bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LBA043: mRNA expression of mTOR signaling components as potential predictive biomarker in pancreatic neuroendocrine neoplasms
Authors: Wolfshöfer Sebastian , Lock Adrian C , Kaemmerer Daniel , Wirtz Ralph M , Briest Franziska , Haugvik Sven P , Buchholz Malte , Rinke Anja , Arsenic Ruza , Pavel Marianne , Hörsch Dieter , Koch Arend , Grabowski Patricia
Published: December 2021

Medical therapeutic options for the treatment of well-differentiated pancreatic neuroendocrine neoplasms (pNENs) include the mTOR pathway inhibitor everolimus (in combination with 5-Fluorouracil). Criteria to assess prognosis in pNEN patients are still limited, as biomarkers to predict the therapeutic response are still unknown. Several studies could show aberrant mTOR signaling pathway activity at different levels of the signaling cascade in pNENs. In this study, we analyzed the mRNA expression of different mTOR pathway components in well-differentiated pNENs, in order to identify potential prognostic and predictive biomarkers. In this retrospective multicenter study, real-time quantitative TaqMan reverse transcriptase-polymerase chain reaction was used to analyze mRNA expression of eleven different mTOR pathway genes (IGF-1, IGFBP-3, PIK3CA, AKT-1, MTOR, MLST8, DEPTOR, RAPTOR, RICTOR, 4EBP1 und VEGF-A), in tumor tissue of 75 patients with well-differentiated pNENs in comparison to normal pancreatic tissue. Relative gene expression was determined according to the 40-ΔCT method using CALM2 as housekeeping gene. The analysis of mRNA expression levels of the aforementioned eleven genes indicated an increased mTOR signaling activity in pNENs. A distinct linear correlation only occurred between MTOR and AKT-1. Clear association between mRNA expression and a clinical feature was only found for RAPTOR: High RAPTOR mRNA expression was significantly correlated with better overall survival in unselected patients. No prediction to everolimus treatment response could be deduced by mRNA expression analysis in a small subgroup of 21 patients. Even though mRNA expression of different mTOR pathway components indicated an enhanced activity of this signaling cascade in tumor tissue of pNEN patients, we could not identify a statistical significant parameter useful for prediction of everolimus treatment response. The predictive value of this study is limited due to the low number of patients who received treatment with everolimus. Further prospective studies analyzing the predictive value of the expression of mTOR pathway genes are desirable.

Citation Format: Sebastian Wolfshöfer, Adrian C Lock, Daniel Kaemmerer, Ralph M Wirtz, Franziska Briest, Sven P Haugvik, Malte Buchholz, Anja Rinke, Ruza Arsenic, Marianne Pavel, Dieter Hörsch, Arend Koch, Patricia Grabowski. mRNA expression of mTOR signaling components as potential predictive biomarker in pancreatic neuroendocrine neoplasms [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 LBA043.
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

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 > 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

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

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

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

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

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

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

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

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.
Abstract P156: Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM
Authors: Zhang Vivian , Huang Cindy , Zhang Chao , Cao Ping
Published: December 2021

Small-molecule drugs exert their therapeutic effects through binding and modulating functions of their target proteins. While most approved drugs have defined target(s), a comprehensive target map is generally lacking for clinical and experimental drugs. This limits both understandings of a drug’s actions and hampers further optimization. Leveraging its proprietary chemoproteomic platform IMTACTM, BridGene Biosciences has developed an approach to generate more comprehensive target maps for approved small-molecule drugs. This approach can also be applied to drug candidates. The approach was successfully applied to a covalent drug ibrutinib and a non-covalent drug sunitinib, revealing previously unknown targets of these drugs. The drug, sunitinib or ibrutinib, was first chemically modified to generate probe compounds, which were then treated on live cells. Quantitative mass spec analysis of the resulting proteomes was performed to identify the binding targets and quantify their apparent binding affinity to the drug. The identified probe-binding proteins were then ranked based on their apparent binding affinity to determine the proteome-wide selectivity to the drug. BridGene’s IMTACTM profiling verified BTK to be the top target and two other kinases (BLK and TEC) to be prominent targets of ibrutinib in Ramos cells. Analogous IMTACTM profiling confirmed sunitinib’s binding to over a dozen of protein kinases with high to moderate affinity in Ramos cells. The kinase targets of sunitinib in Ramos cells include BLK, LYN, PTK2B, etc. Importantly, non-kinase targets included metabolic enzymes were also identified for ibrutinib and sunitinib in the IMTACTM profiling. The binding of the drugs to select new targets was verified using biochemical or binding assays. Our study demonstrates that IMTACTM profiling is a powerful approach for generating comprehensive target maps for clinical and experimental drugs, both covalent and non-covalent ones. Having target scope information will be invaluable at various stages of drug discovery and development, such as the repurposing of existing drugs, the optimization of drug candidates, as well as target identification and deconvolution for phenotypic screening hits.

Citation Format: Vivian Zhang, Cindy Huang, Chao Zhang, Ping Cao. Identification of previously unknown targets for approved small-molecule drugs using chemoproteomic platform IMTACTM [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 P156.
Abstract P172: Rubber- and amoeba-like RNA nanoparticles facilitate drug delivery for lung cancer
Authors: Li Xin , Ellipilli Satheesh , Wang Hongzhi , Lee Wen-Jui , Ho Yuan Soon , Guo Peixuan
Published: December 2021

Lung cancer is the leading cause of cancer death in the United States. Here we report the utilization of the special rubber- and amoeba-like property of RNA nanoparticles to deliver two kinds of anticancer drugs for highly efficient regression of lung cancer. Conjugation of the chemical drugs to RNA nanoparticle enhance the solubility of the drug by 32,000-fold. 5% of the RNA/drug complexes reached the tumor within 30 minutes after systemic injection, and those that did not reach the tumor were excreted from the kidney and found in urine 30 minutes after IV injection. RNA nanoparticles loaded with drugs significantly inhibited the tumor growth in the A549 xenograft mouse model without the need for targeting ligand. This could be explained by several factors, such as the deformative property, the longer circulation time, the passive accumulation, and the quick renal excretion time of the RNA/drug complex.

Citation Format: Xin Li, Satheesh Ellipilli, Hongzhi Wang, Wen-Jui Lee, Yuan Soon Ho, Peixuan Guo. Rubber- and amoeba-like RNA nanoparticles facilitate drug delivery for lung cancer [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 P172.
Abstract P214: MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies
Authors: Briggs Kimberly J. , Cottrell Kevin M. , Tonini Matthew R. , Wilker Erik , Gu Lina , Davis Charles B. , Whittington Doug , Gotur Deepali , Jahic Haris , Goldstein Matthew J. , Huang Alan , Maxwell John P.
Published: December 2021

PRMT5 is a type II arginine methyltransferase that regulates essential cellular functions via symmetric dimethylation of target proteins involved in spliceosome regulation, cell cycle progression, apoptosis, the DNA-damage response, and other functions. PRMT5 dependence in cells with MTAP deletions is a strong and prevalent synthetic lethal interaction. Due to their mechanisms of action, existing clinical PRMT5 inhibitors do not recapitulate the selectivity for MTAPnull cells demonstrated by genetic perturbation. Given that MTAP deletion occurs in approximately 10-15% of all human cancer[i],[ii],[iii], a molecule that selectively kills MTAPnull cancer cells provides an important opportunity to deliver a targeted treatment to a significant patient population. We have discovered small molecules that exhibit MTA-cooperative PRMT5 binding and selectively kill MTAPnull cancer cells. Striking MTAP-dependent viability effects are demonstrated in MTAP-isogenic cell lines representing multiple lineages, and in a multi-lineage cell line panel comprised of 200 cancer cell lines. Furthermore, oral administration of an MTAPnull-selective PRMT5 inhibitor demonstrates dose-dependent antitumor activity and strong regressions across multiple histologies in both cancer cell line and patient-derived xenografts. These data suggest the therapeutic potential of MTAPnull-selective PRMT5 inhibitors in MTAP-deleted cancers. [i] Cerami et al., 2012 [ii] Gao et al., 2013 [iii] Lee et al., 2014

Citation Format: Kimberly J. Briggs, Kevin M. Cottrell, Matthew R. Tonini, Erik Wilker, Lina Gu, Charles B. Davis, Doug Whittington, Deepali Gotur, Haris Jahic, Matthew J. Goldstein, Alan Huang, John P. Maxwell. MTAPnull-selective PRMT5 inhibitors drive regressions in MTAP-deleted xenograft models across histologies [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 P214.
Abstract P229: Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers
Authors: Han Yoon-Chi , Ng Pui Yee , Schulz Ryan , Yang Shao Ning , Lelo Alana , Shin Luisa , O'Connor Matthew , Jewett Ivan , Ishiyama Noboru , Romashko Darlene , Thakur Shalabh , Salomatov Andrei , Smith Sherri , Buck Elizabeth , Roberts Christopher , Lucas Matthew , Lin Tai-An
Published: December 2021

The canonical BRAF V600E (Class I) mutation is a potent oncogene uniquely active as a RAS-independent monomer, successfully targeted by several FDA-approved inhibitors. However, these first-generation BRAF inhibitors are not active against non-canonical BRAF oncogenic mutations, including BRAF-fusions, that drive RAS-independent (Class II) or RAS-dependent (Class III) dimers. As such, developing inhibitors directed against dimeric BRAF oncogenic mutations that avoid paradoxical activation is a major unmet clinical need. We applied proprietary Mutation-Allostery-Pharmacology (MAP) platform technology developed by Black Diamond Therapeutics to identify and validate a group of previously uncharacterized non-canonical oncogenic Class II and Class III BRAF mutation clusters. We further demonstrate that this ensemble of novel and previously validated non-canonical oncogenic BRAF mutants can form the basis of a differentiated drug discovery program aimed at identifying small molecules that potently and selectively target this family of dimeric BRAF mutations. Herein, we describe a small molecule inhibitor, BDTX BRAF-A, with potent anti-proliferative activity directed against tumor cells expressing a wide spectrum of non-canonical Class II/III mutations. This broad activity (“MasterKey” profile) of BDTX BRAF-A is further demonstrated in cell lines that harbor endogenous oncogenic dimer-inducing BRAF mutations and in various solid tumor patient-derived xenograft (PDX) models ex vivo. Importantly, BDTX BRAF-A did not induce paradoxical RAF activation characteristic of Class I BRAF inhibitors. Finally, BDTX BRAF-A achieves robust anti-tumor efficacy and target engagement of dimeric BRAF oncogenes in mouse models. These data support the continued development of rationally designed molecules targeting a broad range of non-canonical BRAF dimer-promoting mutations to extend the prospect of precision medicine in patients.

Citation Format: Yoon-Chi Han, Pui Yee Ng, Ryan Schulz, Shao Ning Yang, Alana Lelo, Luisa Shin, Matthew O'Connor, Ivan Jewett, Noboru Ishiyama, Darlene Romashko, Shalabh Thakur, Andrei Salomatov, Sherri Smith, Elizabeth Buck, Christopher Roberts, Matthew Lucas, Tai-An Lin. Pre-clinical evaluation of next-generation inhibitor targeting a wide spectrum of oncogenic BRAF dimers [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 P229.
Maternal Serum and Cord Blood Leptin Concentrations at Delivery in Normal Pregnancies and in Pregnancies Complicated by Intrauterine Growth Restriction
Authors: Stefaniak Małgorzata , Dmoch-Gajzlerska Ewa
Published: December 2021

Introduction: Leptin is a polypeptide hormone, and in pregnancy, it is secreted by the placenta and maternal and fetal adipose tissues. Normal leptin production is a factor responsible for uncomplicated gestation, embryo development, and fetal growth. The study compared maternal serum and cord blood leptin concentrations at delivery in normal pregnancies and in pregnancies complicated by intrauterine growth restriction (IUGR). Methods: The study was performed in 25 pregnant women with isolated IUGR and in 194 pregnant women without any complications. Leptin concentrations in maternal serum and in cord blood samples collected at delivery were measured by ELISA and subsequently analyzed by maternal body mass index (BMI), mode of delivery, and infant gender and birth weight. For comparative analyses of normally distributed variables, parametric tests were used, that is, the Student t test and a one-way ANOVA. The nonparametric Mann-Whitney test was used when the distribution was not normal. The Pearson correlation coefficient was calculated to assess the correlation between normally distributed variables (p < 0.05). Results: In pregnancies complicated by IUGR, the mean maternal serum leptin concentration at delivery was significantly higher (52.73 ± 30.49 ng/mL) than in normal pregnancies (37.17 ± 28.07 ng/mL) (p = 0.01). The mean cord blood leptin concentration in pregnancies complicated by IUGR was 7.97 ± 4.46 ng/mL and significantly lower than in normal pregnancies (14.78 ± 15.97 ng/mL) (p = 0.04). In normal pregnancies, but not in pregnancies complicated by IUGR, a statistically significant correlation was established between maternal serum leptin concentrations and maternal BMI at delivery (r = 0.22; p = 0.00). No statistically significant correlation was found between cord blood leptin concentrations and maternal BMI in either study subjects or controls. In normal pregnancies, but not in pregnancies complicated by IUGR, a strong correlation was observed between cord blood leptin concentrations and birth weight (r = 0.23; p = 0.00). Conclusions: Elevated maternal blood leptin concentrations in pregnancies complicated by IUGR may indicate a significant adverse effect of elevated leptin on fetal growth. The differences in leptin concentrations, measured in maternal serum and in cord blood, between the study subjects and controls suggest that deregulated leptin levels may increase the risk of obstetric complications associated with placental insufficiency.
Effectiveness of Emollients in the Prevention of Atopic Dermatitis in Infants: A Meta-Analysis
Authors: Xu Di , Stengel Rainer , Sun Pengfei
Published: December 2021

Background: Atopic dermatitis (AD) is a chronic skin disease characterized by dry skin, severe itching, inflammation and impaired quality of life. Moisturizing is an integral part of treatment for AD, but its potential for prevention of AD is unclear. Objective: To evaluate whether the early use of emollients in infancy can prevent later development of AD. Methods: We searched Medline, Embase, Web of Science, PubMed, Cochrane Library and other databases to collect randomized controlled trials on early use of emollients in infants for a meta-analysis. Results: Nine articles were included. The OR value for incidence rate was 0.7 (95% CI: 0.48–1.01). No significant publication bias was found by Egger’s test. The sensitivity analysis indicated that the final conclusion was reliable. Conclusions: We found that the difference in incidence rate of AD between the experimental and control groups was not statistically significant. However, due to different methods of using emollients, different follow-up times and different sample sizes included in this meta-analysis, a definitive conclusion could not be reached in this study. In the future, it is still necessary to carry out randomized controlled, multicenter, large-sample trials with an excellent study design and high methodological quality on early application of emollients in high-risk infants to prevent AD.
Molecular Characterization, Virulence Determinants, and Antimicrobial Resistance Profile of Methicillin-Resistant Staphylococcus aureus in the North of Iran; a High Prevalence of ST239-SCCmec III/t037 Clone
Authors: Ying Hao , Mahmudiono Trias , Alghazali Tawfeeq , Abdelbasset Walid Kamal , Khadivar Parand , Rahimi Somayeh , Amini Abolfazl
Published: December 2021

Objectives: Emergence and prevalence of methicillin-resistant Staphylococcus aureus (MRSA) have become a major universal health concern, limiting therapeutic options. Methods: A total number of 37 MRSA isolates, including 19 clinical isolates from hospitalized patients and 18 colonizing isolates from health care workers were identified from 3 hospitals, in Gorgan, North of Iran. Antimicrobial susceptibility test was performed using the disk diffusion method and E-test. The presence of virulence and antibiotic resistance determinants were evaluated by PCR. The genotypical characterization was further analyzed using multi-locus sequence, spa, staphylococcal cassette chromosome, mec (SCCmec), and agr typing. Results: The frequency of MRSA among S. aureus isolates was 38.14% (37/97). The most frequent S. aureus resistant isolates were found to be obstinate against penicillin (98%) and gentamicin (82.5%). Additionally, the lowest resistance rates were found against daptomycin (0%), vancomycin (2.7%), and quinupristin-dalfopristin (5.4%). All MRSA isolates were susceptible to daptomycin with minimum inhibitory concentration (MIC)50/MIC90 of 0.25/0.5 μg/mL. One isolate belonging to sequence type 239 (ST239)-SCCmecIII/t037 clone (MIC ≥16 μg/mL) was resistant to vancomycin. All but 1 isolate that shares ST22-SCCmec IV/t790 strain were positive for both tsst and pvl genes. The most predominant MRSA isolates (27%) were associated with ST239-SCCmec III/t037, and ST239-SCCmec III/t924 (16.2%) clones, subsequently. In our study, circulating MRSA strains were genetically diverse with a high prevalence of ST239-SCCmec III/t037 clone. Conclusion: These findings emphasize the need for future and continuous surveillance studies on MRSA to prevent the dissemination of existing multidrug resistance MRSA clones in an effective manner.
Mechanisms of Flow-Mediated Dilation of Pial Collaterals and the Effect of Hypertension
Authors: Li Zhaojin , Cipolla Marilyn J.
Published: December 2021

Leptomeningeal anastomoses are small distal anastomotic vessels also known as pial collaterals in the brain. These vessels redirect blood flow during an occlusion and are important for stroke treatment and outcome. Pial collaterals have unique hemodynamic forces and experience significantly increased luminal flow and shear stress after the onset of ischemic stroke. However, there is limited knowledge of how pial collaterals respond to flow and shear stress, and whether this response is altered in chronic hypertension. Using an in vitro system, pial collaterals from normotensive and hypertensive rats (n=6–8/group) were isolated and luminal flow was induced with intravascular pressure maintained at 40 mm Hg. Collateral lumen diameter was measured following each flow rate in the absence or presence of pharmacological inhibitors and activators. Collaterals from male and female Wistar rats dilated similarly to increased flow (2 µL/minute: 58.4±18.7% versus 67.9±7.4%;
P
=0.275), and this response was prevented by inhibition of the transient receptor potential vanilloid type 4 channel, as well as inhibitors of nitric oxide and intermediate-conductance calcium-activated potassium channels, suggesting shear stress-induced activation of this pathway was involved. However, the vasodilation was significantly impaired in hypertensive rats (2 µL/minute: 17.7±7.7%), which was restored by inhibitors of reactive oxygen species and mimicked by angiotensin II. Thus, flow- and shear stress-induced vasodilation of pial collaterals appears to be an important stimulus for increasing collateral flow during large vessel occlusion. Impairment of this response during chronic hypertension may be related to poorly engaged pial collaterals during ischemic stroke in hypertensive subjects.
Morphological and molecular characterization of two species of Gelidium (Gelidiales, Rhodophyta) from Mexico: G. nayaritense sp. nov. and the new record of G. sanyaense
Authors: QUIROZ-GONZÁLEZ NATALY , PONCE-MÁRQUEZ MA. EDITH , LÓPEZ-GÓMEZ NORMA , RODRÍGUEZ DENÍ
Published: December 2021

Gelidium pusillum is a species reported from the northern Gulf of California to the tropical region of the Mexican Pacific, but there is wide morphological variation among populations. The objective of this research was to evaluate of the Mexican species using morphological and molecular approaches, with the markers rbcL and COI-5P. This study examined 12 samples from four sites in the Mexican tropical Pacific. Phylogenetic analyses resolved these specimens within two clades separated from the topotype material of G. pusillum. The main morphological differences with other Mexican and phylogenetic closely related species were size, branching pattern, branching order, distribution of internal rhizoidal filaments, and shape of the tetrasporangial sori. The sequence divergences between these clades and the morphological differences support their representing distinct species so that Gelidium nayaritense sp. nov. is proposed for tropical specimens of the Mexican Pacific, whose diagnostic characteristics are the little or absent branching, its small size, as well as the presence of internal rhizoidal filaments concentrated in the subcortex, further G. sanyaense is register for first time from Mexico and Eastern Pacific.
Sustained Wind Forcing and Water Level Anomalies in Annapolis, Maryland
Authors: Davies Alexander R. , Smith Joseph P. , Mandell David S. , Davis George , Wan Forest Y.
Published: December 2021

Like many coastal communities throughout the mid-Atlantic region, relative sea level rise and accelerating instances of coastal nuisance flooding are having a tangible negative impact on economic activity and infrastructure in Annapolis, Maryland. The drivers of coastal nuisance flooding, in general, are a superposition of global, regional, and local influences that occur across spatial and temporal scales that determine water levels relative to a coastal datum. Most of the research to date related to coastal flooding has been focused on high-impact episodic events, decomposing the global and regional drivers of sea level rise, or assessing seasonal-to-interannual trends. In this study, we focus specifically on the role of short-duration (hours) meteorological wind forcing on water level anomalies in Annapolis. Annapolis is an ideal location to study these processes because of the orientation of the coast relative to the prevailing wind directions and the long record of reliable data observations. Our results suggest that 3-, 6-, 9-, and 12-h sustained wind forcing significantly influences water level anomalies in Annapolis. Sustained wind forcing out of the northeast, east, southeast, and south is associated with positive water level anomalies, and sustained wind forcing out of the northwest and north is associated with negative water level anomalies. While these observational results suggest a relationship between sustained wind forcing and water level anomalies, a more robust approach is needed to account for other meteorological variables and drivers that occur across a variety of spatial and temporal scales.

Significance Statement

Coastal nuisance flooding, often the result of positive water level anomalies, is having a negative economic impact in Annapolis, Maryland. Coastal flooding research has primarily focused on high-impact episodic events, trends in sea level rise, or seasonal to interannual variability in flooding. In this study we show that short-duration wind forcing (≤12 h) likely has a significant impact on both positive and negative water level anomalies in Annapolis. While this was empirically known by local stakeholders, in this study we attempt to quantify the relationship. These results could help local stakeholders to mitigate against economic and infrastructure losses resulting from coastal nuisance flooding.
We need to use words that we’d use in Brazil, right? A Community-Based Content Validation of a Translated Femicide Risk Assessment Instrument
Authors: Manders Olivia C. , Xavier Hall Casey D. , Vertamatti Maria A. F. , Evans Dabney P. , Campbell Jacquelyn C.
Published: December 2021

The Danger Assessment (DA) is a widely-used risk assessment instrument designed to help women understand their risk of femicide. Currently, no validated tool exists in Brazilian Portuguese. The purpose of this study was to conduct a cross-cultural adaptation of the DA for use in the Brazilian context as a precursor to validation and broader testing among women in Brazil. This study describes a community participatory approach for translation and cultural adaptation of the DA from European to Brazilian Portuguese that engages the target population in the process. Using a three-step process, a final version of the DA-Brazil instrument was developed.