bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5287: Aggregation of HER2 receptors on the tumor cell surface induced by a novel anti-HER2 bispecific antibody led to enhanced tumor cell growth inhibition
Authors: Deng Lan , Zhao Jie , Meng Xiaoqing , Xiao Aotian , Zhu Zhenping , Huang Haomin 
Published: June 2022

Abstract
Trastuzumab, an anti-HER2 monoclonal antibody developed by Roche, is now a standard of care for treating HER2 overexpressing cancers. However, patients treated with trastuzumab generally develop resistance to the drug within a year after initiation of the treatment. Pertuzumab, another anti-HER2 monoclonal antibody developed by Roche, targets the domain 2 of the HER2 excellular domain (ECD) instead of the domain 4 to which trastuzumab binds and demonstrates enhanced antitumor activities when combined with trastuzumab. Here, we developed a tetravalent bispecific antibody (BsAb) which targets the domain 2 and 4 of the HER2 ECD simultaneously. Using time-lapse microscopy, we showed that the BsAb induced aggregation of HER2 on NCI-N87 tumor cells, possibly indicating that the receptors could be crosslinked by the BsAb intermolecularly. Furthermore, the tetravalent BsAb induced aggregation faster than did the bivalent BsAb. Importantly, the tetravalent BsAbs exhibited superior tumor cell growth inhibition to that of the two parental monoclonal antibodies alone or combined. In line with the aggregation rates, the tetravalent BsAb was also more potent in inhibiting tumor cell growth than that of the bivalent BsAb. Thus we provide a piece of evidence that the BsAbs targeting two distinct domains of HER2 simultaneously might induce the receptor aggregation which might associate with the enhanced inhibition of tumor cell growth.
Citation Format: Lan Deng, Jie Zhao, Xiaoqing Meng, Aotian Xiao, Zhenping Zhu, Haomin Huang. Aggregation of HER2 receptors on the tumor cell surface induced by a novel anti-HER2 bispecific antibody led to enhanced tumor cell growth inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5287.
Abstract 5308: Therapeutical antibody against CD25 mediating depletion of regulatory T cells without interruption of IL-2 signaling enhances antitumor immunity
Authors: Peng Hao , Hu Shuangshuang , Li Yuli , Ding li , Ning Jinying , Wu Guojin 
Published: June 2022

Abstract
Regulatory T cell or suppressor T cell in tumor diminishes immune response to immunotherapy. CD25, the high-affinity receptor subunit for interleukin (IL)-2, is highly expressed on Treg and considered a selective target for Treg depletion. However, CD25 is also expressed on activated effector T cells (Teff), and antibodies against CD25 with blocking IL-2 signaling have limited antitumor activity. Here we developed a humanized antibody against CD25 (H3F1-4V2) without blocking IL-2 signaling. This antibody was derived from hybridoma of mice immunized with CD25-mFc. Two CD25 antibodies Daclizumab and RG6292 were applied as reference antibodies, and Daclizumab blocked IL-2 signaling, and RG6292 did not block IL-2 signaling. H3F1-4V2 had higher affinity to 293T cells overexpressing human CD25 than Daclizumab (EC50=0.4nM vs 0.45nM), with lower Kd (0.88nM vs 1.5nM). Because of high affinities, H3F1-4V2 and Daclizumab both efficiently depleted Treg from PBMC in vitro, while RG6292 depleted Treg with weaker ability because of low affinity to CD25. In the Teff, downstream signaling of IL-2 was analyzed, and Daclizumab significantly decreased pSTAT5, while RG6292 and H3F1-4V2 kept the pSTAT5 level intact. PBMC was cultured in the presence of CD25 antibodies, and Daclizumab inhibited T cell proliferation (ki67+%) and activation (Granzyme B+%), but not for RG6292 and H3F1-4V2. At last, these CD25 antibodies were tested in humanized mice whose CD25 was replaced with human CD25, and MC38 tumor cells were transplanted into these mice.H3F1-4V2 completely suppressed tumor growth, while RG6292 also suppressed tumor growth with weaker efficiency and Daclizumab had little effect on tumor growth. These results suggested H3F1-4V2 was the best candidate targeting CD25 for cancer therapy.
Citation Format: Hao Peng, Shuangshuang Hu, Yuli Li, li Ding, Jinying Ning, Guojin Wu. Therapeutical antibody against CD25 mediating depletion of regulatory T cells without interruption of IL-2 signaling enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5308.
Abstract 5318: Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study
Authors: Howie Lynn Jackson , Chung Ezra M. , Kim Young-Seung , Jung Yujin , Jung Hyunjin , Yoo Stephen 
Published: June 2022

Abstract
Butyrophilin 1A1 (BTN1A1) is a novel immune checkpoint protein that exhibits an expression pattern mutually exclusive to that of PD-1/PD-L1 and may represent a promising therapeutic target for tumors that are anti-PD-1/PD-L1 antibody refractory. BTN1A1 was identified as a potential stress-inducible candidate immune checkpoint using the STCube in vivo immune target discovery platform. Additional analyses revealed that BTN1A1 was highly expressed in multiple human tumor types including urothelial carcinoma and NSCLC, with no overlap between BTN1A1 and PD-1/PDL-1 expression patterns. Mouse studies demonstrated that an anti-BTN1A1 antibody exhibited antitumor activity both as a single agent and in combination with anti-PD-1/PD-L1 or radiation therapy. A humanized anti-BTN1A1 antibody, hSTC810, was developed and found to suppress tumor growth in A549 CDX humanized murine models. Further studies identified Galectin 9 (Gal9) as a BTN1A1 receptor that can form a three protein complex with BTN1A1 and PD-1, thereby suppressing T cell receptor signaling and T cell activation. As high Gal9 expression levels are correlated with poor prognosis in multiple cancers, our results highlight this BTN1A1-Gal9-PD-1 axis as a novel therapeutic target for immunotherapeutic drug development. Given these findings, a first in human study of hSTC810 is in development to evaluate the safety profile of this therapy and to identify a dose for its further evaluation as an anticancer therapy. PK modeling including allometric scaling was performed to conduct simulations to predict the PK profile of hSTC810 after IV administration in humans and to identify possible doses needed to achieve tumor concentrations corresponding to the minimum anticipated biological effect level (MABEL) of 20% receptor occupancy (RO), 80% RO, or 95% RO. The partition coefficient was used to predict concentrations at the tumor site based on predicted serum concentrations. Simulations were performed for 100 subjects after the administration of multiple Q2W doses. The dose of 0.1 mg/kg was predicted to have &lt;20% RO, 0.3 mg/kg to have ~21-35% RO, 1 mg/kg to have ~47-65% RO and 15 mg/kg to have ~93-96% RO at steady state. We anticipate beginning study enrollment in the first quarter of 2022 at sites in the United States sand South Korea. The study is a standard 3+3 dose-escalation with a dose of 0.3 mg/kg for a single patient followed by a starting dose of 1 mg/kg.
Citation Format: Lynn Jackson Howie, Ezra M. Chung, Young-Seung Kim, Yujin Jung, Hyunjin Jung, Stephen Yoo. Humanized STC10 is a monoclonal antibody to BTN1A1, a novel immunotherapeutic target to be evaluated in a planned phase 1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5318.
Abstract 5322: The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor
Authors: Gazi Md Yeashin , Brandle Caitlin , Okoko Ogacheko , Chen Xi , Keeton Adam , Maxuitenko Yulia , Piazza Gary , Zhou Gang 
Published: June 2022

Abstract
Phosphodiesterase 10 (PDE10) is overexpressed in several types of cancer, including lung, breast and colon cancers. It has been proposed that inhibitors targeting PDE10 may exhibit antitumor activities. Previous studies have shown that PDE10 inhibition can selectively activate cGMP-dependent protein kinase to suppress oncogenic β-catenin signaling in colon cancer cells. However, the impact of PDE10 inhibitors on tumor cell immunogenicity has not been examined. Here we report the antitumor activity and immunomodulatory effect of a novel PDE10 inhibitor (ADT030) in preclinical models. We show that administration of ADT030 significantly inhibited the growth of murine colorectal cancer CT26. In a metastatic breast tumor model (4T1), ADT030 administration not only delayed the growth of the primary tumor but also reduced tumor metastasis, resulting in prolonged mouse survival. Immunological analysis revealed profound reduction of MDSCs in mice, and improved T cell tumor infiltration and function after ADT030 treatment. Moreover, the combination of ADT030 and anti-PD-1 antibody therapy led to further improved tumor growth control and mouse survival. These results implicate PDE10 as a promising therapeutic target and its inhibition may enhance the efficacy of cancer immunotherapy.
Citation Format: Md Yeashin Gazi, Caitlin Brandle, Ogacheko Okoko, Xi Chen, Adam Keeton, Yulia Maxuitenko, Gary Piazza, Gang Zhou. The antitumor activity and immumodulatory effect of a novel phosphodiesterase 10 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5322.
Abstract 5347: miR-15a & miR-20b enhance sorafenib sensitivity of hepatocellular carcinoma through repressing CDC37L1 and consequent PPIA downregulation
Authors: Li Li , Yu Shijun , Chen Jingde , Quan Ming , Gao Yong , Li Yandong 
Published: June 2022

Abstract
Sorafenib is a classical targeted drug for the treatment of advanced hepatocellular carcinoma (HCC), but intrinsic resistance severely limits its therapeutic effects. In the present study, we aimed to identify crucial genes in HCC cells that affect sorafenib resistance by a CRISPR/Cas9 genome-scale screening. Among the candidates, two miRNAs, miR-15a and miR-20b, were finally identified as the essential sorafenib-sensitizing genes of HCC cells. In parallel, Cell Counting Kit-8 (CCK-8) assay,colony formation assays and flow cytometric analysis were carried out to assess cell proliferation and survival, whereas tumor growth in vivo was assessed using xenograft models. The results indicated that the deficiency of miR-15a and miR-20b contributed to sorafenib resistance of HCC cells. By combination of various bioinformatics tools, Cell division cycle 37 like 1 (CDC37L1) was identified as a common target gene of miR-15a and miR-20b. Further cellular and molecular biology experiments demonstrated CDC37L1 was negatively regulated by the two miRNAs, and CDC37L1 could enhance sorafenib resistance of HCC in vitro and in vivo. Mechanistically, we carried out SDS-PAGE and silver staining assays followed by mass spectrometry to analyze the immunoprecipitated proteins of CDC37L1. Our findings indicated that CDC37L1, as a cochaperone, effectively increased the expression of PPIA through strengthen the binding between HSP90 and PPIA. Additionally, CDC37L1 and PPIA expression were examined in a tissue microarray containing 80 pairs of HCC and normal tissues derived from patients who received sorafenib treatment via immunohistochemistry (IHC) staining, the results revealed a positive association between CDC37L1 and PPIA expression, and high expression of CDC37L1 and PPIA predicted worse prognosis of HCC patients after sorafenib therapy. Taken together, our findings suggest that both miR-15a and miR-20b play sorafenib-sensitizing roles in HCC by facilitating the complex of CDC37L1/HSP90/PPIA.
Citation Format: Li Li, Shijun Yu, Jingde Chen, Ming Quan, Yong Gao, Yandong Li. miR-15a & miR-20b enhance sorafenib sensitivity of hepatocellular carcinoma through repressing CDC37L1 and consequent PPIA downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5347.
Abstract 535: Development of a liquid biopsy assay to longitudinally monitor changes in mutations’ allelic frequency in response to treatment with KB-0742
Authors: Amara Suha Naffar-Abu , Noe Christina , Hood Tressa , Paganini Sara , MacKenzie Crystal , Day Melinda A. , Kumar Pavan 
Published: June 2022

Abstract
Liquid biopsies analyzing cell-free DNA (cfDNA) released by tumors are emerging as a powerful noninvasive sampling approach. As opposed to single-site solid tumor biopsy, liquid biopsies allow for better representation of the tumor mutational landscape. In the clinic, liquid biopsies are utilized for early detection of disease, to help inform treatment decisions, to monitor for disease recurrence, and to identify potential resistance mechanisms. Here we describe our approach to developing a liquid biopsy assay that will allow us to monitor, in real time, longitudinal changes in mutations’ allelic frequency in patients with solid tumors. Our approach combines two powerful technologies: next-generation sequencing, that enables the identification of a broad array of mutations, and droplet digital PCR (ddPCR) that provides speed and a cost-effective advantage to monitor mutations in cfDNA obtained from patient plasma samples.
In order to maximize the effectiveness of using liquid biopsy assays in our clinical trial, we prioritized developing an approach that enabled us to meet the following criteria: 1) generating a baseline and end-of-treatment mutational profile for each patient using either a tumor tissue sample or liquid biopsy to identify both driver and potential resistance mutation markers, 2) longitudinal sampling and real-time analysis over the course of treatment, 3) high assay sensitivity to detect low frequency alleles, 4) overall cost-effectiveness, and 5) ability to examine allelic frequency of multiple mutations of interest from limited input of cfDNA isolated from plasma.
Assay development included custom quantification of cfDNA and optimization of a pre-amplification step, which amplified the material allowing us to analyze multiple mutations of interest while ensuring that the quantitative nature of the assay was not impacted. For each individual mutation, gBlocks™ and/or cell-line−derived cfDNA were utilized to optimize annealing temperature and time, cycle number, and input amount to attain an assay with a target 0.1% limit of detection. These customized mutation assays can potentially serve as an accelerated cost-effective surrogate approach, compared to imaging, to monitor in real time the response to KB-0742 (CDK9i) in the ongoing phase 1/2 clinical trial NCT04718675.
Citation Format: Suha Naffar-Abu Amara, Christina Noe, Tressa Hood, Sara Paganini, Crystal MacKenzie, Melinda A. Day, Pavan Kumar. Development of a liquid biopsy assay to longitudinally monitor changes in mutations’ allelic frequency in response to treatment with KB-0742 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 535.
Abstract 5350: OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer
Authors: Kim Da-Som , Choi Yun Jung , Sung Young Hoon , Kim Dong Ha , Lee Chae Won , Lm Kyungtaek , Lee Hyeonjeong , Kim Sung-Eun , Lee Sunho , Ji Wonjun , Choi Chang-Min , Lee Jae Cheol , Rho Jin Kyung 
Published: June 2022

Abstract
Osimertinib, an irreversible, third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is initially developed to overcome EGFR T790M mutation, and use as standard therapy in patients with advanced non-small cell lung cancer (NSCLC) including EGFR activating mutations as well as EGFR T790M mutation. Despite remarkable efficacy of osimertinib, this therapy is limited by the emergence of acquired resistance, like other EGFR-TKIs. Since epidermal growth factor receptor mutation C797S was founded as the factor of acquired resistance to osimertinib, drug targeting the clinically relevant C797S mutation has not yet been developed. Here, we reported the discovery and preclinical efficacy of OBX02-011, fourth EGFR-TKI targeting overcome EGFR C797S mutation. Compared with the approved EGFR-TKIs, this agent showed potent anticancer effects and the inhibition of EGFR-related signaling in various models including EGFR C797S mutation. Additionally, we evaluated the efficacy of OBX02-011 in transgenic models (EGFRL858R+T790M+C797S), showing the enhanced survival, and inhibition of tumor growth and EGFR activity. Collectively, our data suggest that OBX02-011 may be promising new EGFR-TKI to overcome C797S-mediated resistance in NSCLC.
Citation Format: Da-Som Kim, Yun Jung Choi, Young Hoon Sung, Dong Ha Kim, Chae Won Lee, Kyungtaek Lm, Hyeonjeong Lee, Sung-Eun Kim, Sunho Lee, Wonjun Ji, Chang-Min Choi, Jae Cheol Lee, Jin Kyung Rho. OBX02-011, a reversible fourth-generation EGFR-TKI, overcomes C797S-mediated resistance in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5350.
Abstract 5357: mTOR kinase inhibitor AZD8055 reverses acquired rapamycin resistance in prostate cancer cells
Authors: Dai Yao , Siemann Dietmar 
Published: June 2022

Abstract
The mTOR pathway is frequently over-activated in human cancers. However, classic allosteric mTOR inhibitors rapamycin only exerts limited clinical benefits. It has been shown that prostate cancer are able to acquire resistance after rapamycin treatment for a period of time. Such secondary resistance remains as major concerns in rapamycin-based anti-cancer therapies that may inevitably lead to therapeutic failure. In the current study, we evaluated treatment effects of ATP-competitive dual mTOR kinase inhibitor AZD8055 on cancer cells that have acquired resistance to rapamycin, and underpinning molecular mechanisms. To establish cells with acquired rapamycin resistance, PTEN-mt prostate cancer PC-3 cells were gradually treated with increasing concentrations of rapamycin (up to 10 μM) until the cells were completely unresponsive to rapamycin (PC-3RR). Cell proliferation was determined by MTT assay and clonogenic survival was tested by colony formation assay. m7G pull-down assay was employed to detect the cap-dependent translation. mTOR downstream pathways, including p-S6K (T389)/p-S6 (S235/236), p-4EBP1 (T37/S46) and p-Akt (S473) were detected by Western Blotting. PC-3RR cells essentially failed to respond to rapamycin, with IC50 values greater than 1 μM. However, AZD8055 suppressed PC-3RR proliferation in a dose dependent manner, with IC50 &lt; 30 nM. Similarly, clonogenic capacity was impaired by AZD8055 to a greater extent than was the case for rapamycin. At the molecular level, AZD8055, but not rapamycin, strongly prevents the dissociation of 4E-BP1 from eIF4E. Further, while the p-S6K and p-S6 pathway was potently inhibited by both agents, AZD8055 displayed more striking inhibition on p-4E-BP1 and p-Akt than rapamycin. Interestingly, similar to rapamycin, AZD8055 slightly increased p-Akt (T308), suggesting the existence of the PI3K-mediated feedback loop. These findings indicate that AZD8055 significantly inhibits malignant functions in cancer cells that are highly resistant to rapamycin. Such effects are likely to be associated with the deactivation of rapamycin-insensitive mTOR downstream pathways. These data provide preliminary evidence for future evaluation of ATP-competitive mTOR inhibitors in cancer models that are resistant to rapamycin analogs.
Citation Format: Yao Dai, Dietmar Siemann. mTOR kinase inhibitor AZD8055 reverses acquired rapamycin resistance in prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5357.
Abstract 5362: Targeting PIK3CB in glioblastoma
Authors: Fromherz Marc R. , Pridham Kevin J. , Sheng Zhi 
Published: June 2022

Abstract
Background: Glioblastoma (GBM) is the most common and one of the most lethal malignant brain tumors in existence. The poor prognosis of this disease is due in part to tumor recurrence and temozolomide (TMZ) resistance, for which PI3K/AKT pathway overactivation has been implicated. Our work is to demonstrate that p110β inhibition could represent a therapeutic target in sensitizing recurrent tumors to TMZ therapy, and demonstrate the utility of personalized GBM treatments.
Objective: We aim to develop a more effective treatment for TMZ resistant GBM patients. We hypothesize that a p110β inhibitor will sensitize resistant GBM cell lines to TMZ therapy. We intend to support this hypothesis by demonstrating that the p110β inhibitor TGX-221 in combination with TMZ will provide a significantly greater level of cytotoxicity on TMZ resistant GBM cell lines than TGX-221 or TMZ monotherapy alone. We also intend to provide further evidence for this therapy by utilizing it to overcome TMZ resistance in glioblastoma stem cells (GSC’s).
Methods: We compared the cytotoxicity of TMZ, TGX-221, and a TMZ/TGX-221 combination therapy on p110β-high/TMZ resistant and p110β-low/TMZ sensitive GBM cell lines. Cell viability was determined using the MTS assay. We then tested these reagents on normal human astrocytes to determine any potential dose-limiting off-target effects. Lastly, we tested these reagents using human-derived GSC’s.
Results: A statistically significant difference (p &lt; 0.01) in cell viability was found using the TMZ/TGX-221 combination therapy as compared to either TMZ or TGX-221 alone in our TMZ resistant SF295 cells, and a significant different was found between the combination therapy and TMZ monotherapy in our TMZ resistant U87MG cells. No significant difference was found between treatments in our TMZ sensitive A172 cells or normal human astrocytes.
Conclusions: The results of our GBM cell line experiments provide support that combination TMZ/TGX-211 is superior in cytotoxicity to either monotherapy alone in TMZ resistant cell lines. This indicates that TGX-211, through p110β inhibition, is able to sensitize resistant cell lines to TMZ therapy. More experiments are ongoing to determine if this effect will also be demonstrated in human-derived GSC’s.
Citation Format: Marc R. Fromherz, Kevin J. Pridham, Zhi Sheng. Targeting PIK3CB in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5362.