, few studies are available concerning its in vivo pharmacokinetics. In this study, a simple and sensitive LC-MS/MS method was developed and validated to determine CL in rat plasma using 18α-glycyrrhetinic acid as the internal standard. The separation of CL was performed on a Phenomenex Gemini C18 column (150 mm × 2 mm, 5 µm) following sample preparation using liquid-liquid extraction with the optimized extraction solvent of tert-butyl methyl ether and a small plasma sample volume of 50 μL. The analyte was quantitated under positive electrospray ionization and multiple reactions monitoring mode. The assay exhibited a good linearity in the concentration range of 0.5-500 ng/mL. The lower limit of quantification (LLOQ) was 0.5 ng/mL. The method was fully validated to meet the requirements for bioassay with accuracy of 91.1-110.0%, precision (RSD %) of less than 9.1 %, extraction recovery of 63.5-74.7%, and matrix effect of 87.3-101.2%. The developed method was successfully applied to the pharmacokinetic evaluation of CL-encapsulated silk fibroin nanoparticles (CL-SFNP). The results show, after intravenous (IV) and oral (PO) administration of equivalent CL (1 mg/kg and 3 mg/kg, respectively) in rats, the AUC values of CL were 8646.1±1998.9 ng/mL·h after IV dosing and 1065.5±494.6 ng/mL·h after PO dosing for CL-SFNP, which were significantly (P&lt;0.05) higher than those for pure CL (4697.7±723.0 ng/mL·h and 441.9±82.6 ng/mL·h, respectively). The dose-normalized oral bioavailability of CL significantly (P&lt;0.05) increased from 3.1% for pure CL to 7.6% for CL-SFNP.
Citation Format: Shuyu Zhan, Amy Paik, Felicia Onyeabor, Baoyue Ding, Sunil Prabhu, Jeffrey Wang. Development and validation of an LC/MS/MS method for the determination of celastrol in rat plasma and its application to the pharmacokinetic evaluation of celastrol-encapsulated silk fibroin nanoparticles [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6252.
Abstract 6362: TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) cancer
Authors: Annabi Borhane , Demeule Michel , Currie Jean-Christophe , Larocque Alain , Zgheib Alain , Marsolais Christian , Béliveau Richard 
Published: September 2020

Abstract
Rational: Phytochemicals are compounds found in plant foods that can help prevent the occurrence of chronic diseases like cancer. Several studies, over the last decade on the impact of phytochemicals in cancer treatment, have provided experimental evidence that curcumin contains antiproliferative, antiangiogenic, and apoptotic properties. Further evidence suggested that curcumin also suppresses tumor/colon cancer cell progression and angiogenesis by stimulating apoptosis and regulating immune response. Increased expression of the scavenging receptor Sortilin (SORT1), has been clinically observed in numerous invasive tumor biopsies.
Procedures: In light of this, we developed a peptide conjugation platform and a new SORT1 receptor-mediated strategy to increase cell targeting selectivity and cell delivery of anticancer agents. As a proof-of-concept for phytochemicals, curcumin was conjugated to a SORT1-binding proprietary peptide (TH19P01). Curcumin-TH19P01 conjugate (TH1901) and unconjugated curcumin were tested on the proliferation of various cancer cells.
Results: TH1901 showed a stronger anti-proliferation activity against cancer cells, with IC50 values up to 100-fold greater when compared to unconjugated curcumin. In addition, higher accumulation of fluorescence was detected for TH1901 indicating a more efficient cell internalization and release of curcumin from the conjugate. TH1901 uptake was reduced in the presence of SORT1 ligands neurotensin and progranulin as well as of free peptide confirming a preferential SORT1-mediated uptake of TH1901 in ES-2 ovarian cancer cells. Fluorescence microscopy showed that, in contrast to unconjugated curcumin, TH1901 induced cell apoptosis, and showed a stronger effect than unconjugated curcumin on TNF-alpha-induced intracellular signaling pathways involved in pro-inflammation processes. Interestingly, conjugation of curcumin also increased its in vitro stability in solution. In vivo, intraperitoneal administration of TH1901 (60 mg/kg/twice a week) inhibited growth of SORT1+ HT-29 colorectal cancer cell subcutaneous xenograft tumors, whereas at an equivalent dose unconjugated curcumin (15 mg/kg/twice a week) had no effect.
Conclusion: Overall, these proof-of-concept experiments support the future development of this flexible and innovative platform to generate novel anticancer treatments.
Citation Format: Borhane Annabi, Michel Demeule, Jean-Christophe Currie, Alain Larocque, Alain Zgheib, Christian Marsolais, Richard Béliveau. TH1901, a novel curcumin-peptide conjugate for the treatment of Sortilin-positive (SORT1+) cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6362.
Abstract 6375: Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt
Authors: Delgado Yamixa , Pandrala Mallesh , Perez Daraishka , Velazquez Eddian , Vega Jaisy , Milian Melissa , Torres Anamaris 
Published: September 2020

Abstract
Today, CisPt is one of the most successful chemotherapeutic metallodrugs. Unfortunately, the use of CisPt is restricted by the dose-limiting toxic effects and the acquired resistance, especially in lung cancer. As an alternatively, FDA-approved drugs for different diseases which target cancer metabolic pathways, are considered an attractive strategy to diminish systemic toxic effects. In the same way, the mechanistic pathways activated/inactivated by this drug could potentially overcome the acquired resistance induced by CisPt. For this reason in our approach, we incorporated deferasirox (Def), a clinical drug for iron (Fe) overload, as the ligand in the development of novel Pt complexes. In cancer progression, Fe plays a key role as a nutrient for cell growth and energy production. In consequence, we have synthesized and characterized our first library of three Pt-Def complexes: Pt(Def-COOH), Pt(Def-CONH2), Pt(Def-COOCH3). In this strategy, we have modified the OH of the carboxylic group of the Def to see the effects in the metabolic pathways. Viability assay results showed that Pt(Def-CONH2) induced a dramatic decrease in the IC50 in non-small lung adenocarcinoma cells after 24 h of incubation compared to CisPt, Def and Def-CONH2. Gene expression studies were conducted for cell growth, resistance and metastases related genes, where Pt(Def-CONH2) showed a significant downregulation of all of them. In addition, insight into target sites and metabolic pathways (apoptosis, caspase 3, ROS, cell cycle) inhibited or activated was garnered. This study will afford the optimization of the rationale to fine tune the structure of novel potential drugs.
Citation Format: Yamixa Delgado, Mallesh Pandrala, Daraishka Perez, Eddian Velazquez, Jaisy Vega, Melissa Milian, Anamaris Torres. Development of novel Pt-based drugs using Deferasirox as ligand to diminish systemic toxicity and resistance induced by CisPt [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6375.
Abstract 6380: Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032
Authors: Roh Eunmiri , Han Yaping , Reddy Kanamata , Zykova Tatyana A. , Lee Mee Hyun , Yao Ke , Bai Ruihua , Curiel-Lewandrowski Clara , Dong Zigang 
Published: September 2020

Abstract
Non-melanoma skin cancer (NMSC) such as cutaneous squamous cell carcinoma (cSCC) is caused by solar ultraviolet (SUV) exposure and is the most common cancer in the United States. T-LAK cell-originated protein kinase (TOPK), a serine-threonine kinase is activated by SUV irradiation and involved in skin carcinogenesis. Strategies with research focusing on the TOPK signaling pathway and targeted therapy in skin carcinogenesis may helpful for the discovery of additional treatments against skin cancer. In this study, we found that TOPK can directly bind to and phosphorylate c-Jun (as one of the core member of AP-1) at Ser63 and Ser73 after SSL exposure in a JNKs-independent manner. TOPK knocking down, or HI-TOPK-032 (TOPK specific inhibitor) attenuated colony formation and cell proliferation of skin cancer cells. Phosphorylated levels of c-Jun were overexpressed in human AK and cSCC compared to normal skin tissues, and HI-TOPK-032 inhibited the phosphorylation of c-Jun in SCC cell line in a dose-dependent manner. Furthermore, HI-TOPK-032 decreased SSL-induced AP-1 transactivation activity. Moreover, acute SSL-induced inflammation was attenuated by the topical application of HI-TOPK-032 in SKH1 hairless mice. Importantly, HI-TOPK-032 suppressed chronic SSL-induced skin carcinogenesis and c-Jun phosphorylation levels in SKH1 hairless mice. Our results demonstrate that TOPK can phosphorylate and activate c-Jun at Ser63 and Ser73 in the process of skin carcinogenesis and HI-TOPK-032 could be used as a potential chemopreventive drug against cSCC development.
Citation Format: Eunmiri Roh, Yaping Han, Kanamata Reddy, Tatyana A. Zykova, Mee Hyun Lee, Ke Yao, Ruihua Bai, Clara Curiel-Lewandrowski, Zigang Dong. Suppression of the solar ultraviolet-induced skin carcinogenesis by TOPK inhibitor HI-TOPK-032 [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6380.
Abstract 6414: Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer
Authors: Eun Chae Young , DeKalb Charlene , Xiao Weikun , Zhang Xinyu , Hill Reginald 
Published: September 2020

Abstract
Exosomes play a critical role in promoting proliferation and survival of cancer cells. These extracellular vesicles that range in size from 30-100nm in diameter are released by many different cell types and contain proteins, nucleic acids, and micro RNAs that can modify the content and state of recipient cells. Our previous studies have shown that cancer-associated fibroblasts (CAFs), which make up the bulk of pancreatic ductal adenocarcinoma (PDAC) tumors, hypersecrete exosomes upon chemotherapy treatment. When these exosomes were taken up by surrounding cancer cells, we observed more cell proliferation and drug resistance. Considering these findings, there is clearly a need of therapeutic strategies that target exosome biogenesis and secretion. Here, we investigate the effectiveness of several compounds, including farnesyl transferase inhibitors, imidazoles, and nonsteroidal anti-inflammatory drugs (NSAIDs), in blocking exosome secretion and suppressing chemoresistance in PDAC CAF and cancer cell lines. We observed decrease in exosome secretion upon ketoconazole, tipifarnib, and neticonazole treatment, using GW4869 (a neutral sphingomyelinase inhibitor) as our control. Furthermore, we established a 3D organoid model from our PDAC mouse models to better understand the impact of these drugs on exosome secretion in tumors with different genetic alterations. Together, our 2D and 3D models illuminate the potential for pharmacological targeting of exosome secretion as a treatment option that can improve the current standard-of-care treatment in PDAC.
Citation Format: Chae Young Eun, Charlene DeKalb, Weikun Xiao, Xinyu Zhang, Reginald Hill. Using 3D models to test the efficacy of targeting cancer-associated fibroblast exosomes to overcome chemoresistance in pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6414.
Abstract 6433: Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy
Authors: Wang Kaibo 
Published: September 2020

Abstract
G-quadruplexes are noncanonical four-stranded DNA or RNA secondary structures that have emerged as novel therapeutic targets. MYC is one of the most important oncogenes and is overexpressed in a number of human cancers. The G-quadruplex formed in the MYC oncogene promoter (MycG4) is a transcriptional silencer and amenable to small molecule targeting. Indenoisoquinolines are human topoisomerase I inhibitors with improved physicochemical and biological properties as compared to the clinically used camptothecin anticancer drugs. Three indenoisoquinolines, indotecan (LMP400), indimitecan (LMP776), and LMP744, have entered phase I clinical trials in adults with relapsed solid tumors and lymphomas. However, some indenoisoquinolines showed potent anticancer activity without being strong topoisomerase I inhibition activity, suggesting additional mechanisms of action. Herein, we demonstrate that a large number of anticancer indenoisoquinolines strongly bind and stabilize MycG4 in vitro, using fluorescence, nuclear magnetic resonance (NMR), and circular dichroism (CD) spectroscopy, as well as gel electromobility shift assay (EMSA). In addition, MycG4-interactive indenoisoquinolines lower MYC mRNA and protein levels in vivo, as shown by western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) experiments. These results indicate that targeting the MYC promoter G4 to downregulate MYC is a likely mechanism of action for the anticancer activities of these particular indenoisoquinolines. In addition, structure-activity-relationships of MycG4 recognition by indenoisoquinolines were investigated and elucidated the essential structural requirements for strong binding. The analysis of indenoisoquinoline derivatives for their MYC inhibitory, topoisomerase I inhibitory, and anticancer activity led to the discovery of a synergistic effect of MYC inhibition and topoisomerase I inhibition on anticancer activity. In conclusion, our result reveals MYC downregulation by MycG4 binding as a new mechanism of action for anticancer indenoisoquinolines. Moreover, we suggest dual targeting of MycG4 and topoisomerase I as a novel strategy for cancer therapy.
Citation Format: Kaibo Wang. Dual targeting MYC G-quadruplex and topoisomerase I: Lead discovery indenoisoquinolines for cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6433.
Abstract 6448: Oral cancer pain mediators released in exosomes are oncogenes with potential to shape the microenvironment and induce neuronal sensitivity
Authors: Bhattacharya Aditi , Dubeykoskaya Zinaida , Nguyen Huu Tu , Dolgalev Igor , Veeramachaneni Ratna , Schmidt Brian L. , Albertson Donna G. 
Published: September 2020

Abstract
Oral cancer patients suffer severe chronic and mechanically-induced pain at the site of the cancer. Patients with metastatic (N+) cancers report greater pain. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. To identify cancer derived mediators of pain and metastasis, we queried an RNA-seq dataset of 19 cancers and 5 normal tissues for genes overexpressed in N+ cancers from patients who reported high pain on the UCSF Oral Cancer Pain Questionnaire (UCSFOCPQ). The 40 candidate pain mediator genes are enriched for functions in extracellular matrix organization and angiogenesis, and are reported to have oncogenic and neuronal functions. Differentially expressed genes encoding neurotrophic and axon guidance molecules were also identified. The pain and metastasis genes encode secreted or membrane proteins. Most of the pain and metastasis genes have been reported in exosomes. A role for exosomes in induction of cancer pain was demonstrated using a mouse paw withdrawal assay. Intraplantar injection of HSC-3 oral tongue cancer cell line conditioned media induced mechanical allodynia and thermal hyperalgesia. By contrast, when conditioned medium depleted of exosomes and extracellular vesicles (EVs) by size exclusion chromatography was injected into the paw, nociceptive behavioral responses to mechanical or thermal stimuli were reduced or abolished, respectively. Nociceptive responses to these stimuli were restored by reconstitution of the EV depleted media with the EV fraction. In conclusion, functional analysis of genes overexpressed in painful N+ cancers highlighted the composition of the N+ oral cancer microenvironment for promotion of angiogenesis and axonogenesis. Preclinical studies implicated cancer-derived exosomes in induction of pain. The autocrine and paracrine actions of identified pain and metastasis genes, as well as communication via exosomes, are potential therapeutic targets for stopping cancer and alleviating pain.
Citation Format: Aditi Bhattacharya, Zinaida Dubeykoskaya, Huu Tu Nguyen, Igor Dolgalev, Ratna Veeramachaneni, Brian L. Schmidt, Donna G. Albertson. Oral cancer pain mediators released in exosomes are oncogenes with potential to shape the microenvironment and induce neuronal sensitivity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6448.