bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LBA049: Possibility of total body irradiations for lymph node metastasis and lung metastasis
Authors: Sora Shouta , Mishra Radhika , Sukhbaatar Ariunbuyan , Sakamoto Maya , Mori Shiro , Kodama Tetsuya 
Published: December 2021

Abstract
Metastatic lymph nodes (MLNs) are one of the most common causes of distant metastasis, and their presence signals a serious deterioration in the life prognosis of an affected patient. The treatment of MLNs at an early stage is necessary to inhibit metastases to distant LNs and organs. Radiation therapy is an effective therapeutic modality for local tumor control in many cancers, and its effect is enhanced by fractionated radiation therapy or in combination with other therapeutic regimens. In addition, recent studies have reported that total body irradiation (TBI) increases the activation of immune cells such as NK cells and infiltration of CD4+ T cells to tumor tissue. However, the effects of TBI on LN metastasis remains unclear. This study assessed the effect of TBI by changing the radiation dose and number of irradiations in an MLN mouse model. To induce metastasis into the proper axillary lymph node (PALN) and lung, mouse breast cancer FM3A-Luc cells were inoculated into the subiliac lymph node (SiLN) of MXH10/Mo/lpr mice. Mice were assigned to 4 groups thus: received no TBI; received a single dose of 0.2 Gy as low-dose TBI (single L-TBI); received a single dose of 1.0 Gy as middle-dose TBI (single M-TBI); or received two fractions of 2.0 Gy (fractionated M-TBI). The irradiation was carried out on day 4 post-inoculation in the single L-TBI and M-TBI groups. In the fractionated M-TBI group the irradiation was carried out on days 4 and 7 post-inoculation. Tumor growth was evaluated using an in vivo bioluminescence imaging system. In the non-irradiated group, tumor activity in the SiLN and PALN increased over time and lung metastasis was confirmed on day 28 post-inoculation. In addition, the single L-TBI dose did not delay tumor growth in the SiLN and PALN or inhibit lung metastasis. In other words, the tumor activity was not significantly changed compared to the non-irradiated group. Single and fractionated M-TBI doses significantly delayed tumor growth in the SiLN and PALN and inhibited lung metastasis. Furthermore, the fractionated M-TBI group exhibited the greatest delay in tumor growth in the PALN compared to the other three groups. These results suggest that the TBI at a dose &gt; 1.0 Gy can delay tumor growth of MLNs in the early stage and distant metastasis. Moreover, the radiation dose and number of irradiations may be essential factors for enhancing the anti-tumor effects of TBI. We anticipate that TBI will contribute to the prevention and treatment of cancer metastasis via LNs.
Citation Format: Shouta Sora, Radhika Mishra, Ariunbuyan Sukhbaatar, Maya Sakamoto, Shiro Mori, Tetsuya Kodama. Possibility of total body irradiations for lymph node metastasis and lung metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA049.
Abstract P004: Orthotopic patient-derived xenografts are effective precision oncology models in predicting therapeutic response and acquired drug resistance
Authors: Nakashima Jonathan , Sperry Jantzen 
Published: December 2021

Abstract
Patient-derived xenografts are a functional test system in a living organism, making them the leading assay for precision oncology and drug development. In vivo pharmacology studies are widely performed using subcutaneous implantation; however, due to significant changes in the tumor microenvironment, this methodology falls short of modeling the full complexities of human cancer. Recently evidence has shown different engraftment and growth rates and therapeutic responses if engrafted orthotopically (O-PDX). In this study we sought to compare the differences in pharmacological response between a subcutaneous PDX and O-PDX and apply O-PDX to predict therapeutic response and acquired resistance to therapy.
Citation Format: Jonathan Nakashima, Jantzen Sperry. Orthotopic patient-derived xenografts are effective precision oncology models in predicting therapeutic response and acquired drug resistance [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P004.
Abstract P023: Achieving synergism in combination chemotherapy for gastric cancer treatment
Authors: Leylek Ozen , Ozcan Gulnihal 
Published: December 2021

Abstract
Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of deaths from cancer. Although the combination of conventional chemotherapeutics with molecular targeted agents targeting tumor-specific biomarkers has increased the treatment efficacy in certain types of cancer such as breast cancer, similar success could not be achieved in GC treatment. Therefore, there is an urgent need for combination protocols that can increase the therapeutic success in GC therapy. Synergism is the most important requirement for the success of drug combinations in cancer therapy. Besides the choice of anti-cancer agents included in combination protocols, the order of application and the time interval between drug applications, are important determinants of synergism. In this study, we aim to test whether sequential application of conventional chemotherapeutic-molecular targeted agent pairs can transform antagonistic response into synergistic response in GC. To achieve the goals of this study, we have screened dual combinations of five different chemotherapeutics from anthracyclins, platinium derivatives, taxanes, fluoropyrimidines and topoisomerase inhibitors, and three different molecular-targeted agents targeting EGFR, mTOR or c-Met in four different GC cell models to identify synergistic and antagonistic drug pairs. The most antagonistic drug pairs are selected to test whether sequential application schedules can transform antagonism into synergism for these drug pairs. Drug pairs that display strongest synergism in concomitant applications are also further analyzed in detail to investigate their potential in GC treatment. The degree of synergism is measured with Chou-Talalay Method, and apoptosis, autophagy and cell cycle responses were investigated to identify possible molecular mechanisms of synergism. Our data shows that sequential application schedules can transform antagonism into synergism. We believe that the treatment schedules that will be defined in this study can increase the success of chemotherapeutic-molecular targeted agent combinations in GC.
Citation Format: Ozen Leylek, Gulnihal Ozcan. Achieving synergism in combination chemotherapy for gastric cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P023.
Abstract P067: VRN10s, a series of HER2 inhibitors to overcome NRG-mediated drug resistance and acquired-drug resistant HER2 mutations
Authors: Park Chan Mi , Yoo Jihye , Son Mingyeong , Jung Hong-ryul , Park Jin-Hee , Son Jeongbum , Ko Eunhwa , Kim Sunghwan 
Published: December 2021

Abstract
The overexpression of Human epidermal growth factor receptor 3 (HER3) and increased Neuregulin (NRG) production are well known resistance mechanisms to Human epidermal growth factor receptor 2 (HER2) kinase inhibitors. FDA-approved HER2 kinase inhibitors show significantly decreased activities in the presence of NRG, which induces HER2-HER3 heterodimer and activates HER3. VRN10s, HER2 kinase inhibitors, maintained potency to inhibit proliferation of HER2-positive breast cancer cell lines even in the presence NRG1. Western blot confirmed that VRN10s inhibited phosphorylation of HER2 and HER3 as well as downstream signaling, such as AKT and ERK pathways. Emergence of acquired resistance mutations against tyrosine kinase inhibitors (TKI) are also nearly inevitable, but less is known about the acquired drug resistance mutations of the HER2 kinase domain. To predict the drug resistance mutations against two representative HER2 TKIs, Tucatinib (non-covalent) and Neratinib (covalent), we performed an ENU mutagenesis assay and identified HER2 mutant sequences from clonal cells survived from Tucatinib and Neratinib treatment in Ba/F3 HER2 WT cells. There were 9 types of Tucatinib-resistant mutations. The most common Tucatinib-resistant mutation type was T862A/S, which was found in 5 out of total 15 clones. All types of mutations showed 6~70 folds resistance for Tucatinib compared to WT. These mutant types were also resistant against another non-covalent HER2 TKI, Lapatinib. In case of Neratinib, HER2 S963P was derived from two different clones, showing 4~8 folds resistance against Neratinib compared to WT. However, a series of VRN10 was relatively sensitive toward all Tucatinib or Neratinib resistant mutants. Based on our in vitro assay and ENU mutagenesis studies, VRN10s can be a new option to overcome HER2 TKI drug resistance derived by HER3 activation or HER2 mutagenesis.
Citation Format: Chan Mi Park, Jihye Yoo, Mingyeong Son, Hong-ryul Jung, Jin-Hee Park, Jeongbum Son, Eunhwa Ko, Sunghwan Kim. VRN10s, a series of HER2 inhibitors to overcome NRG-mediated drug resistance and acquired-drug resistant HER2 mutations [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P067.
Abstract P070: Targeting SOX10 deficient cells to reduce resistance to targeted therapy in melanoma
Authors: Capparelli Claudia , Purwin Timothy , Aplin Andrew 
Published: December 2021

Abstract
Cellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, traits that enable tumor cell adaptation to metastatic microenvironments and resistance to targeted therapies. Despite these wide-ranging effects, the key mechanisms that underlie tumor cell plasticity remain poorly understood. We studied the role of SOX10, a neural crest lineage transcription factor, and its role in cutaneous melanoma plasticity. SOX10 was heterogeneously expressed in melanoma patient samples. Loss of SOX10 was sufficient to induce a slow cell cycling phenotype in vitro and in vivo, which was associated with invasive properties including expression of mesenchymal genes and extracellular matrix, as well as tolerance to BRAF and/or MEK inhibitors. Long-term exposure of co-mixtures of SOX10-proficient and SOX10-deficient cells to targeted therapy selected for SOX10 knockout cells. Furthermore, cell lines generated from BRAF-MEK inhibitor resistant xenografts showed dramatic reductions in SOX10 expression. To identify synthetic lethal interactions with SOX10 loss, we screened a drug compound library and identified the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as selectively inducing cell death in SOX10-deficient cells. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delayed the onset of acquired resistance in melanomas in vivo. Together, these data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a novel strategy by selectively eliminating SOX10-deficient cells.
Citation Format: Claudia Capparelli, Timothy Purwin, Andrew Aplin. Targeting SOX10 deficient cells to reduce resistance to targeted therapy in melanoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P070.
Abstract P089: Discovery of novel small-molecule inhibitors for an epigenetic modulator WDR5
Authors: Huang Cindy , Guo Shirley , Cao Ping 
Published: December 2021

Abstract
WDR5, the histone H3 lysine 4 (H3K4) presenter WD repeat-containing protein 5, is a widely expressed protein that forms complexes with H3K4 methyltransferases MLL1-MLL4 and partner proteins including RBBP5, ASH2L, DPY30, and MYC. It plays an important role in epigenetic machinery assembly, transcriptional regulation, and chromatin regulation. As a result, WDR5 has become an increasingly attractive target for therapeutic intervention against cancers, including mixed-lineage leukemia, neuroblastoma, breast cancer, bladder cancer, pancreatic cancer, and colorectal cancer. Using its proprietary chemoproteomic platform IMTACTM (Isobaric Mass Tagged Affinity Characterization), BridGene has screened its unique covalent library against live-cell proteomes and discovered small-molecule ligands for hundreds of hard-to-drug targets, including transcription factors, splicing factors, epigenetic modulators, and E3 ligases. WDR5 is among these targets that BridGene has discovered a novel ligand for. Preliminary characterization of the “hit” compound, BGS1989, showed that it interacts with WDR5 in a dose-dependent manner, and it can inhibit MLL1 methyltransferase activity at low µM potency. After one round of chemical optimization, we identified an improved inhibitor BGS2597 that has ~200 nM potency in the WDR5-MLL interaction and H3K4 methylation assays. Additional optimizations are being conducted to further improve BGS2597’s activity and selectivity for WDR5. Comprehensive characterizations are being performed to delineate which of WDR5’s functions are modulated by BGS2597. The WDR5 inhibitor discovered using IMTACTM platform provides an excellent starting point for the development of new drugs targeting WDR5-dependent cancers.
Citation Format: Cindy Huang, Shirley Guo, Ping Cao. Discovery of novel small-molecule inhibitors for an epigenetic modulator WDR5 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P089.
Abstract P101: Combined metronomic chemo-immunotherapy in head and neck cancers: An experience from the developing and resource poor country
Authors: Madabhavi Irappa , Sarkar Malay , Quy Pham Nguyen , Patel Apurva 
Published: December 2021

Abstract
Background: Head and Neck squamous cell carcinomas (HNSCC) have proven to be inherently resistant to systemic treatments; with limited treatment option after progression on systemic chemotherapy in HNSCCs Immunotherapy has a role to play with improved results. Methods: All 7 patients with advanced, metastatic-HNSCCs, received Inj. Nivolumab 240mg flat dose or 3mg per kg, intravenously every 2 weekly along with low dose capecitabine 500mg twice a day, were prospectively assessed. Patient’s clinical, hematological and staging characteristics were described and Clinical Benefit Rate (CBR) was calculated. Results: Total 7 patients received the combined metronomic chemo-immunotherapy (CMCI). Majority of patients were belonging to ECOG-PS 1(66%), with all patients being in stage IV disease. Three, three &one patient received Immunotherapy as 5th, 3rd and 4th line of therapy respectively. Nivolumab and low dose Capecitabine was used in all 7 patients. CBR was seen in 71.42% (5/7) patients, one patient died due hepatitis and hepatic encephalopathy, and one patient was having progressive disease, and one patient with stable disease discontinued of treatment because of financial constraints and kept on capecitabine alone. Majority tolerated therapy well with no grade 3/4 Immune related adverse events (IRAEs). One patient required supportive therapy with packed red cell transfusion and Albumin infusions. Conclusions: To conclude nivolumab along with metronomic chemotherapy with low dose capecitabine was very well tolerated and exhibited antitumor activity with CBR of 71% in extensively pretreated patients with HNSCCs. Additional studies of Nivolumab and metronomic chemotherapy and immuno-immuno combination therapy in these diseases are ongoing.
Citation Format: Irappa Madabhavi, Malay Sarkar, Pham Nguyen Quy, Apurva Patel. Combined metronomic chemo-immunotherapy in head and neck cancers: An experience from the developing and resource poor country [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P101.
Abstract P135: Systemic targeting of a CNS tumor (medulloblastoma) using a novel cell-penetrating, nucleic acid binding, monoclonal antibody
Authors: Quijano Elias , Khang Minsoo , Turner Bruce C. , Squinto Stephen , Bindra Ranjit , Saltzman W. Mark , Glazer Peter 
Published: December 2021

Abstract
Targeting tumors of the central nervous system remains challenging given the physiological barriers preventing the delivery of therapeutics across the blood brain barrier (BBB). This is particularly true for nucleic acids, which degrade rapidly in serum and often fail to penetrate cells even with proper formulation into AAVs or LNPs. To overcome these barriers, many current efforts rely on invasive methods of delivery, including intrathecal or intraparenchymal injection. Here we report studies evaluating the ability of a novel cell-penetrating antibody, GMAB, to penetrate the BBB and target a CNS model of medulloblastoma (DAOY) following intravenous administration. Studies with fluorescently labeled GMAB demonstrated that the antibody readily penetrated into the CNS following systemic administration, achieving tumor-specific delivery while sparing surrounding normal brain tissue. Subsequent studies with 3p-hpRNA, a known activator of RIG-I, a cytosolic pattern recognition receptor which detects viral RNA and elicits a type-I interferon response, demonstrated that GMAB could deliver RNA ligands to tumors, resulting in significantly reduced intracranial tumor burden 10 days after a single-dose administered systemically while also preventing the development of spinal metastases. These results highlight a novel approach for the systemic delivery of immunostimulatory RNAs in a targeted manner to multiple tumors including often difficult to treat CNS tumors, which may offer treatment advantages over current approaches.
Citation Format: Elias Quijano, Minsoo Khang, Bruce C. Turner, Stephen Squinto, Ranjit Bindra, W. Mark Saltzman, Peter Glazer. Systemic targeting of a CNS tumor (medulloblastoma) using a novel cell-penetrating, nucleic acid binding, monoclonal antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P135.
Abstract P153: Claudin-1 is a therapeutic target for hepatocellular carcinoma
Authors: Roehlen Natascha , Muller Marion , Cherradi Sara , Juehling Frank , Duong Francois H.T. , Almeida Nuno , Zompo Fabio Del , Fernandez Mirian , Riedl Tobias , Saghire Hussein El , Saviano Antonio , Durand Sarah , Ponsolles Clara , Oudot Marine , Felli Emanuele , Pessaux Patrick , Davidson Irwin , Crouchet Emilie , Laquerriere Patrick , Heikenwälder Mathias , Iacone Roberto , Meyer Markus , Elson Greg , Schweighoffer Tamas , Schuster Catherine , Mailly Laurent , Lupberger Joachim , Baumert Thomas F 
Published: December 2021

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the fastest rising and fourth leading cause of cancer death worldwide. While new therapeutic modalities have been recently approved, treatment response and survival in patients remain poor. Claudin-1 (CLDN1) is a cell membrane protein mediating cell-cell adhesion, fate and differentiation. While the function of CLDN1 within tight junctions is well characterized, the role of non-junctional CLDN1 in HCC remains unexplored. Aim and methods: Using humanized monoclonal antibodies (mAbs) targeting specifically the extracellular loop of human non-junctional CLDN1 and a large series of patient-derived cell-based and animal model systems we aimed to investigate the role of CLDN1 as therapeutic target for treatment of HCC. Results: Targeting non-junctional CLDN1 robustly suppressed tumor growth in a large series of patient-derived model systems, including multicellular tumorspheres and patient-derived xenograft (PDX) mouse models. In vivo and ex vivo studies further suggested synergistic efficacy in combination with sorafenib. Mechanistic studies revealed that CLDN1 mAbs suppressed tumor cell proliferation, invasion and stemness by interfering with Src, Wnt-β-catenin and STAT3 signaling. Treatment with humanized anti-CLDN1 mAbs is considered to be safe, as administration in non-human primates and mouse models did not reveal any major toxicity even when high doses largely exceeding the therapeutic need were repeatedly applied. Conclusion: Our results provide robust pre-clinical proof-of-concept for humanized CLDN1-specific mAbs for treatment of HCC. The unique and differentiated mechanism of action has the potential to break the plateau of limited response and survival offered by currently approved therapies.
Citation Format: Natascha Roehlen, Marion Muller, Sara Cherradi, Frank Juehling, Francois H.T. Duong, Nuno Almeida, Fabio Del Zompo, Mirian Fernandez, Tobias Riedl, Hussein El Saghire, Antonio Saviano, Sarah Durand, Clara Ponsolles, Marine Oudot, Emanuele Felli, Patrick Pessaux, Irwin Davidson, Emilie Crouchet, Patrick Laquerriere, Mathias Heikenwälder, Roberto Iacone, Markus Meyer, Greg Elson, Tamas Schweighoffer, Catherine Schuster, Laurent Mailly, Joachim Lupberger, Thomas F Baumert. Claudin-1 is a therapeutic target for hepatocellular carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P153.