bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2742: Small interfering RNA targeting CD24 inhibits proliferation and migration of triple-negative breast cancer cells
Authors: Liu Yanli , Cheng Kun 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) is defined as the lack of human epidermal growth factor receptor 2 (HER2), progesterone receptor (PR), and estrogen receptor (ER) expression. TNBC accounts for 10-20% of all cancer cases and is more aggressive than other subtypes of breast cancer. Although chemotherapy is the mainstay of treatment for TNBC, its therapeutic efficacy is limited. Therefore, developing new therapies to address the unmet need of TNBC is urgently needed.
CD24 protein is a heavily glycosylated glycosylphosphatidylinositol (GPI)-anchored surface protein. The high expression level of CD24 is observed in a variety of cancers, such as TNBC and ovarian cancer. CD24 plays an important role in tumor growth, invasion, and metastasis of different types of cancers. Besides, overexpression of CD24 in tumors is associated with resistance to chemotherapy agents and targeted therapies.
Here, we design four siRNAs targeting different regions of the CD24 mRNA. The silencing activity of the predesigned siRNAs is evaluated by quantitative real-time RT-PCR and western blot. The biological effects of designed siRNAs on human breast cancer cells are investigated by cell proliferation, migration, invasion, cell cycle arrest, and apoptosis. The data demonstrate that the CD24 siRNAs significantly reduce CD24 expressions at both mRNA level and protein level in human TNBC cells. Moreover, silencing of CD24 suppresses breast cancer cell proliferation. Cell cycle assay shows that the anti-proliferation effect of CD24 siRNA is mediated by arresting the cells in the S phase. Furthermore, we reveal that silencing of CD24 inhibits migration and invasion of human breast cancer cells. Significant apoptosis is observed in CD24 siRNA transfected cells compared with the scrambled siRNA group. These data suggest that silencing CD24 using siRNA can be a potential therapeutic strategy for triple-negative breast cancer.
Citation Format: Yanli Liu, Kun Cheng. Small interfering RNA targeting CD24 inhibits proliferation and migration of triple-negative breast cancer 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 2742.
Abstract 2755: Identification of novel GPX4 inhibitors using global transcriptional reporters
Authors: Read Timothy , Winigrad Zoe , Goliaei Ardeshir , Liechty Cole , Grochala Carter , Damon Leah , Dickson John , Harris Jason , Pham Casey , Rimel Jenna , Rhine Christy , Simpson Dave , Martin Eric , Azofeifa Joey 
Published: April 2023

Abstract
Induction of Ferroptosis is a promising strategy for treating therapy-resistant tumors including mesenchymal tumor types. We performed a phenotypic screen to identify small molecules that induce ferroptosis in mesenchymal cancer cells by screening for compounds whose toxicity could be rescued by the lipophilic antioxidant Ferrostatin-1. To identify compounds that induce GPX4-mediated ferroptosis, we identified several pharmacodynamic biomarkers specific to GPX4 inhibition using our nascent RNA sequencing platform, which allows for time-resolved snapshots of global transcription. We measured the transcriptional changes that occur in the hours following inhibition of GPX4 and identified HMOX1 as a robust biomarker of GPX4i-induced ferroptosis in mesenchymal cancer cell lines. Using HMOX1-induction as a guide, we uncovered a small number of compounds as potential GPX4 inhibitors. One such compound was validated as a bonafide GPX4 inhibitor through a variety of biochemical assays and selected for a hit-to-lead campaign. In addition to standard medicinal chemistry strategies, we are currently employing a newly-developed global transcriptional reporter system to stratify several novel series of GPX4 inhibitors by their transcriptional signatures. This approach represents a unique strategy for determining on- and off- target effects of a compound and for defining structure activity relationships within a chemical series.
Citation Format: Timothy Read, Zoe Winigrad, Ardeshir Goliaei, Cole Liechty, Carter Grochala, Leah Damon, John Dickson, Jason Harris, Casey Pham, Jenna Rimel, Christy Rhine, Dave Simpson, Eric Martin, Joey Azofeifa. Identification of novel GPX4 inhibitors using global transcriptional reporters [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 2755.
Abstract 2846: The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression
Authors: Terrero David , Malla Saloni , Raman Dayanidhi , Babu Jayachandra , Tiwari Amit 
Published: April 2023

Abstract
Multidrug efflux transporter ABCB1 (MDR1) encodes P-glycoprotein (P-gp), a well-known transporter that is believed to contribute to the development of multidrug resistance (MDR). Furthermore, P-gp plays an important role in drug disposition, pharmacokinetics, and drug development. Thus, P-gp transporter expression, function, and modulation of MDR in human cancers have been extensively studied. In spite of significant progress in understanding P-gp, ABCB1 regulation and its impact on clinical trials remain unclear. Through sequential exposure of SUM159PT to paclitaxel, we created a paclitaxel resistant triple negative breast cancer cell line SUM159PT-PAC200. We observed a significant increase in the phosphorylation of the mitochondrial fission protein dynamin related protein kinase 1 (Drp1) at Ser616 and its upstream kinase ERK1/2a of Drp1. Through the use of CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in PAC200. When Drp1 is genetically abated (PAC200 Drp1-/-), paclitaxel resistance is significantly reversed. It was also observed that clonogenicity under paclitaxel pressure was significantly decreased in both the PAC200/Drp1-/- line and the partial KO Drp1-/+ line, compared to the PAC200 line. Parallelly, a significant increase in the expression of P-gp transporters was also observed in the PAC200 cell line. As a surprise, genetically targeting Drp1 in PAC200 cells (i.e., PAC200 Drp1/KO) reduced P-gp expression to virtually undetectable levels. Until now, there has been no description of how Drp1 and P-gp are related. Furthermore, PAC200 Drp1/KO cells showed reduced proliferation, migration, and invasion potential, while their soft agar clonogenic capacities were almost nonexistent, suggesting that Drp1 plays a key role in breast cancer proliferation and dissemination. It appears that modulating or targeting Drp1 might be a useful strategy for modulating P-gp in the development and maintenance of the cancer's MDR phenotype, proliferation, and invasion. Understanding how mitochondrial dynamics determine the transactivation and coordination of drug-resistant P-gp phenotypes would make Drp1 an attractive molecular target for cancer treatment.
Citation Format: David Terrero, Saloni Malla, Dayanidhi Raman, Jayachandra Babu, Amit Tiwari. The mitochondrial dynamics of breast cancer regulate P-glycoprotein expression [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 2846.
Abstract 2978: YH013, a novel EGFR x MET bispecific antibody-drug conjugate, exhibits potent antitumor efficacy
Authors: Han Yanfei , Shang Chengzhang , li Zhuon , Han Zhenyan , Li Jun , Cui Zixu , An Gao , Hao Wanjun , Liu Yujie , Li Hao , Liu Baihong , Zhang Ellen , Lin Qingcong , Yang Yi , Shen Yuelei 
Published: April 2023

Abstract
Bispecific antibodies (BsAb) that target dual tumor-associated antigens have the advantages of invoking synergistic effects between two signaling pathways, increasing target tissue specificity, and reducing systemic toxicity. By combining the antibody-mediated specific targeting with potent killing from a cytotoxic payload, antibody-drug conjugates (ADC), and especially bispecific ADCs (BsADC), have become powerful therapeutic strategies. EGFR and MET are oncogenic proteins that are co-expressed in a wide range of tumors. Moreover, MET amplification is largely associated with drug resistance of EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC) patients. Biocytogen developed a fully human EGFR x MET BsADC using our proprietary common light chain RenLiteTM mouse platform and knobs-into-holes technology. The BsAb showed enhanced internalization and binding affinity compared to parental monoclonal and monovalent antibodies in the EGFR/MET co-expressing NCI-H1975 cell line. After conjugating the BsAb with monomethyl auristatin E (MMAE) via a protease-cleavable linker, the resulting BsADC, YH013, exhibited a remarkable and dose-dependent anti-tumor efficacy in NCI-H1975 and NCI-H292 cell line-derived xenograft models. Moreover, in multiple patient-derived xenografts of NSCLC and pancreatic ductal adenocarcinoma (PDAC), which co-express EGFR and MET, YH013 demonstrated superior and durable efficacy that outperformed benchmark antibodies at a lower dose (3 mg/kg). Collectively, these results suggest that YH013 can be an effective treatment option for EGFR and MET co-expressing tumors and overcome MET-driven EGFR-TKI resistance to improve patient outcomes.
Citation Format: Yanfei Han, Chengzhang Shang, Zhuon li, Zhenyan Han, Jun Li, Zixu Cui, Gao An, Wanjun Hao, Yujie Liu, Hao Li, Baihong Liu, Ellen Zhang, Qingcong Lin, Yi Yang, Yuelei Shen. YH013, a novel EGFR x MET bispecific antibody-drug conjugate, exhibits potent antitumor efficacy [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 2978.
Abstract 3023: Identifying colorectal cancer biomarkers using a targeted proteomics platform with extensive coverage
Authors: Harbs Justin , Rentoft Matilda , Liu Xijia , Melin Beatrice S. , Harlid Sophia , Van Guelpen Bethany 
Published: April 2023

Abstract
Despite advances in treatment, colorectal cancer remains one of the leading causes of cancer-specific death. To decrease colorectal cancer mortality, better and more cost-efficient tools for risk prediction and early detection are needed. One area that has shown promise is using protein biomarkers, measured in blood, to detect individuals with early-stage disease or at increased risk. The primary aim of this study was therefore to identify novel protein biomarkers associated with colorectal cancer risk and the secondary aim was to validate protein biomarkers that had been described in previous studies. We included data and samples from 185 incident colorectal cancer cases and 185 controls (matched on age, sex, sampling date, and the number of freeze-thaw cycles) from the Northern Sweden Health and Disease Study (NSHDS). Samples were collected between six years and three months prior to the diagnosis date of each case and concentrations of 1536 individual proteins were measured in plasma samples using the Olink Explore 1536 platform (Olink Proteomics). Prior to statistical analyses, 249 proteins were excluded, either due to not passing quality control or having more than 50% of the concentrations below the limit of detection. In addition, we also excluded extreme outliers. Conditional logistic regression was used to estimate Odds Ratios (ORs) and 95% confidence intervals (95% CI) for the association between protein concentrations and colorectal cancer risk. Multivariable models were adjusted for predetermined colorectal cancer risk factors, including body mass index, alcohol consumption, physical activity, smoking status, and level of education. When considering p&lt;0.005 as a cut-off, we identified 20 proteins that were associated with colorectal cancer risk. Our top hit was TFF3 (Trefoil Factor 3) which was positively associated with colorectal cancer at a high significance level (multivariable OR per SD: 1.84 95% CI: 1.38 - 2.45). TFF3 was significant in men (FDR&lt;0.1), but not in women (pheterogeneity &lt;0.05). In addition, several of the top 20 proteins such as AREG, MMP7, and CXCL16 have been linked to the diagnosis or prognosis of colorectal cancer in earlier studies. To conclude, we identified one novel protein biomarker, TFF3, strongly associated with colorectal cancer risk and validated several proteins previously linked to the diagnosis or prognosis of colorectal cancer.
Citation Format: Justin Harbs, Matilda Rentoft, Xijia Liu, Beatrice S. Melin, Sophia Harlid, Bethany Van Guelpen. Identifying colorectal cancer biomarkers using a targeted proteomics platform with extensive coverage [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 3023.
Abstract 3072: Estrogen receptor β4 regulates chemotherapy resistance and induces cancer stem cells in triple negative breast cancer
Authors: Bano Ayesha , Stevens Jessica , Modi Paulomi S. , Strom Anders , Gustafsson Jan-Ake 
Published: April 2023

Abstract
TNBC has the worst prognosis among all breast cancers, and survival in patients with recurrence is rarely beyond 12 months due to acquired resistance to chemotherapy, which is the standard of care for these patients. Our hypothesis is that Estrogen Receptor Beta 1 (ERB1) increases response to chemotherapy but is opposed by ERB4, which it preferentially dimerizes with. The role of ERB1 and ERB4 in influencing chemotherapy sensitivity has never been studied before. CAS9/CRSPR was used to truncate ERB1 Ligand Binding Domain (LBD) and knock down the exon unique to ERB4. We show that the truncated ERB1 LBD in a variety of mutant p53 TNBC cell lines, where ERB1 ligand dependent function was inactivated, had increased resistance to Paclitaxel, whereas the ERB4 knockdown cell line was sensitized to Paclitaxel. We further show that ERB1 LBD truncation as well as treatment with ERB1 antagonist PHTPP leads to increase in the drug efflux transporters. Hypoxia Inducible Factors (HIFs) activate factors involved in pluripotency and regulate the stem cell phenotype, both in normal and cancer cells. Here we show that the ERβ1 and ERB4 regulate these stem cell markers like SOX2, OCT4, and Nanog in an opposing manner; and we further show that this regulation is mediated by HIF. We show the upregulation of cancer cell stemness due to ERB1 LBD truncation is attenuated when HIF1/2a is knocked down by siRNA. Finally we show, an increase in the frequency of breast cancer stem cell population due to ERB1 antagonist using both ALDEFLUOR and SORE6 reporter in SUM159 and MDA-MB-231 cell lines. Since most TNBC cancers are ERβ4 positive, while only a small proportion of TNBC patients are ERβ1 positive, we believe that simultaneous activation of ERß1 with agonists and inactivation of ERB4, in combination with paclitaxel, can be more efficacious and yield better outcome for chemo resistant TNBC patients.
Citation Format: Ayesha Bano, Jessica Stevens, Paulomi S. Modi, Anders Strom, Jan-Ake Gustafsson. Estrogen receptor β4 regulates chemotherapy resistance and induces cancer stem cells in triple negative breast 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 3072.
Abstract 3184: Single-cell analysis of CAR T-cells helps uncover distinct functional signatures following CAR T-cell manufacturing
Authors: Colina Alfredo Sebastian , Shah Ravi , Kozlik Tanya , Dwinell Michael B. , Johnson Bryon , Shah Nirav , Zamora Anthony 
Published: April 2023

Abstract
Chimeric antigen receptor T cell (CAR-T) therapy has proven a major success for patients with B cell malignancies. Despite recent advancements, some patients never mount an effective antitumor response and ultimately succumb to their disease. While modifications to specific CAR construct domains have resulted in greater CAR-T expansion and functional responses in some patients, it has become increasingly evident that more studies are needed to evaluate the impact of intra- and inter-patient functional heterogeneity on clinical efficacy. To begin deciphering the factors governing these disparate functionalities, we performed single-cell polyfunctional assessments of bispecific CD20/CD19 CAR-T cells and accounted for how differences in their manufacturing could further alter functional capacity. Based on our preliminary data, we hypothesized that differences in CAR-T’s underlying biology, such as their phenotypic, transcriptional, and functional status, mediate their persistence, cytotoxicity, and clinical efficacy. By taking advantage of BLI’s Lightning platform, which interrogates and links CAR-T’s cytotoxic function, secretory profile, and transcriptional state at single-cell resolution, we uncovered key manufacturing processes that alter CAR-T cell antitumor function. We’ve also identified distinct immune signatures associated with clinical response. Future studies will utilize in vivo mouse tumor models to validate the immunological signatures driving CAR-T cell functionality and persistence after infusion. Our studies suggest that differences in CAR T-cell manufacturing protocols alter the immunological signatures of T cells, which can be exploited to guide future therapeutic interventions and the design of future clinical trials.
Citation Format: Alfredo Sebastian Colina, Ravi Shah, Tanya Kozlik, Michael B. Dwinell, Bryon Johnson, Nirav Shah, Anthony Zamora. Single-cell analysis of CAR T-cells helps uncover distinct functional signatures following CAR T-cell manufacturing [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 3184.
Abstract 3250: Targeting CD38 on exhausted T cells overcomes resistance to cancer immunotherapy
Authors: Revach Or-Yam , Cicerchia Angelina M. , Sade-Feldman Moshe , Anderson Seth , Manguso Robert T. , Hacohen Nir , Jenkins Russell W. 
Published: April 2023

Abstract
Despite the unprecedented success of immune checkpoint blockade (ICB) in melanoma and other cancers, therapeutic resistance remains a major challenge. CD38, an ecto-enzyme involved in NAD+ catabolism, is upregulated in dysfunctional/exhausted CD8+ T cells in human melanoma. As enrichment of dysfunctional CD8+ T cells is associated with lack of response to ICB, and NAD+ depletion via enhanced CD38 activity has been associated with diminished immune response, we hypothesized that CD38 might represent an attractive target to overcome resistance to ICB. While CD38 blockade has been shown to augment response to ICB in murine tumor models, the specific role of CD38 signaling in CD8 T cell exhaustion, and the therapeutic relevance of CD38 in human cancer have not been defined. Here, we confirm and extend previous observations that CD38 is enriched in exhausted CD8+ T cells during tumor progression and in response to ICB. Further, we demonstrate that disrupting CD38 signaling via neutralizing antibodies or pharmacological inhibition enhances response to ICB using established murine tumor models and patient-derived tumor explant models. Notably, we observed 54% response rate to combination PD-1/CD38 blockade using a cohort (n=35) of patient-derived organotypic tumor spheroids (PDOTS) from patients with ICB-refractory melanoma (11.4% response rate to single-agent PD-1 blockade). Supplementation of nicotinamide riboside (NR) to boost NAD+ levels mimicked the effects CD38 blockade/inhibition on PD-1 response, whereas FK866, an inhibitor of NAMPT a key step in NAD+ biosynthesis, blunted the response to combined PD-1/CD38 blockade, suggesting a major role for NAD+ in the efficacy of CD38 blockade/inhibition. Lastly, we demonstrate that in vitro CD38 inhibition/blockade in CD8+ T cells increases the levels of TCF7 (an effector/memory T cell transcription factor), decreases surface expression of co-inhibitory receptors (e.g., TIM-3, CD39, PD-1), and improves effector CD8 T cell function. Taken together, these data confirm a role for CD38 in CD8+ T cell exhaustion in melanoma and support further pre-clinical and clinical development of this novel therapeutic strategy to enhance anti-tumor immune responses.
Citation Format: Or-Yam Revach, Angelina M. Cicerchia, Moshe Sade-Feldman, Seth Anderson, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins. Targeting CD38 on exhausted T cells overcomes resistance to cancer immunotherapy [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 3250.