bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5287: TGF-β-acetylated KLF5-Bcl-2 signaling mediates docetaxel resistance in prostate cancer cells
Authors: Li Yixiang , Zhang Baotong , Dong Jin-Tang 
Published: September 2020

Abstract
Purpose: In this study, we explored the role of KLF5 in TGF-β-induced drug resistance in prostate cancer cells to identify novel therapeutic targets.
Procedures: We used DU 145 and PC-3 prostate cancer cell lines in in vitro cell survival assay, colony survival assay, and xenograft mouse model to measure docetaxel (DTX) resistance. TGF-β1, the SB505124 TGF-β receptor I inhibitor, and the ABT-199 Bcl-2 inhibitor were used to determine if Bcl-2 mediates TGFβ induced docetaxel resistance. To measure the function of KLF5 and its acetylation at lysine 369 in drug resistance, stable cell lines were constructed with different forms of KLF5 after the endogenous KLF5 was deleted with the CRISPR-Cas9 system.
Results: We found that TGF-β induced DTX resistance depends on KLF5 expression. As a downstream molecule of TGF-β signaling, acetylated KLF5 at lysine 369 mediated TGF-β-induced DTX resistance. Moreover, acetylated KLF5 induced DTX resistance in xenograft mouse model. Mechanistically, we found that TGF-β and acetylated KLF5 upregulated Bcl-2 transcription, and inhibition of Bcl-2 sensitized cells to DTX. In addition, DTX promoted Bcl-2 degradation via a proteasome dependent pathway, and TGF-β signaling stabilized Bcl-2 via inhibition of Bcl-2 ubiquitination. Lastly, the TGF-β/acetylated KLF5/Bcl-2 signaling axis induced survival disadvantage in prostate cancer patients.
Conclusions: TGF-β induces transcriptional upregulation of Bcl-2 through acetylated KLF5 at lysine 369, and TGF-β stabilizes Bcl-2 via inhibition of DTX-induced Bcl-2 ubiquitination. The TGF-β-acetylated KLF5-Bcl-2 signaling axis is thus a novel mechanism mediating DTX resistance in prostate cancer.
Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. TGF-β-acetylated KLF5-Bcl-2 signaling mediates docetaxel resistance in prostate cancer cells [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 5287.
Abstract 529: Oncostatin M receptor as a therapeutic target of radio-immune therapy in metastatic synovial sarcoma
Authors: Luelling Sarah 
Published: September 2020

Abstract
Synovial sarcoma is a soft tissue malignancy of the muscle tissue which primarily affects adolescents. While it is a rare disease, little advancement has been made in the treatment of this cancer. With an overall survival rate of roughly 40%, the need for new treatments for synovial sarcoma is evident. Oncostatin M Receptor (OSMR) is a type I cytokine receptor and is overexpressed in metastatic synovial sarcoma. OSMR does not have high expression in normal tissues, making it an ideal target for cancer therapy. We hypothesize that by using an anti-OSMR monoclonal antibody conjugated to a radioactive Cu67 isotope, synovial sarcoma can be targeted at both primary and metastatic locations through systemic therapy. Copper 67 is a gamma radiation emitting isotope which is tissue damaging and able to induce cell death in cancer cells. By conjugating the chelating molecule p-SCN-Bn-NOTA to an anti-OSMR antibody, Cu67 was able to be captured to the antibody. Capture efficiency of Cu67 was measured through TLC and found to be 64 % efficient. Binding studies through Surface Plasmon Resonance (SPR) found that the conjugation did not interfere with the binding affinity of the antibody. This data suggests that targeting OSMR through radio-immune therapy is a viable treatment and indicates further testing in animal models.
Citation Format: Sarah Luelling. Oncostatin M receptor as a therapeutic target of radio-immune therapy in metastatic synovial sarcoma [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 529.
Abstract 5293: A molecular classification of gastric cancer in Chilean patients
Authors: Pinto Mauricio P. , Muñoz-Medel Matias , Cordova-Delgado Miguel , Retamal Ignacio N. , Owen Gareth , Bravo Maria Loreto , Armisen Ricardo , Garrido Marcelo 
Published: September 2020

Abstract
Objective: Incidence and mortality rates of gastric cancer (GC) are characterized by their geographical heterogeneity. In Chile, GC is the leading cause of cancer death. To date, GC patients' response to standard therapies remains limited. A molecular classification of GCs may deliver better stratifications. Herein, we obtained clinical data, protein expression and genetic profiles in a cohort of Chilean patients and present a molecular classification that correlated with overall survival (OS) rates.
Methods: A total of 71 patients were included. Clinical data were obtained from medical records; protein expression was analyzed by a Tissue MicroArray. We also performed Next Generation Sequencing to assess p53 status (WT or Mut). Supervised clustering was used to generate a molecular classification. Kaplan-Meier method was used to calculate OS. Hazard ratio was calculated by Cox regression.
Results: We defined 5 GC subgroups: Epstein-Barr virus+ (EBV, n=9; 13%), Microsatellite Instable (MSI, n=9; 13%), E-cadherin loss (EMT-like, n=12; 17%). The remaining patients (those MSS-/EBV-/not EMT-like) were classified either as p53 WT (n=21; 30%) or p53 Mutated (n=20; 28%). According to subgroups, 5-year survival rates were: MSI=77,8%; EBV=43.2%; p53WT=43.5%; p53Mut=25% and EMT-like=16.7%. Hazard ratios for p53Mut and EMT-like were 5.1 (IC 95%: 1.16-22.41; p=0.031) and 6.81 (IC 95%: 1.48-31.24; p=0.014), respectively against the MSI group used as reference. This association is maintained in a multivariate model using age, gender and stage.
Conclusions: Our study defined 5 GC subgroups. These are associated to OS rates. EMT-like and p53Mut subgroups displayed poorer survival. Future studies should explore actionable targets in these subsets in order to improve their survival.
Citation Format: Mauricio P. Pinto, Matias Muñoz-Medel, Miguel Cordova-Delgado, Ignacio N. Retamal, Gareth Owen, Maria Loreto Bravo, Ricardo Armisen, Marcelo Garrido. A molecular classification of gastric cancer in Chilean 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 5293.
Abstract 5321: Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT signaling network and metabolic reprogramming
Authors: Yeung Chi Lam Au , Hu Wen , Zhang Li , Ferri-Borgogno Sammy , Tarapore Rohinton S. , Allen Joshua E. , Lu Karen H. , Mok Samuel C. 
Published: September 2020

Abstract
Uterine serous carcinoma (USC) is the most aggressive subtype of endometrial cancer. Patients with advanced stage USC have poor survival rates and new treatment regimens are lacking. ONC201 is the first clinical bitopic antagonist of dopamine receptor D2 (DRD2), that is well tolerated and currently being investigated in several clinical trials for oncology. ONC206 is a chemical derivative of ONC201 with the same impridone core structure, which is also a DRD2 antagonist that exhibits distinct receptor pharmacology and nanomolar potency in various preclinical cancer models. However, the effects of ONC206 on USC progression and the mechanism of action have not been thoroughly explored. Using both in vitro and in vivo models, and multiple USC cell lines, the effects of ONC206 on cell proliferation and apoptosis were determined. Reverse phase protein arrays (RPPAs) and Western blot analyses were used to determine the effect of ONC206 on the expression of key proteins in various signaling networks in ONC206 treated USC cells. The results showed that ONC206 suppressed USC cell proliferation and induces apoptosis in a dose-dependent manner. Luciferase labeled USC cell ARK1-bearing mice treated with 100mg/kg ONC206 had significantly lower chemiluminescent signals than those treated with the control buffer. RPPA data showed that ONC206 treated USC cells had markedly lower expression signals in p38MAPK, p-AKT, p-S6, and multiple mitochondrial proteins associated with mitochondrial ATP synthesis including MTCO1, and TFAM than the control cells did. Significantly lower ATP levels and cytochrome c oxidase activities in ONC206 treated USC cells than in control cells were demonstrated by luminescent ATP detection assay kit and the cytochrome c oxidase assay kit. These data suggest that ONC206 suppresses USC progression through inhibiting MAPK/AKT network, which subsequently leads to metabolic reprogramming and increased apoptosis. Moreover, by knocking-out DRD2, USC cells became more resistant to ONC206 treatment. This suggested that the effect of ONC206 is likely mediated through its binding to DRD2. ONC206 also showed a synergistic effect with paclitaxel in vitro. Further studies which demonstrate the optimal dosage and the efficacy of treatment of USC using ONC206 are warranted.
Citation Format: Chi Lam Au Yeung, Wen Hu, Li Zhang, Sammy Ferri-Borgogno, Rohinton S. Tarapore, Joshua E. Allen, Karen H. Lu, Samuel C. Mok. Novel imipridone ONC206 inhibits cell proliferation and induces apoptosis in uterine serous cancer through altering MAPK/AKT signaling network and metabolic reprogramming [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 5321.
Abstract 5324: Structure-based design of CDC42/RHOJ effector inhibitors for the treatment of cancer
Authors: Flesher Jessica L. , Jahid Sohail , Ortega Jose A. , La Sala Giuseppina , Brindani Nicoletta , Arencibia Jose M. , Manigrasso Jacopo , Hachey Stephanie , Chen Chi-Fen , Hughes Chris , De Vivo Marco , Ganesan Anand K. 
Published: September 2020

Abstract
The CDC42 family of GTPases (RHOJ, RHOQ, CDC42) control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. While recent studies have developed small molecules that target RAS GTPases, little progress has been made in targeting the related CDC42 family of GTPases for cancer treatment. Here, we use computer-aided drug design to identify a novel class of inhibitors that act on an allosteric pocket in the active form of the CDC42 GTPase, RHOJ. These allosteric inhibitors prevent RHOJ and CDC42 from binding to their downstream effector PAK, while having no effect on the interactions between the closely related GTPase RAC1 and PAK or RAS and its downstream effector RAF. Our lead compound ARN22089 has a druglike profile and can block both tumor growth and tumor angiogenesis in a three-dimensional vascularized microtumor (VMT) model, indicating that ARN22089 blocks RHOJ/CDC42 signaling in both the tumor cell and the tumor endothelium. Short term treatment of nascent melanoma tumors with ARN22089 halted the growth of BRAF mutant autochthonous mouse melanoma tumors, slowed the growth of melanoma patient-derived xenografts, and induced tumor necrosis in PDX models. In summary, we describe a multidisciplinary structure-based drug discovery platform that can identify new RHO family allosteric inhibitors and use this system to identify RHOJ inhibitors that block tumor growth in vivo.
Citation Format: Jessica L. Flesher, Sohail Jahid, Jose A. Ortega, Giuseppina La Sala, Nicoletta Brindani, Jose M. Arencibia, Jacopo Manigrasso, Stephanie Hachey, Chi-Fen Chen, Chris Hughes, Marco De Vivo, Anand K. Ganesan. Structure-based design of CDC42/RHOJ effector inhibitors for the treatment of 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 5324.
Abstract 5339: Paradoxical androgen receptor regulation by small molecule enantiomers
Authors: Patsch Katherin , Liu Chao , Kashemirov Boris , Sura Harish , Zapotoczny Grzegorz , Sun Yuanye , Shah Pavan P. , Katz Jonathan E. , Chilakala Sujatha , Joo Ah Young , Ung Nolan , Aljehani Maya , Sun Ren X. , Agus David B. , Ruderman Daniel , McKenna Charles E. 
Published: September 2020

Abstract
Small molecules that target the androgen receptor (AR) are the mainstay of therapy for lethal castration-resistant prostate cancer (CRPC), but they ultimately lead to resistance and progression to terminal disease. While individual resistance-associated AR mutations have been identified, the underlying mechanisms remain poorly understood. Here, we report a new class of AR-targeting compounds derived from the anti-androgen BMS-641988 (N-((3aR,4R,5R,7R,7aS)-2-(4-cyano-3-(trifluoromethyl)phenyl)-4,7-dimethyl-1,3-dioxooctahydro-1H-4,7-epoxyisoindol-5-yl)ethanesulfonamide) that reveal unexpected biological behavior: as expected, the C-5 (R)-enantiomers are antagonists, however the corresponding (S)-enantiomers, including the previously unknown C-5 (S)-enantiomer of BMS-641988 itself, are potent agonists of AR, with ED50 values comparable to dihydrotestosterone and R1881. A series of in vitro assays that interrogate different steps of AR functionality–including AR binding via fluorescence polarization, nuclear translocation and hyperspeckling via live cell confocal microscopy, ARE-luciferase, and RT qPCR arrays–confirm that the (R)-enantiomers are potent antagonists of AR in multiple cell lines, including AR T877A mutation-expressing LNCaP and AR overexpressing VCaP. While these cells are virtually resistant to BMS-641988, two of the novel derivatives, (R)-USC-1702 and (R)-USC-1707, inhibited their growth with IC50 values in the lower nM range. Importantly, these compounds do not produce the toxic metabolite that led to the clinical failure of BMS-641988. This is the first documented evidence of small molecule enantiomer pairs showing opposite functional effects while targeting AR. This new AR regulation duality augments our understanding of AR function and may have implications for anti-androgen drug development.
Citation Format: Katherin Patsch, Chao Liu, Boris Kashemirov, Harish Sura, Grzegorz Zapotoczny, Yuanye Sun, Pavan P. Shah, Jonathan E. Katz, Sujatha Chilakala, Ah Young Joo, Nolan Ung, Maya Aljehani, Ren X. Sun, David B. Agus, Daniel Ruderman, Charles E. McKenna. Paradoxical androgen receptor regulation by small molecule enantiomers [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 5339.
Abstract 534: Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format
Authors: Zhu Guidong , Ye Jingdong , Ma Jichun , Qin Jingdong , Cai Yi 
Published: September 2020

Abstract
This research aimed to produce anti-claudin18.2 (CLDN 18.2)/anti-PD-L1 bispecific antibodies to enhance the therapeutic index and expand the responsive population of the parent anti-CLDN 18.2 and anti-PD-L1 antibodies through the mechanisms of tumor-specific distribution and synergistic tumor killing. CLDN 18.2 is highly expressed in several tumors but is minimally expressed in normal tissues and a chimeric IgG1 CLDN 18.2 antibody zolbetuximab significantly improved PFS and OS in gastric cancer patients in a CLDN 18.2-dependent manner on the background of EOX. However, the response rate was moderate (~10%), leaving room for further improvement. Anti-PD-L1 antibodies showed remarkable efficacy in lung cancer and melanoma but in various settings of gastric cancer they showed weaker benefits, which warrant optimization. We designed anti-claudin18.2/anti-PD-L1 bispecific antibodies in the SMARTOPTM format, where a single-chain diabody containing optimized CLDN 18.2 and PD-L1 binding variable domains is connected to the Fc domain by linkers that can be optimized by phage display libraries. The bispecific antibodies were selected by affinity at low pH values and slow off-rate to improve the therapeutic window by enhancing tumor retention and preserving or improving binding affinity in the low pH tumor microenvironment. Immunogenicity was optimized by mutating the surface residues and disulfide bonds were inserted to improve stability. A representative bispecific antibody SPX-301 showed comparable binding affinity to the CLDN 18.2 and PD-L1 antigens to the parent antibodies (SPX-101 and durvalumab, respectively). SPX-301 represents a novel anti-claudin18.2/anti-PD-L1 bispecific antibody in the SMARTOPTM format. The format demonstrated excellence retention of antigen binding affinity, high expression levels, minimal aggregation, and straightforward purification. The preclinical characterizations of SPX-301 will also be presented.
Citation Format: Guidong Zhu, Jingdong Ye, Jichun Ma, Jingdong Qin, Yi Cai. Discovery of an anti-claudin18.2/anti-PD-L1 bispecific antibody SPX-301 in the SMARTOPTM format [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 534.
Abstract 535: T-cell recruitment tumor lysis via a novel c-MET/CD3 bispecific antibody
Authors: Huang Lei , Xie Kun , Wang Ruiqin , Gu Hua , Fang Jianmin 
Published: September 2020

Abstract
Anti-receptor tyrosine kinases (RTKs) therapy has been used for the treatment of a number of solid tumors in clinic. C-MET, also known as the hepatocyte growth factor receptor (HGFR), is a representative member of the RTK family. C-MET overexpression is commonly observed in tumor biopsies and associated with poor patient survival. Various kinase inhibitor and monoclonal antibody (e.g. Emibetuzumab and Onartuzumab) have been developed to block the HGF/c-MET interactions, however, those kinase-inhibiting-based therapeutics have shown limited success in clinical trials. There is an urgent need to develop new treatments targeting c-MET to overcome these limitations. Bispecific antibodies that recruit immune cells to the tumor microenvironment have been considered as effective therapeutic candidates. An example of this design strategy is the FDA-approved bispecific antibody blinatumomab. In this study, we have constructed an asymmetric bispecific antibody, which binds both c-MET and CD3, using a novel platform that is monovalent to epitope. Our c-MET/CD3 bispecific antibody showed potent T-cell mediated tumor cells killing in vitro. Meanwhile, this antibody inhibited the phosphorylation of c-MET and downstream signal transduction in tumor cells due to its monovalent nature. In c-MET-overexpressing lung cancer and ovarian cancer xenograft models, c-MET/CD3 bispecific antibody inhibited tumor growth and increased the proportion of activated CD56+ tumor infiltrating lymphocytes. Moreover, in vivo combination therapy with FDA-proved PD-1/PD-L1 antibodies showed higher tumor inhibition than monotherapy in above two tumor models. Collectively, the novel c-MET/CD3 bispecific antibody can provide immunotherapy for c-MET-overexpressing tumors which conventional antibody or small molecular inhibitor might not. These findings also support the immunotherapeutic effects on combination of T-cell dependent bispecific antibody and immune checkpoint blockade.
Citation Format: Lei Huang, Kun Xie, Ruiqin Wang, Hua Gu, Jianmin Fang. T-cell recruitment tumor lysis via a novel c-MET/CD3 bispecific antibody [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 535.
Abstract 5356: Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas
Authors: zhang Zhuoran , Zhao Xingli , Moreira Dayson , Su Yu-Lin , Swiderski Piotr , Forman Stephen , Kwak Larry , Kortylewski Marcin 
Published: September 2020

Abstract
Despite recent advances in the treatment of non-Hodgkin B-cell lymphoma (BCL), significant numbers of patients relapse or remain refractory to current therapies. Treatment resistance in BCL is associated with survival signaling via NF-κB transcription factor. While NF-κB is an attractive molecular target in BCL and many other human cancers, as a transcription factor it remains undruggable. Here, we describe a B-cell-selective NF-κB inhibitor consisting of a NF-κB-specific decoy oligodeoxynucleotide (dODN) conjugated to a type B CpG ODN sequence targeting Toll-like receptor-9 (TLR9)-expressing B-cell lymphoma cells. Bc-NFκBdODN showed efficient uptake by human diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), such as U2932, OCI-Ly3 and Jeko1, respectively. In addition, we confirmed that Bc-NFκBdODN inhibited nuclear translocation and DNA-binding activity of NF-κB together with the expression of CCND2 and MYC target genes. In vitro Bc-NFκBdODN enhanced direct and ionizing radiation-induced cytotoxicity in lymphoma cells. In xenotransplanted models of human U2932 and Ly3 lymphomas, local injections of Bc-NFκBdODN reduced NF-κB activity in whole tumors and effectively arrested lymphoma progression when combined with a single, local 3Gy or 10Gy dose of radiation. In immune-competent mice, intratumoral treatment with Bc-NFκBdODN abrogated growth of directly treated as well as distant A20 lymphomas and triggered CD8+ T cell-mediated anti-tumor immune responses. Bc-NFκBdODN but not control Bc-scrambled oligonucleotides downregulated PD-1 expression on CD8+ and CD4+ T cells, while reducing Treg percentage in tumor draining lymph nodes (TDLN). Bc-NFκBdODN treatment also downregulated PD-L1 on tumor-associated myeloid cells and reduced percentage of tumor-infiltrating M-MDSCs. Our results underscore clinical relevance of NF-κB-specific decoy strategy, which can restore efficacy of standard radiation therapy to benefit patients with resistant or relapsed BCL.
Citation Format: Zhuoran zhang, Xingli Zhao, Dayson Moreira, Yu-Lin Su, Piotr Swiderski, Stephen Forman, Larry Kwak, Marcin Kortylewski. Targeted in vivo delivery of NF-κB decoy oligodeoxynucleotide augments efficacy of radiation therapy against B-cell lymphomas [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 5356.