tbuckley/cabot-search huggingface dataset:
Abstract 3041: The small MAF transcription factor MAFG is a potent driver of melanoma
Authors: Olga Vera, Michael Martinez, Zulaida Soto-Vargas, Xiaonan Xu, Florian Karreth
Journal: Cancer Research (2024)

Abstract While common mutations in potent proto-oncogenes and tumor suppressors induce melanoma formation, no recurrent mutations associated with the late stages of melanomagenesis have been identified. Instead, non-mutational mechanisms such as the deregulation of transcriptional or epigenetic programs typically promote the malignant progression and metastasis of melanoma. We have previously identified the small MAF transcription factor MAFG as a critical target of the melanoma suppressor miRNA miR-29, prompting an in-depth evaluation of the role of MAFG in melanoma. MAFG expression is elevated in melanoma compared to melanocytes and increases with tumor stage. Ectopic expression of MAFG in human melanocytes and melanoma cells enhances proliferation in vitro and promotes melanoma growth in vivo. Moreover, MAFG overexpression in BrafV600E; PtenFL/+ mice accelerated melanomagenesis, significantly shortening overall survival. Despite being a critical NRF2 dimerization partner, NRF2 was dispensable for the effects of MAFG. Moreover, MAFG overexpression in melanoma cells had no effect on the activity of NRF2 transcriptional reporters, nor did it induce transcriptional programs associated with NRF2. RNA sequencing and pathway analysis revealed MAFG-mediated effects on melanoma-associated processes such hypoxia, the PI3K/AKT pathway, and pigmentation. Indeed, MAFG induced HIF1a under normoxic conditions, enhanced AKT phosphorylation, and downregulated MITF and its target genes in the pigmentation pathway in melanoma cells. Interestingly, MAFG also potently enhanced AXL expression, suggesting that MAFG may promote melanoma, at least in part, by affecting the MITF/AXL balance that is associated with melanoma phenotype switching. We next analyzed whether MAFG is required for melanoma. Interestingly, silencing MAFG in human melanoma cells robustly inhibited growth in vitro. Moreover, the CRISPR/Cas9-mediated knockout of MAFG in an aggressive BrafV600E; PtenFL/FL model potently prevented melanoma formation. Given the mild phenotype of MAFG whole-body knockout mice, our results suggest targeting of MAFG or its downstream pathways as a viable therapeutic approach in melanoma. In conclusion, our study establishes MAFG as a potent driver of melanoma development and nominates it as a therapeutic target. Citation Format: Olga Vera, Michael Martinez, Zulaida Soto-Vargas, Xiaonan Xu, Florian Karreth. The small MAF transcription factor MAFG is a potent driver of melanoma [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 3041.
Abstract 2010: TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell carcinoma
Authors: Hao Zhang, Chunxiang Li, Jie He
Journal: Cancer Research (2024)

Abstract Esophageal squamous cell carcinoma (ESCC) accounts for 85% of cases of esophageal cancer worldwide and is the predominant form of esophageal cancer in Asia. A significant number of patients with ESCC are diagnosed at an advanced stage, resulting in poor prognosis. Cisplatin resistance and cancer metastasis are the main clinical challenges in the treatment of advanced ESCC. KLF12 has been extensively characterized as a transcriptional repressor, and previous studies have unveiled its roles in angiogenesis, neural tube defect, and NK cell proliferation. However, the precise contribution of KLF12 to cancer treatment remains undefined. Here, we show that KLF12 is downregulated in various cancer types, and KLF12 downregulation promotes cisplatin resistance, cancer metastasis and recruitment of regulatory T cells (Tregs) in ESCC cell lines. Mechanistically, KLF12 binds to the promoters of L1CAM and represses its expression. Depletion of L1CAM abrogates cisplatin resistance, cancer metastasis, and Treg recruitment caused by KLF12 loss. Moreover, the E3 ubiquitin ligase TRIM27 binds to the N-terminal region of KLF12 and ubiquitinates KLF12 at K326 via K33-linked polyubiquitination. Notably, TRIM27 depletion enhances the transcriptional activity of KLF12 and consequently inhibits L1CAM expression. Overall, our study has firstly elucidated a novel regulatory mechanism involving TRIM27, KLF12 and L1CAM, which plays a substantial role in cisplatin resistance and cancer metastasis in ESCC, and targeting KLF12/L1CAM axis may be a promising approach for ESCC treatment. Citation Format: Hao Zhang, Chunxiang Li, Jie He. TRIM27 Interacts with KLF12 to regulate L1CAM expression, influencing cisplatin resistance and cancer metastasis in esophageal squamous cell 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 2010.
Abstract 2722: CTN001, a first Twin Fc-immune cell engager, with a superior potency against Her2+ and Her2-low cancers by engaging multiple Fc-mediated mechanisms
Authors: Deokjae Lee, Sujin Yoon, Jiseon Bae, Minju Kim, Ki-June Lee, Eunmi Kim, Hyunkyu Park, Eun S. Choi, Gi-Hyeok Yang
Journal: Cancer Research (2024)

Abstract Many therapeutic monoclonal antibodies mediate the immune effector functions through the engagement of their fragment crystallizable (Fc) domain and Fcγ receptors on the immune cells. However, these functions are limited due to the low affinity of their interactions and the requirement of abundancy of antigens for the avidity effects. Recently, mutation-based Fc engineered antibodies showed their enhanced immune effector functions mostly through the NK cell-mediated ADCC. To overcome the limited improvement of current Fc engineering, we developed an innovated platform, Twin Fc-Immune Cell Engager (Twin Fc-ICE) composed of a single Fab domain and two Fc domain with drug-like properties. Here we demonstrated the superior efficacy of CTN001, a first Twin Fc-ICE, in in vitro and in vivo Her2+ tumor models. CTN001 bound to various types of Fcγ receptor-expressing immune cells with stronger affinity, supported by its better in vitro affinity to all types of Fcγ receptors than wild type and Fc-engineered antibodies. To evaluate the pharmacological efficacies, CTN001 was tested for its functions of in vitro antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC) and in vivo efficacy with Her2+ xenograft models. In Her2+ models, both CTN001 and trastuzumab induced ADCC-mediated effects, but CTN001 showed better anti-tumor cytotoxicity through ADCP and CDC than trastuzumab. Importantly, CTN001 also showed cytotoxic effects on Her2-low tumor cells. Consistently, CTN001 showed better anti-tumor efficacy than trastuzumab or its combination with pertuzumab in Her2+ tumor xenograft model and, surprisingly, even in Her2-low or resistant models. These results suggest that CTN001 can provide new therapeutic options for treating Her2-low patients differentiated from antibody-drug conjugates (ADCs), and that the Twin Fc-ICE can be an innovative platform to overcome limitations of existing therapeutics. Citation Format: Deokjae Lee, Sujin Yoon, Jiseon Bae, Minju Kim, Ki-June Lee, Eunmi Kim, Hyunkyu Park, Eun S. Choi, Gi-Hyeok Yang. CTN001, a first Twin Fc-immune cell engager, with a superior potency against Her2+ and Her2-low cancers by engaging multiple Fc-mediated mechanisms [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 2722.
Abstract 7139: Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian cancer
Authors: Jeong-Won Lee, Kwangho Lee, Byumseok Koh, Yoo-Young Lee, Duk-Soo Bae
Journal: Cancer Research (2024)

Abstract Ovarian cancer, a leading cause of cancer-related deaths in women, remains a formidable challenge, especially in the context of platinum-resistant disease. This study investigated the potential of the benzimidazole derivative BNZ-111 as a novel treatment strategy for platinum-resistant ovarian cancer. With improved pharmacokinetic parameters, BNZ-111 effectively disrupts tubulin polymerization through hydrogen bonds and hydrophobic interactions. It demonstrated strong cytotoxicity in both chemo-sensitive and chemo-resistant epithelial ovarian cancer cell lines, inducing apoptosis and G2/M cell cycle arrest. In vivo experiments using orthotopic and patient-derived xenograft models showed significant tumor growth inhibition without apparent toxicity to vital organs. Unlike paclitaxel, BNZ-111 proved effective in paclitaxel-resistant cells, potentially by bypassing interaction with MDR1 and modulating β-3 tubulin expression to suppress microtubule dynamics. This study suggests that BNZ-111, with favorable drug-like properties, holds promise as a therapeutic option for platinum-resistant ovarian cancer, addressing a critical clinical need in gynecologic oncology Citation Format: Jeong-Won Lee, Kwangho Lee, Byumseok Koh, Yoo-Young Lee, Duk-Soo Bae. Anti-cancer effects of benzimidazole derivative BNZ-111 on paclitaxel-resistant ovarian 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 7139.
Abstract 3039: Pan cancer therapeutic inhibition of oncogenic c-MYC by the engineered destabilized 3’UTR of c-MYC
Authors: Chidiebere U. Awah
Journal: Cancer Research (2024)

Abstract c-MYC is a master transcription factor that is over expressed in more than 70% of human cancers. There is no clinically approved direct inhibitor of c-MYC. Recently, we reported the development of the engineered destabilized 3’UTR of MYC constructs which is a novel mRNA overwriting technology through which we directly destabilized and degraded c-MYC. Here we report that we have extended this technology in directly targeting and degrading c-MYC in multiple ethnically diverse triple negative breast cancer cell lines, ovarian cancers, neuroendocrine prostate cancers and pancreatic cancers. The constructs are specific, titratable, and directly engaged the c-MYC target validated by RNA transcript technologies. We have performed head-to-head IC50 dose dependent titration comparison with the engineered destabilized 3’UTR of c-MYC constructs and chemotherapies (DNA damaging agents, microtubules inhibiting drugs, alkylating agents) as well as immune checkpoint inhibitor. We found evidence that suggests that the engineered destabilized 3’UTR of c-MYC is likely to be superior to these therapies in pan cancers driven by c-MYC. Citation Format: Chidiebere U. Awah. Pan cancer therapeutic inhibition of oncogenic c-MYC by the engineered destabilized 3’UTR of c-MYC [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 3039.
Abstract 4263: Prostate cancer cell-derived small extracellular vesicles regulate monocyte migration via STEAP4 and promote a monocyte transitional state
Authors: Nicole M. Naranjo, Anna Testa, Santosh K. Yadav, Ulhas P. Naik, Lei Yu, William K. Kelly, Qin Liu, Jianyi Ding, Hushan Yang, Hsin Yao Tang, Cecilia E. Verrillo, Craig D. Hooper, Lucia R. Languino
Journal: Cancer Research (2024)

Abstract Our group has previously shown that prostate cancer (PrCa)-derived small extracellular vesicles (sEVs) are powerful cell communication mediators as they carry an array of proteins that have the ability to change recipient cell functions. Here, we describe a novel pathway of cancer cell-monocyte communication mediated by sEVs. Since sEVs carry cargoes that alter recipient cell phenotypes, we analyzed via proteomic analysis sEVs released from PC3 PrCa cells. Using CRISPR Cas9 methods, we downregulated IFIT3 (Interferon-induced proteins with tetratricopeptide repeats-3, member of the interferon-stimulated gene family) in PC3 PrCa cell (IFIT3KO). We then isolated sEVs from PC3 or IFIT3KO cells by using differential ultracentrifugation followed by iodixanol density gradient. Our proteomic analysis of IFIT3KO sEVs compared to PC3 sEVs shows that IFIT3 downregulation results in a significant upregulation of a metalloreductase, STEAP4 (six-transmembrane-epithelial antigen of the prostate 4), which is increased in PrCa cells and promotes PrCa cell proliferation and survival. STEAP4 is also known to promote an anti-inflammatory response in monocytes and macrophages. We then, investigated whether PrCa sEVs enriched in STEAP4 have a causal effect on monocyte functions and phenotype by using adhesion and migration assays as well as flow cytometry. Our results show that while all PrCa sEVs stimulate the adhesion of healthy donor or non-metastatic PrCa patient monocytes, only PrCa sEVs expressing STEAP4 increase their migration. In parallel, we provide evidence that all PrCa sEVs affect some of the M2 (CD163 or CD204) and M1 (CD80 or HLA DR) polarization markers analyzed in healthy donor monocytes. We show that there is a transitional state induced by PrCa sEVs in healthy donor monocytes, which occurs in a STEAP4-independent manner. This state mimics the non-metastatic PrCa patient monocyte phenotype. In conclusion, we describe a unique pathway whereby PrCa cell sEVs expressing STEAP4 promote monocyte migration with partial changes to their polarization. Funding: This study was supported by NCI P01-CA140043, R01-CA224769, Pennsylvania DOH - Cure award to L.R.L Citation Format: Nicole M. Naranjo, Anna Testa, Santosh K. Yadav, Ulhas P. Naik, Lei Yu, William K. Kelly, Qin Liu, Jianyi Ding, Hushan Yang, Hsin Yao Tang, Cecilia E. Verrillo, Craig D. Hooper, Lucia R. Languino. Prostate cancer cell-derived small extracellular vesicles regulate monocyte migration via STEAP4 and promote a monocyte transitional state [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 4263.
Abstract 5440: TM4SF1 maintains cancer stemness in cholangiocarcinoma
Authors: Xiao Bin Zhu, Jihye Golino, Xin Wang, Changqing Xie
Journal: Cancer Research (2024)

Abstract Cholangiocarcinoma (CCA) is an aggressive liver malignancy with increased incidence globally but poor prognosis. Cancer stemness plays critical roles on tumor initiation, recurrence, and resistance to therapy. However, the mechanism of stemness maintenance in CCA has been less explored. Previously, we have reported TM4SF1 is associated with poor survival in CCA and high expression of TM4SF1 tends to promote tumorigenesis. In this study, we found that the expression of TM4SF1 gene is upregulated in tumor tissues compared to adjacent normal tissues in CCA based on bulk RNA sequencing dataset from The Cancer Genome Atlas (TGCA) CCA cohort. There is a positive correlation between the expression of TM4SF1 and stemness genes, ITGB3, SOX9, ALDH1A3, and ITGB1. Interestingly, knockdown of TM4SF1 with siRNA in CCA cell line HuCCT-1 cells demonstrated a decrease in expression of cancer stem cell surface markers, CD24 and Prom1. Furthermore, with a CRISPR-based lentivirus construct to knockdown TM4SF1 gene in HuCCT-1 cells in vitro, we found that spheroid formation in TM4SF1 knockdown was attenuated in comparison to TM4SF1 wild type. In addition, the results from flow cytometry and RT-PCR showed a corresponding decrease in CD24 and CD133 expression with TM4SF1 knockdown when comparing to TM4SF1 wild type. In conclusion, TM4SF1 is associated with the stemness of CCA and could be a therapeutic target for CCA therapy to overcome therapy resistance in future. Citation Format: Xiao Bin Zhu, Jihye Golino, Xin Wang, Changqing Xie. TM4SF1 maintains cancer stemness in cholangiocarcinoma [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 5440.
Abstract 2729: Discovery and characterization of LILRB2XPD-L1 bispecific antibody SPX-303
Authors: Anthony Haight, Qian Chen, Brandon William, Dinh-Duc Nguyen, Robert Cai, Jichun Ma, Michael White, Jindong Jin, Jadon Shen, Martin Siekierzycki, Victoria Hall, Hua Jin, Roland Meier, Justin Moser
Journal: Cancer Research (2024)

Abstract The advent of immunotherapy has led to deep and sometimes durable remissions in certain cancers. However, the variable response rates and development of resistance mechanisms pose significant challenges to the current therapies. The immunosuppressive nature in the tumor microenvironment (TME) can drive many of these observations. Reversing this immunosuppression is a promising avenue for enhancing and broadening the applicability of IO therapies. Macrophages are critically modulated by LILRB2, a pivotal receptor in their maturation and polarization to the M2 immunosupressive phenotype. We report the discovery and development of a novel anti-LILRB2/PD-L1 bispecific antibody, SPX-303, designed using an anti-LILRB2 IgG4 derived from a mouse hybridoma screen and linked with an anti-PD-L1 epitope. SPX-303 demonstrates sub-nanomolar binding affinity to both LILRB2 and PD-L1 targets, effectively blocking the interaction between LILRB2 and its ligand, as well as inhibiting PD-1 binding to PD-L1. In in vitro functional assays, SPX-303 exhibits effects comparable to the parental monomeric anti-LILRB2 (SPX-104) in redirecting macrophage polarization from M2 to M1 stage, as observed in both cultured PBMC and human monocyte-derived macrophage (HMDM) models. Furthermore, SPX-303 demonstrates a synergistic effect in inducing T cell activation in the autologous mixed lymphocyte reaction assay (auto-MLR), surpassing the effects of the anti-LILRB2 epitope (SPX-104) and the anti-PDL1 fragment (single-domain anti-PDL1) alone or in combination. In vivo experiments reveal that SPX-303 significantly inhibits tumor growth. Collectively, these results support SPX-303 as a novel therapeutic antibody that effectively enhances anti-cancer immunity in the treatment of advanced solid tumors. The pre-clinical data as well as the clinical plan of SPX-303 will be presented. Citation Format: Anthony Haight, Qian Chen, Brandon William, Dinh-Duc Nguyen, Robert Cai, Jichun Ma, Michael White, Jindong Jin, Jadon Shen, Martin Siekierzycki, Victoria Hall, Hua Jin, Roland Meier, Justin Moser. Discovery and characterization of LILRB2XPD-L1 bispecific antibody SPX-303 [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 2729.
Abstract 1398: The role of ST8SIA2 &amp; ST8SIA4 in melanoma progression and metastasis
Authors: Amirali Amirfallah, Kayla Gallant, Maria Cavallo, Zongguan Huang, Edward Hartsough
Journal: Cancer Research (2024)

Abstract Melanoma is the deadliest form of skin cancer; while early detection affords patients a 5-year survival rate greater than 90 percent, survival for metastatic patients is poor. Metastatic dissemination is reliant on melanoma’s ability to escape immune surveillance and migrate to distant organs. These processes are heavily influenced by cell surface proteins, which themselves can be regulated by post-translational modifications (PTM) like protein glycosylation. An understudied glycosylation that may affect immune evasion and cancer progression is polysialylation (polySia). Here, a long-chained polymer of sialic acid moieties is formed by the polysialyltransferases ST8SIA2 and ST8SIA4. In silico analysis suggests that compared to normal skin, primary cutaneous melanoma has elevated expression of both ST8SIA2 and ST8SIA4. Interestingly, although ST8SIA4 is upregulated in metastatic samples, its expression is associated with increased survival. Further analysis revealed a positive correlation between CD8+ T cell infiltrates and ST8SIA4 expression. Furthermore, analysis of ST8SIA2 expression shows an inverse correlation with survival and T Cell CD8+ cells infiltration, suggesting ST8SIA2 and -4 differentially regulate the tumor immune microenvironment. One potential polySia modified cell surface protein, mediating these effects is Cell Adhesion Molecule 1 (CADM1). CADM1 is a target of ST8SIA2 and may also be modified by ST8SIA4. Loss of CADM1 increases the invasive properties of melanoma cells and our recent point mutational analysis reveals that the adhesive function of CADM1 might be regulated by polySia at Asp 113. In addition to its role in cancer migration and invasiveness, CADM1 expression may also affect the tumor immune environment. Further investigations are needed to untangle the complex relationship between PolySia modification and melanoma immune evasion and metastasis. Citation Format: Amirali Amirfallah, Kayla Gallant, Maria Cavallo, Zongguan Huang, Edward Hartsough. The role of ST8SIA2 &amp; ST8SIA4 in melanoma progression and metastasis [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 1398.
Depletion of lamins B1 and B2 promotes chromatin mobility and induces differential gene expression by a mesoscale-motion-dependent mechanism
Authors: Emily M. Pujadas Liwag, Xiaolong Wei, Nicolas Acosta, Lucas M. Carter, Jiekun Yang, Luay M. Almassalha, Surbhi Jain, Ali Daneshkhah, Suhas S. P. Rao, Fidan Seker-Polat, Kyle L. MacQuarrie, Joe Ibarra, Vasundhara Agrawal, Erez Lieberman Aiden, Masato T. Kanemaki, Vadim Backman, Mazhar Adli
Journal: Genome biology (2024)

B-type lamins are critical nuclear envelope proteins that interact with the three-dimensional genomic architecture. However, identifying the direct roles of B-lamins on dynamic genome organization has been challenging as their joint depletion severely impacts cell viability. To overcome this, we engineered mammalian cells to rapidly and completely degrade endogenous B-type lamins using Auxin-inducible degron technology.