tbuckley/cabot-search huggingface dataset:
Abstract 5796: A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations
Authors: Weiyi Toy, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup
Journal: Cancer Research (2024)

Abstract HER3 activation, via NRG1 ligand-dependent and -independent heterodimerization with HER2 or EGFR, has been associated with tumor progression and acquired resistance to therapies in multiple indications. HER3 mutations, detected in around 3% of cancer cases, may drive oncogenic signaling, leading to rapid tumor growth. Currently, there are no approved targeted therapies for HER3 mutations. Through analysis of real-world data and structural modelling of HER3 heterodimers, we identified four common HER3 mutations located within or close to the dimerization interface of HER3, suggesting a potential impact on HER3 heterodimerization. Immunoprecipitation assays confirmed that all four mutations increased the heterodimerization of HER3 with both HER2 and EGFR. Further, conversion of an endogenous HER3 mutation to wild type via CRISPR editing significantly reduced the growth of KYSE-150, a HER3 mutant cell line. HMBD-001 is a clinical-stage anti-HER3 antibody rationally developed to uniquely block the HER3 dimerization interface to potently inhibit HER3 heterodimerization. Through structural analysis and FACS binding on HER3 mutation cell lines, we confirmed that the binding epitope of HMBD-001 does not overlap with the selected HER3 mutations and therefore may be a good therapeutic option for patients with HER3 mutations. In vitro, HMBD-001 suppressed HER3 mutation-driven PI3K/AKT signaling, as demonstrated by the reduction of phosphorylated HER3 and AKT levels. In multiple cell- and patient-derived xenograft models with HER3 mutations HMBD-001 response achieved &amp;gt;80% tumor growth inhibition. Based on this encouraging preclinical data, a Phase Ib clinical trial (NCT05919537) has been initiated, evaluating HMBD-001 in patients with aberrant HER3 signaling, including HER3 mutations. Citation Format: Weiyi Toy, Dipti Thakkar, Roberto Magallanes, Sharon Wu, Ming Poi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. A HER3 antibody that uniquely blocks the HER3 heterodimerization interface effectively inhibits tumor growth in pre-clinical models with potentially oncogenic HER3 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5796.
Abstract 4613: Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells
Authors: Chongbiao Huang, Huizhi Sun, Antao Chang, Jihui Hao
Journal: Cancer Research (2024)

Abstract Rapid drug resistance after chemotherapy is a key cause of treatment failure in human pancreatic ductal adenocarcinoma (PDAC). Here, we found that tumor-derived interleukin 35 (IL-35) mediated the rapid resistance of PDAC to gemcitabine (GEM). The role of IL-35 in GEM resistance was determined by molecular and cell biology approaches in PDAC cells and in patient-derived tumor xenograft (PDX) models. We used whole genome RNA sequencing, molecular cloning and other molecular biological methods to study the molecular mechanism of IL-35 mediated GEM resistance. An anti-IL-35 neutralizing antibody was used in mouse models to investigate the feasibility of targeting IL-35 to overcome drug resistance in pancreatic cancer. We observed the phenomenon that GEM resistance could spread from GEM resistant PDAC cells to GEM sensitive ones. The results of sequencing and experiments confirmed that the IL-35 secretion is responsible for the dissemination of chemoresistance. IL-35 secreted from GEM resistant cells activated the IL35 expression in GEM sensitive cells and upregulated SOD2 expression via GP130-STAT1 signaling, which scavenges reactive oxygen species (ROS) and then leads to GEM resistance.Furthermore, we found that a neutralizing antibody against IL-35 significantly enhanced the tumor suppressive effect of GEM. These findings collectively reveal that IL-35 plays crucial roles in mediating GEM resistance in pancreatic cancer. Moreover, IL-35 might serve as a promising therapeutic target for combating PDAC chemoresistance. Citation Format: Chongbiao Huang, Huizhi Sun, Antao Chang, Jihui Hao. Tumor-derived interleukin 35 facilitates the gemcitabine resistance in pancreatic adenocarcinoma by mediating the dissemination of chemoresistance among PDAC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4613.
Abstract 5803: Tumor treating fields alter PDGFR-β localization in immortalized human pericytes in an <i>in vitro</i> model of the blood-brain barrier
Authors: Ellaine Salvador, Theresa Koeppl, Almuth F. Kessler, Malgorzata Burek, Ralf-Ingo Ernestus, Mario Löhr, Carsten Hagemann
Journal: Cancer Research (2024)

Abstract Background: Tumor Treating Fields (TTFields) are alternating electric fields of intermediate frequency (100-500 kHz) and low intensity (1-3 V/cm). TTFields at 200 kHz, together with adjuvant chemotherapy, increased progression-free and overall survival of newly diagnosed Isocitrate dehydrogenase (IDH) wildtype and IDH mutant glioblastoma (GBM, WHO CNS 2016) patients in a randomized controlled trial and were therefore approved for the treatment of these patients. We recently demonstrated that TTFields at lower frequencies transiently increase the permeability of blood-brain barrier (BBB) models of murine and human origin by delocalizing junctional proteins such as claudin-5, ZO-1, and occludin in endothelial cells. The interaction between pericytes and endothelial cells contributes to the rigorous integrity of the BBB and is driven by endothelial cells releasing the platelet-derived growth factor β-subunit (PDGF-β), which binds to the receptor PDGFR-β on the surface of pericytes. Here, we investigated the effects of TTFields on pericytes in a human cell-based in vitro BBB model in order to gain a better understanding of the effects of TTFields on BBB integrity. Methods: We prepared an in vitro BBB model composed of human brain microvascular endothelial cells and human pericytes. The model was subjected to TTFields at 100-300 kHz for 24 to 72 h. Afterwards, pericytes were incubated with Alexa Fluor 488-labeled anti-PDGFR-β antibody in order to visualize PDGFR-β localization and cell morphology under the microscope. To make sure that no cell loss occurred due to TTFields treatment, the nuclei of pericytes were counted. Results: TTFields treatment altered the distribution of PDGFR-β staining after treatment, with fewer, less distinct and more punctate PDGFR-β foci. These changes were most prominent after 72 h of TTFields treatment at 300 kHz. We also observed larger nuclei in the pericytes after treatment but no significant loss of cells could be observed as per the nuclei count. Conclusion: Together with the previously observed delocalization of tight junctional proteins in endothelial cells, the altered distribution of PDGFR-β pericytes could reveal new mechanistic insights into the effects of TTFields on BBB integrity. Citation Format: Ellaine Salvador, Theresa Koeppl, Almuth F. Kessler, Malgorzata Burek, Ralf-Ingo Ernestus, Mario Löhr, Carsten Hagemann. Tumor treating fields alter PDGFR-β localization in immortalized human pericytes in an in vitro model of the blood-brain barrier [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5803.
Abstract 5246: Therapeutic efficacy of glypican-3 peptide-linked chimeric antigen receptor-macrophages in hepatocellular carcinoma
Authors: Wing Hei Leung, Oi Ning Leung, Tsun Ting Wong, Kin Wah Lee
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the third most lethal cancer and sixth most diagnosed cancer worldwide. Recently, chimeric antigen receptor-T cell (CAR-T) therapy has been demonstrated to be a promising immunotherapy for the treatment of hematologic malignancies such as leukemia. However, its application in solid tumors has proven to be challenging. To overcome this limitation, chimeric antigen receptor-macrophages (CAR-Ms) have emerged as a new immunotherapy against solid cancers, capitalizing on the unique attributes of macrophages in penetrating the tumor microenvironment, promoting antigen presentation, and priming T cells. Traditionally, CAR-M therapy involves the transfer of an edited CAR gene into macrophages via viral infection. However, this method is expensive, involves tedious procedures, and has long-term safety concerns. In the present study, we employed peptides to mimic the genetic approach for producing CAR-Ms to reduce the above uncertainties. To achieve this, we developed a novel bioconjugation method called the phthalaldehydeamine capture (PAC) reaction to produce peptidic CAR-Ms (pCAR-Ms) targeting Glypican-3 (GPC3) in HCC cells. This was achieved by linking GPC3 specific peptides to Raw264.7 murine macrophages. Using an in vitro co-culture system, we demonstrated the specificity and efficacy of pCAR-Ms against GPC3, as evidenced by a significant increase in the number of phagocytosed cells with high GPC3 expression when compared to their low-expression counterparts, by flow cytometry and confocal microscopy. The specificity of pCAR-Ms was further proven in GPC3-knockdown HCC cells, with a significant decrease in the phagocytic rate. Using an HCC xenograft model derived from MHCC97L cells, we confirmed the specific homing of pCAR-Ms to tumor sites via intravenous injection of lipopolysaccharide (LPS)-differentiated pCAR-Ms. Strikingly, pCAR-Ms suppressed HCC tumor growth when compared with untagged macrophages and PBS control. In conclusion, we provided evidence of the potency and specificity of non-viral-based pCAR-Ms in targeting HCC with simple and short production time and increased flexibility. Citation Format: Wing Hei Leung, Oi Ning Leung, Tsun Ting Wong, Kin Wah Lee. Therapeutic efficacy of glypican-3 peptide-linked chimeric antigen receptor-macrophages in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5246.
Abstract 4401: GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer
Authors: Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is one of the most lethal and prevalent malignancies with elusive molecular causes. While the abnormal activity of transcription factors has been reported as a vital component of cancer progression, the mechanism through which they function remains unclear. Here, through the analysis of primary human CRC tissue data, we identified GATA6 as a CRC specific regulator, whose expression upregulation is potentially associated with promoter hypomethylation. In the human genome, GATA6 showed preferential binding at tumor specific active enhancers. Through both auxin-inducible degron (AID) and CRISPR knockout, we showed that GATA6 depletion severely impaired clonogenicity and proliferation. GATA6 depletion caused the loss of CRC specific open chromatin, suggesting a specific regulatory role of GATA6 in CRC pathogenesis. Interestingly, we also discovered the co-occupancy of GATA6 with CTCF and its direct involvement in promoter enhancer loops, suggesting the possibility that GATA6 mediate transcriptional regulation through 3D genome. The loss of GATA6 led to alterations in E-P chromatin interactions of a panel of oncogenes, accompanied by the oncogene downregulation. Finally, we showed that GATA6 loss is detrimental to the xenograft tumor growth and thereby rescued mice survival. Taken together, we unrevealed a novel mechanism by which GATA6 contributes to CRC. Citation Format: Huijue Lyu, Xintong Chen, Yang Cheng, Te Zhang, Ping Wang, Josiah Hiu-yuen Wong, Juan Wang, Lena Stasiak, Leyu Sun, Guangyu Yang, Lu Wang, Feng Yue. GATA6 is a novel regulator of gene expression and 3D genome in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4401.
Abstract 5608: The BRCA1-associated role of CDK9 in response to DNA damage is independent of its canonical role in transcription
Authors: Thales C. Nepomuceno, Marcelo A. Carvalho, Alvaro N. Monteiro
Journal: Cancer Research (2024)

Abstract The understanding of the biological role of BRCA1 in maintaining genomic integrity through homologous recombination (HR) repair has driven the development of targeted treatments with PARP inhibitors (PARPi) in BRCA1-linked tumors with promising results. Recently, cyclin-dependent kinase 9 (CDK9) inhibitors have emerged as therapeutic options to treat cancer. We have previously implicated CDK9 in genome integrity maintenance through HR repair by modulating BRCA1 recruitment to double-stranded break sites. CDK9 is a component of the positive transcription elongation (PTEF-b) complex and more recently was proposed by the hereditary breast case-control (BEACCON) study as a putative breast cancer (BC) predisposition gene in non-BRCA families. Differently from BRCA1-linked BCs, loss-of-function mutations in CDK9 were significantly correlated with ER-positive and Lobular BCs. CDK9 expression is also elevated in metastatic and recurrent ovarian cancer (OC) tissue and correlates with poor prognosis in OC patients. Here we characterize the BRCA1/BARD1/CDK9 complex using protein-protein interaction assays. Our data indicate that the CDK9/BARD1 interaction occurs indirectly through BRCA1. We also generated a separation-of-function mutation in CDK9 (mutCDK9) that disrupts its interaction with BRCA1 but retains its kinase activity and preserves its role in transcription. We rescued the mutCDK9/BRCA1 interaction using a complementary mutation in BRCA1 (cmutBRCA1), that retains BRCA1 role in cell viability. Further, we employed CRISPR-based genome editing to generate genetically defined haploid HAP1 cell lines that express mutCDK9 in various TP53BP1 and BRCA1 backgrounds. The mutCDK9 cells preserve global RNA transcription and the phosphorylation status of the RNA polymerase II. We observed that mutCDK9 cells are more sensitive to the PARPi, rucaparib when compared to wild-type cells in proficient and deficient TP53BP1 backgrounds. However, mutCDK9 expression did not affect the sensitivity of HAP1 cells expressing cmutBRCA1. Collectively, our data suggest that CDK9 acts in genome integrity maintenance by HR through its interaction with BRCA1 independently of its canonical role in transcription. Citation Format: Thales C. Nepomuceno, Marcelo A. Carvalho, Alvaro N. Monteiro. The BRCA1-associated role of CDK9 in response to DNA damage is independent of its canonical role in transcription [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5608.
Abstract 6275: Exposure to neighborhood violence rewires glucocorticoid receptor binding and drives proliferation and invasiveness in lung tumor samples
Authors: Hannah Heath, Jin Young Yoo, Vani Sharma, Hannah McGee, Aiman Soliman, Abeer Mohamed, Alicia K. Matthews, Robert Winn, Zeynep Madak-Erdogan, Sage Kim
Journal: Cancer Research (2024)

Abstract Background: Despite smoking less, Black men experience higher incidence of lung cancer compared to white men. This health disparity is even more prevalent in Black men from Chicago, suggesting local neighborhood factors impacting tumorigenesis. Preliminary data indicate that, compared to white men, Black men are more likely to reside in neighborhoods with high levels of violence and have elevated levels of hair cortisol. Objective: To understand the link between lung tumorigenesis and exposure to neighborhood violence, our objective is to investigate the chromatin recruitment of the receptor for cortisol, called the glucocorticoid receptor (GR), and to correlate this recruitment with target gene expression levels. Methods: Utilizing CUT &amp; RUN, we identified the gene binding sites of GR using 15 lung tumor and corresponding healthy tissue samples from lung cancer patients living in Chicago. GR recruitment to chromatin was correlated with the neighborhood homicide rate obtained using patients’ zip codes. Spatial transcriptome profiles for these 15 lung tumor samples were obtained from the Space Ranger pipeline and gene expression hot spots of GR target genes were visualized using Loupe Browser (10x Genomics). Results: GR recruitment to regulatory regions of chromatin increases with greater zip code level violence rates. In patients from high violence neighborhoods, tumor samples had higher magnitude of binding compared to normal neighboring tissue. In tumor samples from patients living in high violence compared to low violence neighborhoods, GR binding is seen in genes that are associated with increased tumor aggressiveness. Hot-spot analysis of these genes found strong co-expression of genes associated with proliferation and invasion in samples from high violence but not low violence neighborhoods. Conclusion: Exposure to neighborhood violence may impact tumor biology via increased GR recruitment to genes associated with proliferation and invasion. Citation Format: Hannah Heath, Jin Young Yoo, Vani Sharma, Hannah McGee, Aiman Soliman, Abeer Mohamed, Alicia K. Matthews, Robert Winn, Zeynep Madak-Erdogan, Sage Kim. Exposure to neighborhood violence rewires glucocorticoid receptor binding and drives proliferation and invasiveness in lung tumor samples [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6275.
Abstract 7387: Fully automated segmentation and volumetric measurement of intracranial meningioma using deep learning
Authors: Ho Kang, Joseph N. Witanto, Kevin Pratama, Doohee Lee, Kyu Sung Choi, Seung Hong Choi, Min-Sung Kim, Jin Wook Kim, Yong Hwy Kim, Sang Joon Park, Chul-Kee Park
Journal: Cancer Research (2024)

Abstract Most intracranial meningiomas are small, asymptomatic, and incidentally found tumors. Since the growth of meningioma is the principal indication of treatment, accurate and rapid measurement of the volume of intracranial meningiomas is essential in clinical practice to determine the growth rate of the tumor. It could be useful for the management of meningiomas given their increasing incidence and the wait-and-see policy currently in use for asymptomatic meningiomas. The aim of this study was to develop and validate a computational model for fully automated meningioma segmentation and volume measurement on contrast-enhanced MR scans using deep learning. The retrospectively collected axial contrast-enhanced T1-weighted section images from patients diagnosed with meningioma were manually segmented and used to construct automatic segmentation models with six U-Net- and nnU-Net-based architectures. The performance of each model was evaluated with the Sørensen-Dice similarity coefficient (DSC) with internal (IVS) and external validation sets (EVS), each consisting of 100 independent MRI examinations. A total of 12,909 section images from 459 patients were applied for the training (median age 58 [52-66] [IQR]; 385 women [83.9%]). The median tumor volume of the training set was 2.36 cm3. A 2D nnU-Net showed the highest median DSCs of 0.922 and 0.893 for the IVS and EVS, respectively. The nnU-Nets achieved superior performance in meningioma segmentation than the U-Nets. The DSCs of the 2D nnU-Net for small meningiomas less than 1 cm3 were 0.769 and 0.780 with the IVS and EVS, respectively. We successfully developed a fully automated and accurate volumetric measurement tool for meningioma using nnU-Net. The volumetry performance for small meningioma was significantly better than that achieved in previous studies. The results of this study are clinically applicable and are expected to be of great use in the management of monitored meningioma patients. Citation Format: Ho Kang, Joseph N. Witanto, Kevin Pratama, Doohee Lee, Kyu Sung Choi, Seung Hong Choi, Min-Sung Kim, Jin Wook Kim, Yong Hwy Kim, Sang Joon Park, Chul-Kee Park. Fully automated segmentation and volumetric measurement of intracranial meningioma using deep learning [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7387.
Abstract 6190: Patterns of EGFR and HER3 co-expression in solid tumors
Authors: Matthew Wood, Cody Morrison, Jahan Salar Khalili, Yi Zhu
Journal: Cancer Research (2024)

Abstract EGFR and HER3 are members of the ERBB receptor family and transmit growth and survival signals to cancer cells upon ligand binding. While both receptors are well established targets for cancer therapy, greater understanding of the relationship of their expression patterns in human cancer is needed to establish the scope of therapeutic potential. To evaluate the co-expression pattern of EGFR and HER3, cancer FFPE tissue microarrays from several cancer types were evaluated by immunofluorescence imaging and digital pathology, including cell-by-cell marker intensity and spatial analyses within the tumor and stromal compartments. Tissue cores were assigned H-scores, and individual cells were binned into 0, 1+, 2+, 3+ scoring based on established digital pathology methods using QuPath software. Spatial cytometry was used to further evaluate single-cell expression intensity. Analysis was conducted widely on multiple normal human tissues as well as cases of NSCLC adenocarcinoma n=86, NSCLC squamous cell carcinoma n=84, SCLC n=43, TNBC n=45, Biliary tract cancers n=80, Nasopharyngeal carcinomas n=60. Overall, the results of this analysis show the intermediate to high prevalence of EGFR and HER3 co-expression within each indication, as well as the frequency of EGFR and HER3 expressing cells. Furthermore, EGFR and HER3 heterodimers were confirmed by proximity ligation assay in certain index cases. Notably, of several observations, we observe NSCLC cases show a profound absence of EGFR- HER3+ tumor cells. Additionally, we observe that co-expression of EGFR and HER3 in normal human tissues is rare and of low signal intensity. Citation Format: Matthew Wood, Cody Morrison, Jahan Salar Khalili, Yi Zhu. Patterns of EGFR and HER3 co-expression in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6190.