bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3952: Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration
Authors: Cruz Arielle De La , George Andrew , Cruz Payton De La , Pinho-Schwermann Maximilian P. , Meza Kimberly S. , Arnoff Taylor , Sahin Ilyas , Graff Stephanie L. , Carneiro Benedito A. , El-Deiry Wafik S. 
Published: April 2023

Abstract
MDM2 and MDM4/MDMX have emerged as potential mediators of tumor progression, organ-specific metastasis, and hyper-progression after immune checkpoint blockade therapy. While there are currently a number of MDM2 inhibitors in clinical trials, we found no pure MDM4/MDMX inhibitors under clinical investigation. Because hormone-resistant cancers pose a significant challenge for clinical intervention, the identification of translatable novel therapeutic targets remains an important goal. Analysis of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) reveals overexpression of p53 negative regulator MDM4/MDMX as a frequent alteration in these cancers. There is an urgent need to study and target MDM4/MDMX in cancer therapy and this may ultimately include dual MDM2 and MDM4/MDMX inhibitors. However, it is clear that MDM4/MDMX is a primary oncogenic driver that requires specific therapeutic targeting. As metastasis is often observed clinically in patients diagnosed with breast and prostate cancer, we sought to expand our understanding of the metastasis reduction potential of a previously described preclinical MDM4/MDMX inhibitor, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895). In a scratch assay using breast and prostate cancer cell lines, increasing doses of XI-006 decreased tumor cell migration in a time and dose-dependent manner, demonstrating the benefit of MDMX inhibition in preventing the induction of tumor cell migration. The exact mechanism of this result remains unclear, and further investigation is needed to elucidate the impact of XI-006 on TNBC and CRPC cell proliferation and migration. Our future directions include identifying the synergistic potential of combining MDM4/MDMX inhibitor XI-006 with other cancer therapies, assessing the impact of XI-006 on immune responses in co-culture studies, and testing therapeutic efficacy in vivo.
Citation Format: Arielle De La Cruz, Andrew George, Payton De La Cruz, Maximilian P. Pinho-Schwermann, Kimberly S. Meza, Taylor Arnoff, Ilyas Sahin, Stephanie L. Graff, Benedito A. Carneiro, Wafik S. El-Deiry. Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3952.
Abstract 3982: Anti-Stanniocalcin 1 antibody as a potential therapeutic strategy for liver fibrosis and hepatocellular carcinoma
Authors: Suen Alfred Long-Hin , Chan Kristy Kwan-Shuen , Lo Regina Cheuk-Lam 
Published: April 2023

Abstract
Introduction: Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third leading cause of cancer deaths. Liver fibrosis (LF) is a progressive disease and cirrhosis, the advanced stage of LF, is per se a risk factor for HCC. Moreover, LF persists after the development of HCC. Stanniocalcin 1 (STC1), as a serum biomarker of both HCC and LF as we previously reported, was found to be secreted from HCC cells and hepatic stellate cells (HSCs). STC1 promoted cell migration and invasion of HCC and activation of HSCs, suggesting that STC1 could be an actionable target of both diseases. As a secretory protein, STC1 could potentially be targeted by an antibody approach.
Objectives: This study aims to investigate the therapeutic values of targeting secretory STC1 in HCC and LF models using antibody approach, including in the interplay between HSCs and HCC cells.
Methods: Human anti-STC1 antibody was harvested and purified from a hybridoma cell line of a designed epitope. In vitro transwell migration and invasion assays were performed on human HCC cell lines. Co-culture assays were set up with HCC cells cultured in conditioned medium (CM) collected from LX2, a human HSC cell line. Expression of fibrogenic markers were measured by western blotting, qPCR and ELISA.
Results: Enforcement of STC1, either by viral transfection of STC1-overexpressing vector or by the treatment of recombinant STC1 protein, increased the migration and invasion of HCC cells. The effects were abrogated by the co-treatment of anti-STC1 antibody. The enhanced migratory and invasive abilities of HCC cells induced by activated HSC CM were abolished by anti-STC1 antibody. In addition, anti-STC1 antibody suppressed the secretion of type I collagen (COL1) and the intracellular expression of fibrogenic markers alpha-smooth muscle actin (ɑSMA) and TIMP metallopeptidase inhibitor 1 (TIMP1) in TGFβ1-activated HSCs.
Conclusion: Anti-STC1 antibody displays therapeutic effects on HCC in vitro. It is also shown to suppress the expression of fibrogenic markers in activated HSCs. Anti-STC1 antibody is a potential therapeutic strategy for both HCC and LF.
Citation Format: Alfred Long-Hin Suen, Kristy Kwan-Shuen Chan, Regina Cheuk-Lam Lo. Anti-Stanniocalcin 1 antibody as a potential therapeutic strategy for liver fibrosis and hepatocellular carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3982.
Abstract 4062: The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy
Authors: Liu Yarong , Sun Jingwei , Sheng Yao , Wang Jingman , Jin Jiahui , Li Fei , Chen Lingyun , Zhou Di , Tan Yongchao , Wang Quanwei , Xu Zhao , Li Haibao , Wang Pin , Cui Jun 
Published: April 2023

Abstract
Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic effects in multiple types of solid tumors and significantly prolonged the survival of late-stage patients. However, the “prone-to-exhaustion” phenotype of the final TIL product after rapid expansion during manufacture and the presence of various immunosuppressive mechanisms in tumor microenvironment (TME) compromises the persistence and anti-tumor efficacy of TIL post infusion. To discover potential immunoregulatory targets that could maximize the function of TIL, we established a genome-wide CRISPR/Cas9 screening platform, ImmuT Finder®, to unbiasedly identify functional gene targets in primary T cells. Notably, this platform employed T cells bearing a tumor-antigen specific TCR-T that were repeatedly stimulated by tumor cells with cognate tumor antigen and demonstrated similar exhaustion profile as TIL. We selected top 30 targets after several rounds of screening and quickly validated their function in a 96-well array. Then, the top targets that showed significantly enhancement in proliferation and function of TCR-T were further selected, and their combinational effects on TIL were tested both in vitro and in vivo. Finally, double KO of GT304 and GT312 (GT316) stands out as the most potent combination, which significantly improves TIL proliferation and cytokine release, eradicates tumor growth in both CDX and PDX mouse models and promotes long-term in vivo persistence with low-dependence on IL-2. Specific and potent sgRNAs targeting both targets have been selected, and manufacturing process of GT316 TIL product has been developed (KOReTIL®). In summary, these data demonstrated that our ImmuT Finder® platform enables unbiased discovery of potent and novel targets for the development of T cell therapy and support the clinical assessment of GT316 as a next-generation TIL therapy. Currently, an investigator-initiated trial of GT316 is ongoing in China.
Citation Format: Yarong Liu, Jingwei Sun, Yao Sheng, Jingman Wang, Jiahui Jin, Fei Li, Lingyun Chen, Di Zhou, Yongchao Tan, Quanwei Wang, Zhao Xu, Haibao Li, Pin Wang, Jun Cui. The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4062.
Abstract 4103: The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Authors: Li Nan , Quan Alex , Li Dan , Ren Hua , Ni Weiming , Zhou Jing , Cachau Raul , Ho Mitchell 
Published: April 2023

Abstract
Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we developed CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4) based-CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We found that a structurally rigid IgG4H and CD28TM domain making the two D4 fragments in proximity drove CAR dimerization, which led to enhanced T cell signaling and tumor regression in orthotopic pancreatic cancer models with low antigen density. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR-T cells revealed specific genes (e.g., ID1) associated with high T cell polyfunctionality. This study demonstrates the potential of VHH-based CAR-T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.
Citation Format: Nan Li, Alex Quan, Dan Li, Hua Ren, Weiming Ni, Jing Zhou, Raul Cachau, Mitchell Ho. The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4103.
Abstract 4104: Development of adoptive T-cell therapies to target heterogeneity of mCRPC
Authors: Lopez Lupita S. , Bangayan Nathanael , Witte Owen , Priceman Saul J. 
Published: April 2023

Abstract
Metastatic castration resistant prostate cancer (mCRPC) remains a significant challenge with limited durable therapeutic responses, and innovative and effective treatment strategies are needed. Advanced mCRPC often comprises a heterogeneous population of prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC), and current targeted therapies often result in transient anti-tumor responses. Chimeric antigen receptor (CAR) T-cell therapies are being actively investigated to target mCRPC, including CARs targeting antigens that are overexpressed in PrAd. Our group has developed a CAR T cell targeting the PrAd antigen, prostate stem cell antigen (PSCA), and have an ongoing phase 1 trial at City of Hope in patients with mCRPC. However, we anticipate that targeting NEPC in addition to PrAd will be required to achieve durable anti-tumor responses in patients. Here, we have developed novel dual-targeting approaches for the simultaneous treatment of both PrAd and NEPC. Our first approach optimizes a tandem CAR T-cell approach capable of targeting distinct antigens found on both PrAd and NEPC. Additionally, we are actively developing combinations of PSCA-CAR T-cells with secretable T-cell bispecific antibodies to target NEPC antigens. Our studies encompass the in vitro and in vivo safety and efficacy of CAR T-cells engineered to co-target PrAd and NEPC for the treatment of heterogeneous mCRPC.
Citation Format: Lupita S. Lopez, Nathanael Bangayan, Owen Witte, Saul J. Priceman. Development of adoptive T-cell therapies to target heterogeneity of mCRPC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4104.
Abstract 4180: Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida
Authors: Sankar Harini , Odahowski Cassie L. 
Published: April 2023

Abstract
Purpose of the study: The purpose of this study is to assess how existing knowledge about colorectal cancer screenings and access to resources affect the ability to obtain colorectal cancer screening in people experiencing homelessness in Central Florida.
Procedures: A team of researchers from the University of Central Florida will survey subjects who do not have stable housing in two Central Florida locations: a local shelter for men, women, and children and a resource center for the unsheltered. The survey will take place in February 2023 with a sample size goal of 400. The survey will assess current understanding of CRC screenings and available/lacking resources necessary for completing CRC screening in this population. Our inclusion criteria include those who are undomiciled, age 45 and over who speak Spanish or English.
Preliminary Results: Anticipated results from previous work by our research team with this population indicate that we will have a large, diverse study sample. The results will include demographic data, frequency of insurance coverage, type of insurance coverage, knowledge of CRC screening recommendations, concerns related to CRC, rate of past completed screening, and perceived barriers to accessing CRC screening.
Conclusions: This study will be the first to examine this research topic in Florida. The results will identify the knowledge of CRC screening recommendations, barriers to CRC screening and identify resources needed for the unhoused population to achieve CRC screening in the future.
Citation Format: Harini Sankar, Cassie L. Odahowski. Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4180.
Abstract 419: Elevated Akt/mTOR signaling drives therapy resistance in ALM
Authors: Narula Jeremy A. Bravo , Rebecca Vito W. 
Published: April 2023

Abstract
Metastatic acral lentiginous melanoma (ALM) is the most lethal subtype of cutaneous melanoma and effective therapies for patients have not been established. Studies revealed a link between the dysregulation of CDK4/6 and ALM mortality, however CDK4/6 inhibitors (CDK4i/6i) have proved ineffective in patients with advanced ALM. The tumor suppressor Rb was recently shown to have a novel suppressive role towards mTORC2. Here, we elucidate the role of a non-canonical tumor suppressor function of Rb in negative regulation of mTOR in CDK4i/6i-resistance. We hypothesize that the loss of Rb induced by CDK4i/6i triggers phosphorylation of Akt and downstream mTORC1 signaling pathways. We characterized baseline activity of the PI3K/AKT/mTOR pathway in a panel of ALM cell lines, finding heterogeneity across signaling. We immunoblotted for key proteins involved in the signal reprogramming hypothesized: pRb, pAkt, pS6 to define activation status and found the loss of Rb phosphorylation preceded the enrichment of pAKT, supporting the non-canonical role of Rb tumor suppression and the Rb-mTORC2 signaling axis as intrinsic CDK4i/6i mechanism. In parallel, we assessed the essential protein-protein interactions required for mechanistic mTORC1 activation—mTOR and Rheb GTPase. The enrichment of these interactions shortly after introducing CDK4i/6i supported our hypothesized mechanism. Translational utility of CDK4i/6i and mTORi dual inhibition was determined via long-term Colony Formation Assays (CFAs) using Palbociclib, rapamycin and sapanisertib (TAK228), a catalytic mTOR inhibitor. We generated Palbociclib (acquired)-resistant ALM cell lines and investigated the pharmacological inhibition of PI3K signaling pathways through immunoblot and colony-formation assays. Concurrent mTORi and CDK4i/6i inhibition showed effective reduction in pRb, pS6, Cyclin D and increases in Cleaved PARP protein, suggesting apoptotic cell death was elevated with combined CDK4i/6i+mTORi treatment. Similarly, CFAs revealed dual inhibition elicited superior antiproliferative effect over the monotherapy treatments. CFAs with acquired-resistance cell lines also showed that combination inhibition decreased colony formation, showing the potential utility of concurrent CDK4i/6i and mTORi as an approach against acquired resistance. Our results show the efficacy of combined inhibition as an anti-tumor strategy.
Citation Format: Jeremy A. Bravo Narula, Vito W. Rebecca. Elevated Akt/mTOR signaling drives therapy resistance in ALM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 419.
Abstract 4245: Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[def,p] in human oral cells
Authors: Sun Yuan-Wan , Chen Kun-Ming , Sales Ana H. , Geacintov Nicholas , El-Bayoumy Karam 
Published: April 2023

Abstract
We previously reported that black raspberries (BRB) powder inhibits dibenzo[def,p]chrysene (also known as dibenzo[a,l]pyrene; DBP)-induced DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity. The effects of BRB on the capacity of DNA repair was investigated in an established in vitro system using HeLa cells to assess the DNA repair capacity. We found that pre-treatment of Hela cells with BRB extracts (BRBE) can enhance the nucleotide excision repair (NER) of a bulky DNA adduct derived from the tobacco oral carcinogen benzo[a]pyrene by ~24% and this effect is correlated with the enhanced expressions of NER factors XPA and XPB. The NER activity of guanidinohydantoin (Gh), an oxidatively-derived non-bulky DNA lesion, is also enhanced by ~24%, while its base excision repair activity is enhanced by only ~6%. Using human oral leukoplakia (MSK-Leuk1) and oral squamous cell carcinoma SCC1483, we demonstrated that BRBE can inhibit DNA damage induced by DBP through the induction of GSH synthesis and enhancing GSH conjugates thereby inhibiting DNA damage. The effects of BRBE in MSK-Leuk1 and SCC1483 cells were further investigated on the DNA excision repair protein ERCC1 at 1, 6 and 24 h. ERCC1 forms the ERCC1-XPF enzyme complex that participates in several DNA repair pathways. Western blot analyses revealed that BRBE induced higher ERCC1 expression in SCC1483 than those observed in MSK-Leuk1 cells in a time-dependent manner. The results of our study demonstrate that BRBE is capable of inhibiting the metabolic activation, enhancing the detoxification pathway and DNA repair capacity which are consistent with its chemopreventive activity in vivo. Supported by NIH grant #CA173465.
Citation Format: Yuan-Wan Sun, Kun-Ming Chen, Ana H. Sales, Nicholas Geacintov, Karam El-Bayoumy. Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[def,p] in human oral cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4245.
Abstract 4283: scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model
Authors: Liu Yuqian , Chen Yan , Wu Huanwen , Zhang Xuanping , Lai Xin , Yi Xin , Liang Zhiyong , Wang Jiayin 
Published: April 2023

Abstract
Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment. For some cancers with high-degree of heterogeneity, e.g. endometrial cancer, the existing approaches always fail to identify the micro-satellite instability on one or multiple sub-clones, which would deprive the chance for patients to benefit from treatments. However, it is a computational challenge to estimate the sub-clonal MSI because multiple sub-clones may share the genomic status. Herein, in this paper, we propose an accurate and efficient algorithm, named scMSI, to estimate the sub-clonal microsatellite status. scMSI adopts an alternating iterative model to de-convolute the length distribution, which is a mixture of sub-clones. During the deconvolution, an optimized division of each sub-clone is achieved by a heuristic algorithm, which is bounded to the clonal proportions best consistent with the known clonal structure. To evaluate the performance, we conducted a series of experiments on simulation datasets. The results supported that scMSI solved the detection problem of MSI on sub-clones. It outperforms the existing approaches on multiple metrics. In addition, we collected a cohort of 16 endometrial cancer patients, who have positive responses on the treatment but with negative MSI status. We sequenced these patients. scMSI reported MSI on sub-clones according the sequencing data, which are further validated by the conclusions on immunohistochemistry. Thus, scMSI could provide a powerful tool for MSI analysis.
Citation Format: Yuqian Liu, Yan Chen, Huanwen Wu, Xuanping Zhang, Xin Lai, Xin Yi, Zhiyong Liang, Jiayin Wang. scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4283.