bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6426: Novel mechanism of PIM2 inhibition leads to significant effect on solid tumors
Authors: Katsuta Eriko , Takabe Kazuaki , Adjei Alex , Opyrchal Mateusz 
Published: September 2020

Abstract
Background: PIM2 is overexpressed in hematopoietic and solid cancers, and is involved in multiple signaling pathways. In hematologic malignancies, PIM2 has been shown to be a pro-survival factor and demonstrated to be a possible therapeutic target. However, the role of PIM2 as a therapeutic target in solid cancers has not been fully elucidated.
Methods: PIM2 expression was compared between normal and cancer tissues in The Cancer Genome Atlas (TCGA) datasets. Pan-PIM inhibitor treatment, as well as PIM2 overexpression/knockdown technique was utilized to investigate the PIM2 role in solid cancers. Multiple cancer models were utilized for in vitro and in vivo experiments to investigate if PIM2 as a therapeutic target and examine mechanism of anti-tumor activity by JP11646.
Results: PIM2 was overexpressed in several types of cancer tissues, including breast, esophageal, head-neck, kidney, liver and endometrial cancers in TCGA. PIM2 overexpression promoted tumor growth in in vivo breast cancer mouse model. PIM2 inhibition by siRNA as well as pan-PIM inhibitor JP11646 activated apoptosis as seen by increased cleaved PARP. JP11646 treatment inhibited cancer cell proliferation in a dose-dependent manner in vitro in various types of solid cancers, including head-neck, ovarian, breast, prostate, liver, pancreatic, colorectal and non-small cell lung cancers. Interestingly, treatment with pan-PIM inhibitor JP11646 resulted in selective downregulation of PIM2 protein expression, but not PIM1 or PIM3 in breast cancer cell lines, BT549 and MDA-MB-231. The treatment also resulted in downregulation of phosphorylated downstream targets, 4EBP1 and TSC2 in breast cancer cells. However, additional proteasome inhibitor treatment blocked PIM2 downregulation and apoptosis activation was not seen. The result suggests that proteasome complex is required for PIM2 degradation which is necessary to induce apoptosis. JP11646 treatment inhibited tumor growth in breast, liver, pancreas, and non-small cell lung cancer in vivo xenograft models and was compared to multiple standard of care treatments showing advantage in lung tumors.
Conclusion: We found that PIM2 promoted cancer progression in solid tumors. We show novel mechanism of JP11646 targeting PIM2 for degradation and induction of apoptosis. We show that PIM2 may serve as a novel therapeutic target for multiple types of solid cancers with enhanced therapeutic effect through protein degradation rather than kinase inhibition alone.
Citation Format: Eriko Katsuta, Kazuaki Takabe, Alex Adjei, Mateusz Opyrchal. Novel mechanism of PIM2 inhibition leads to significant effect on solid tumors [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 6426.
Abstract 643: Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene
Authors: Amari Keigo , Toda Yuki , Hosogi Shigekuni , Imamura Toshihiko , Ashihara Eishi 
Published: September 2020

Abstract
Mixed-lineage leukemia (MLL)-related leukemia which has MLL rearrangement is an intractable disease. Recently, bromodomain and extra-terminal (BET) inhibitors are promising agents, and clinical trials are undergone. However, drug resistance against BET inhibitors has been reported, therefore, it is important to elucidate its mechanism. In this study, we established OTX015-resistant leukemic cells with MLL-AF5q31 fusion gene (OTX015-R cells) and identified molecules that contribute to drug resistance. In addition, we evaluated whether identified molecules are effective as therapeutic target for BET inhibitor-resistant MLL-related leukemia.
To generate OTX015-R cell line, we cultured MLL-AF5q31 cells in the complete medium containing OTX015 with stepwise increasing concentrations. OTX015-R cells exhibited cross-resistance to various BET inhibitors. In addition, protein expressions of bromodomain-containing protein 4 (Brd4) and Brd4-regulated molecules c-Myc, Cdk6 and Bcl-2 were remarkably increased in OTX015-R cells compared with the parental cells. Furthermore, treatment of Cdk4/6 inhibitor Abemaciclib showed a significant antitumor effect on OTX015-R cells and protein expressions of Brd4 and Brd4-regulated molecules were decreased after Abemaciclib treatment. Abemaciclib exhibits antitumor effects on the parental MLL-AF5q31 cells by induction of cell cycle arrest. On the other hand, interestingly, apoptosis in the OTX015-R cells was induced without cell cycle arrest. These results suggest that Abemaciclib induces apoptosis in OTX015-R cells by another mechanism different from cell cycle regulation. We are going to clarify this mechanism.
In conclusion, BET inhibitor-resistant MLL-AF5q31 cells upregulated expression levels of BRD4 and its downstream molecules. We suggest that Cdk6 is a potent therapeutic target for BET inhibitor-resistant MLL-related leukemias.
Citation Format: Keigo Amari, Yuki Toda, Shigekuni Hosogi, Toshihiko Imamura, Eishi Ashihara. Cdk4/6 inhibitor Abemaciclib overcomes resistance to BET inhibitor in leukemic cells with MLL-AF5q31 fusion gene [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 643.
Abstract 646: CRISPR/Cas9 screening to identify mechanisms of azacitidine failure in myelodysplastic syndrome
Authors: Schieber Michael , Crispino John D. 
Published: September 2020

Abstract
Myelodysplastic syndrome (MDS) is a heterogenous myeloid lineage malignancy characterized by blood cell morphological dysplasia, ineffective clonal hematopoiesis, and risk of secondary transformation to acute myeloid leukemia (sAML). The mainstay of treatment in patients with higher-risk MDS are the hypomethylating agents (HMAs) azacitidine and decitabine, which extend overall survival by approximately 12 to 18 months. Unfortunately, disease relapse and HMA resistance are inevitable and carry a very poor prognosis. Genomic sequencing of large MDS cohorts has led to the identification of recurrent genetic abnormalities in MDS, some of which predict sensitivity to HMA therapy. For example, abnormalities in TET2, but not ASXL1, are associated with a favorable response to the HMAs. However, it is unknown why some patients with otherwise similar clinical features have variable responses to HMA therapy. We hypothesize that there are common cellular mechanisms promoting resistance to HMA therapy and that these can be therapeutically targeted to enhance treatment responses.
To uncover cellular processes promoting HMA treatment failure we performed duplicate genome-wide CRISPR/Cas9 screen in the human MDS-L cell line using resistance to azacitidine as a positive selection readout. MDS-L was established from bone marrow mononuclear cells in a 52-year-old male patient with high-risk MDS. We transduced the Brunello sgRNA CRISPR library into Cas9 expressing MDS-L cells and subjected the cells to azacitidine treatment for 7 days. Cells surviving azacitidine treatment were then expanded and harvested for genomic DNA. High throughput sequencing of the barcoded DNA produced raw reads that were analyzed using the PinAPL-Py web-based software. sgRNAs appearing in duplicate with over 10-fold enrichment compared to the control library were considered significant.
We identified 125 candidate genes involved in HMA resistance from the CRISPR-Cas9 screen. Pathway analysis revealed a significant enrichment of genes involved in lipid metabolism, DNA methylation, and response to small molecule catabolism. Future experiments to validate these candidates as well as test whether they contribute in vivo to HMA resistance are underway. We conclude genome-wide CRISPR-Cas9 screens for drug-resistance in the MDS-L model are feasible and may uncover future therapeutic targets to augment HMA therapy or utilize upon HMA failure.
Citation Format: Michael Schieber, John D. Crispino. CRISPR/Cas9 screening to identify mechanisms of azacitidine failure in myelodysplastic syndrome [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 646.
Abstract 6462: Radiomics features of 18F-fluorodeoxyglucose positron-emission tomography as a novel prognostic signature in colorectal cancer
Authors: Kang Jeonghyun , Clemenceau Jean Rene , Park Sunho , Xu Hongming , Hong Changjin , Hwang Tae Hyun 
Published: September 2020

Abstract
Background: The aim of this study was to investigate the prognostic value of radiomics signatures derived from 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) in patients with colorectal cancer (CRC).
Methods: This was a retrospective, single-center study. From April 2008 to Jan 2014, we identified CRC patients who underwent 18F-FDG-PET before starting any neoadjuvant treatments and surgery. Radiomics features were extracted from the primary lesions identified on 18F-FDG-PET. Patients were divided into a training and a validation set by random sampling. A least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for prognostic signature building with progression-free survival (PFS) using the training data set. Using the calculated radiomics score, a nomogram was developed, and the clinical utility of this nomogram was assessed in the validation set.
Results: Three-hundred-and-eight-one patients with surgically resected CRC patients (training set 228 vs. validation set 153) were included. In the training set, a radiomics signature called a rad_score was generated using two PET-derived features such as Gray Level Run Length Matrix_Long-Run Emphasis (GLRLM_LRE) and Grey-Level Zone Length Matrix_Short-Zone Low Gray-level Emphasis (GLZLM_SZLGE). Patients with a high-rad_score in the training and the validation set had shorter PFS (P &lt; 0.001 in the training set and P = 0.008 in the validation set). In the multivariable analysis with forward selection, presence of lymphovascular invasion (LVI) (hazard ratio [HR] 3.73; 95% confidence interval [CI], 1.63-8.47; P = 0.001), pathological node-positivity (HR 2.52; 95% CI, 1.01-6.26; P = 0.046), and a high rad_score (HR 7.82; 95% CI, 2.36-25.85; P &lt; 0.001) remained independent predictors of a worse prognosis in the training set. The rad_score was also identified as an independent prognostic factor in the validation and the overall set. A radiomics nomogram was developed using the rad_score, pathological node stage, and lymphovascular invasion, and showed good performance in the calibration curve in the validation set.
Conclusions: Textural features, such as GLRLM_LRE and GLZLM_SZLGE, derived from 18F-FDG-PET images may enable more detailed stratification of prognosis in patients with CRC.
Citation Format: Jeonghyun Kang, Jean Rene Clemenceau, Sunho Park, Hongming Xu, Changjin Hong, Tae Hyun Hwang. Radiomics features of 18F-fluorodeoxyglucose positron-emission tomography as a novel prognostic signature in colorectal 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 6462.
Abstract 6474: FAT1 and CASP8 co-mutations are associated with poor prognosis in HPV negative head and neck squamous cell carcinoma
Authors: Yilmaz Emrullah , Lee David , Cowan Andrew , Gan Gregory , Ozbun Michelle , Guo Yan 
Published: September 2020

Abstract
INTRODUCTION: FAT1 alterations with somatic mutations or deletions are observed in head and neck squamous cell carcinomas (HNSCC). These alterations lead to loss of function of FAT1. FAT1 loss of function was known to be associated with aberrant Wnt activation, cell migration and invasion. In this study, we present analysis and outcomes of co-mutations seen in FAT1-mutation positive HNSCC.
METHODS: TCGA data were analyzed for mutation, gene expression data and overall survival. We examined mutation data in 415 HPV negative samples and 72 HPV positive samples. The Fisher's Exact test was used to determine if differences in mutation frequency existed between the different cohorts. Mantel-Cox method was used for overall survival (OS) comparison between the cohorts.
RESULTS: FAT1 somatic mutation was the third most commonly mutated gene in HPV-negative HNSCC while it was not common in HPV-positive HNSCC. FAT1 mutation was seen in 25.8% of HPV negative HNSCC (107/415), while 4.2% (3/72) HPV positive HNSCC had FAT1 mutation. We then analyzed the frequency of co-mutations in FAT1-mutated HPV-negative HNSCC. CDKN2A, NOTCH1, CASP8, FBXW7, ZFHX4, HRAS, DCC, ATR mutations were more common in FAT1-mutated cancers. CASP8 mutation was seen in 24.30% (26 out of 107 samples) of FAT1-mutations positive HPV negative HNSCC, while it was less common in FAT1-mutation negative HNSCC (9.08% 28/308) (P=0.002). The patients with FAT1 and CASP8 co-mutation were associated with shorter overall survival when compared with patients with FAT1-mutation (19.8 months vs 52.3 months P=0.02). FAT1 only or CASP8 only mutation without co-mutation did not affect survival. To determine the mutation impact of the FAT1 and CASP8 mutations in HNSCC, differentially expressed genes between mutated and non-mutated genes were analyzed in HNSCC. CASP8 mutation was the top gene among the genes with somatic mutation in HNSCC and associated with gene expression changes in more than 6000 genes. FAT1 was ranked 11th resulting in differential gene expression in more than 1000 genes.
DISCUSSION: FAT1 somatic mutations are commonly seen in HPV negative HNSCC. We have demonstrated for the first time that CASP8 and FAT1 co-mutations are associated with poor prognosis with decreased overall survival in HPV negative HNSCC. Both CASP8 and FAT1 mutations are among the top genes with mutation impact on differential gene expression in HNSCC suggesting significance of these mutations in HNSCC.
Citation Format: Emrullah Yilmaz, David Lee, Andrew Cowan, Gregory Gan, Michelle Ozbun, Yan Guo. FAT1 and CASP8 co-mutations are associated with poor prognosis in HPV negative head and neck squamous cell carcinoma [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 6474.
Abstract 6484: Cross-linked multimeric pro-peptides of type III collagen (PC3X) in hepatocellular carcinoma - A biomarker that provides additional prognostic value in AFP positive patients
Authors: Jensen Christina , Nielsen Signe H. , Eslam Mohammed , Genovese Federica , Nielsen Mette J. , Vongsuvanh Roslyn , Uchila Raj , van der Poorten David , George Jacob , Karsdal Morten A. , Leeming Diana J. , Willumsen Nicholas 
Published: September 2020

Abstract
Background: Non-invasive biomarkers for diagnosing and prognosing hepatocellular carcinoma (HCC) are urgently needed. Cirrhosis, a consequence of deposition and cross-linking of collagens, underlies HCC in 80-90% of cases, and associates with HCC initiation and progression. We evaluated circulating cross-linked pro-peptides of type III collagen (PC3X) as a diagnostic and prognostic biomarker for HCC.
Methods: PC3X was measured by ELISA in plasma from patients with HCC (n=79), cirrhosis (n=86), non-cirrhotic hepatitis-B infection (n=74) and from healthy controls (n=44). PC3X was compared to the liver fibrosis marker PRO-C3 and the HCC tumor-cell derived marker alpha-fetoprotein (AFP). Diagnostic and prognostic potential was evaluated by AUROC and by calculating hazard ratios (HR) for progression free survival (PFS) and overall survival (OS).
Results: PC3X, PRO-C3 and AFP were significantly elevated in patients with HCC compared to other liver diseases and healthy controls (p=0.0002, p&lt;0.0001). In patients with normal AFP (&lt;20 IU/ml), PC3X and PRO-C3 separated HCC from cirrhosis with an AUROC of 0.69 and 0.67, respectively. High PC3X and AFP predicted for poor PFS (HRPC3X=1.80, p=0.032; HRAFP=1.70, p=0.031) and OS (HRPC3X=2.12, p=0.024; HRAFP=2.55; p=0.003), whereas PRO-C3 did not (PFS: HR=1.19, p=0.059 and OS: HR=1.12, p=0.324). PC3X was independent of AFP (PFS: HR=1.74, p=0.045 and OS: HR=2.21, p=0.018) and combining the two improved prognostic value (PFS: HR=2.66, p=0.004 and OS: HR=5.86, p&lt;0.0001).
Conclusions: PC3X is associated with HCC independent of AFP and provides diagnostic and prognostic value for HCC patients. If validated, this suggests that PC3X has biomarker potential for HCC.
Citation Format: Christina Jensen, Signe H. Nielsen, Mohammed Eslam, Federica Genovese, Mette J. Nielsen, Roslyn Vongsuvanh, Raj Uchila, David van der Poorten, Jacob George, Morten A. Karsdal, Diana J. Leeming, Nicholas Willumsen. Cross-linked multimeric pro-peptides of type III collagen (PC3X) in hepatocellular carcinoma - A biomarker that provides additional prognostic value in AFP positive patients [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 6484.
Abstract 6512: Tissue engineered metastases to improve cancer immunotherapy
Authors: Sultanpuram Nikhila Reddy 
Published: September 2020

Abstract
Background: Radiotherapy can induce the abscopal effect when combined with immune checkpoint inhibition. The main limitations to this treatment are the lack of control over the tumor microenvironment and the tumor is not amendable for radiosurgery. To overcome this, we hypothesize that using ex-vivo engineered cancer metastases treated with radiotherapy can improve the impact of the abscopal effect, as the immune cascade reaction is radiotherapy dose dependent and tumors can be exposed to higher amounts of radiation ex-vivo without the risk of radiation toxicity using our tissue engineered metastases model to boost immune response.
Methods: Using B16F10 as a model, we first engineered B16F10 lung metastasis ex-vivo using decellularized rat lung biomatrix scaffolds. The engineered lung metastases were then lethally irradiated with 100 Gy of radiotherapy. The cells were then injected subcutaneously into tumor bearing C57BL6 mice in combination with anti PD-1 checkpoint inhibitor. Experimental groups included: no treatment, anti PD-1 only, cell lysate with and without anti PD-1, and irradiated engineered metastases with and without anti PD-1. All the mice were inoculated with 50,000 plastic grown B16F10 cells. On days 3, 6, and 9 the mice received immunotherapy and radiotherapy combinations based on their respective groups. The tumors were then analyzed by flow cytometry and IHC staining for different T cell populations.
Results: We successfully engineered B16F10 lung metastasis ex vivo. We then demonstrated that mice treated irradiated engineered lung metastasis had significantly better survival than any other treatment arms with median survival twice that of irradiated cells (P &lt;0.01). Correlative studies showed that mice that received irradiated engineered metastasis had increased CD8+ cells and lower Treg cells when compared to other experimental groups. This indicates that engineered metastasis increased immune activation and response to tumor.
Conclusions: Our data demonstrates that engineered metastases can indeed improve cancer immunotherapy and induce a robust abscopal/vaccine effect.
Citation Format: Nikhila Reddy Sultanpuram. Tissue engineered metastases to improve cancer immunotherapy [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 6512.
Abstract 6524: A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) shows potent anti-tumor effect through tumor-directed T cell activation
Authors: Song Moo Young , Lee Eun-Jung , Chung Hyejin , Lee Yangsoon , Park Young Bong , Jee Min Hyeok , Kim KyeongBae , Ju Mikyeong , Lee Jun Kyung , Choi Byung Hyun , Park Ju Young , Kim DaeWon , Kim Junhwan , Ahn Sujin , Ahn Kyoung Kyu , Park Kyeongsu , Jung Uijung , Son Wonjun , Eom Jaehyun , Kim Eunjung , Yeom Donghoon , Ahn Jinhyung , Song Daehae , Sung Byungje , You Weon-kyoo , Kim Jong Gyun , Oh Se-Woong , Jung Jaeho 
Published: September 2020

Abstract
4-1BB (TNFSF9, CD137) is a member of the tumor necrosis factor receptor superfamily that functions as a potent costimulator to immune cells, especially T-cell. Although current 4-1BB-targeted strong agonistic antibody exhibit a considerable anti-tumor effect through T cell activation, it has a limitation of liver toxicity. To overcome the challenges of targeting the 4-1BB, we developed a bispecific antibody that can induce tumor-directed T cell activation.
A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) targets human epidermal growth factor receptor 2 (HER2) and 4-1BB simultaneously and binds to both targets with high affinity. YH32367 (ABL105) exhibited a strong activation of 4-1BB signal in tumor cells expressing HER2 such as NCI-N87, BT474 and HCC1954 cell lines. In co-culture assay using human peripheral blood mononuclear cell (hPBMC) and HER2-expressing tumor cells, YH32367 (ABL105) stimulated IFN-γ secretion from hPBMC and thereby induced tumor cell lysis. The anti-tumor efficacy of YH32367 (ABL105) was evaluated in HCC1954-bearing hPBMC engrafted humanized mice and MC38/hHER2-bearing h4-1BB knock-in mice. YH32367 (ABL105) had more potent efficacy on tumor growth inhibition in both mouse models compared to the equimolar dosing of trastuzumab. Peripheral T cell increase was not observed in these studies. In particular, YH32367 (ABL105) showed a tumor regression in MC38/hHER2-bearing h4-1BB knock-in mice.
In conclusion, YH32367 (ABL105) significantly inhibited tumor growth in a HER2 expression dependent manner and showed potent in vivo efficacy through tumor-directed T cell activation without non-specific systemic T-cell activation.
Citation Format: Moo Young Song, Eun-Jung Lee, Hyejin Chung, Yangsoon Lee, Young Bong Park, Min Hyeok Jee, KyeongBae Kim, Mikyeong Ju, Jun Kyung Lee, Byung Hyun Choi, Ju Young Park, DaeWon Kim, Junhwan Kim, Sujin Ahn, Kyoung Kyu Ahn, Kyeongsu Park, Uijung Jung, Wonjun Son, Jaehyun Eom, Eunjung Kim, Donghoon Yeom, Jinhyung Ahn, Daehae Song, Byungje Sung, Weon-kyoo You, Jong Gyun Kim, Se-Woong Oh, Jaeho Jung. A novel HER2/4-1BB bispecific antibody, YH32367 (ABL105) shows potent anti-tumor effect through tumor-directed T cell activation [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 6524.