tbuckley/cabot-search huggingface dataset:
Abstract 2611: Non-specific elimination of tumor-associated neutrophils by antibody-drug conjugates boosts anti-tumor immunity for PD-1 immunotherapy
Authors: Shili Yao, Lu Sun, Xiu Zhu, Hanfei Xie, Tong Yang, Peng Guo, Huarong Tang, Tao Zhu
Journal: Cancer Research (2024)

Abstract Background: Antibody-drug conjugates (ADCs) play a key role in targeted therapy of solid tumors. However, few studies have examined the impact of ADCs on the tumor microenvironment (TME), particularly on innate immune cells. To elucidate this, this study focuses on investigating the comprehensive impacts of ICAM1-DXd on the tumor microenvironment, especially on tumor-associated neutrophils (TAN) and its synergistic effect with PD-1 immunotherapy. Methods: Firstly, the efficacy and prognosis of ICAM1-DXd, a potent ADC for cervical cancer, were determined in pre-clinical tumor models, providing crucial transcriptomic and biological function information by using RNA-seq. Then, pathological studies were performed to evaluate the abundance and location of TAN (Ly6G+/MPO+) in TME post-ADC treatment. The interaction between TAN and ICAM1-DXd and subsequent impacts on adaptive immune cells (e.g., CD8+ cells) was examined by flow cytometry (FACS), confocal fluorescent imaging, and western blot techniques (WB). Eventually, the synergistic effect of ICAM1-DXd and PD-1 monoclonal antibody were investigated in an immunocompetent animal model. Results: ICAM1-DXd potently inhibits cervical tumor growth in preclinical models, and RNA-seq analysis revealed that ICAM1-DXd treatment induces a strong down-regulation of neutrophil activation, especially for Ly6G+/MPO+ TANs, a subtype with pro-tumor function. IHC and FACS results confirmed that pro-tumor TANs were efficiently eliminated in TME by ICAM1-DXd treatment via non-specific phagocytosis in comparison with peripheral blood neutrophils. ICAM1-DXd-phagocytised TANs also elicit a strong bystander killing effect by cleaving the quadra peptide linker of ICAM1-DXD by cathepsin B. This ADC-mediated TAN elimination effectively ameliorates immunosuppressive TME and works in synergy with PD-1 immunotherapy in preclinical models. Conclusion: In preclinical models of cervical cancer, ICAM1-DXd not only directly ablates cancer cells via antigen recognition but also non-specifically kills tumor-promoting TANs, resulting in an improved tumor immune microenvironment, providing a shred of mechanistic evidence supporting ADC and PD-1 combination therapy. Citation Format: Shili Yao, Lu Sun, Xiu Zhu, Hanfei Xie, Tong Yang, Peng Guo, Huarong Tang, Tao Zhu. Non-specific elimination of tumor-associated neutrophils by antibody-drug conjugates boosts anti-tumor immunity for PD-1 immunotherapy [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 2611.
Abstract 7663: Identification of high-risk patients in multiple myeloma using a clonal gene signature
Authors: Jian-Rong Li, Christiana Wang, Chao Cheng
Journal: Cancer Research (2024)

Abstract Introduction: Multiple myeloma (MM) is a heterogeneous disease with a small subset of high-risk patients associated with poor prognosis. The identification of these patients is crucial for treatment management and strategic decisions. Methods: We developed a novel computational framework that only requires gene expression profiles to define prognostic gene signatures by selecting genes with expression driven by inferred clonal copy number alterations. We applied this framework to MM and developed a clonal gene signature (CGS) consisting of only 22 genes. This prognostic signature was evaluated in 5 independent datasets with gene expression data of a total of 2,155 MM samples. For each patient, we calculated a prognostic score based on the expression of the signature genes. Multivariate Cox regression analyses were performed to investigate the association of these signature scores with patient prognosis after adjusting established clinical factors. The performances of CGS and the only commercialized MM gene signatures, GEP70 and SKY92, in identifying high-risk patients were carefully compared by multiple different approaches. Results: Our results indicated that CGS provided significant prognostic values after adjusting for well-established prognostic factors including cytogenetic abnormalities, International Staging System (ISS), and Revised ISS (R-ISS). In addition, it showed significant prognostic associations in patient subsets stratified by these conventional prognostic factors. Importantly, CGS demonstrated a better performance in identifying high-risk patients compared to the GEP70 and SKY92 signatures, which have been recommended for prognostic stratification in MM. Moreover, CGS can further stratify patients into subgroups with significantly differential prognoses when applied to the high-risk and low-risk groups already identified by GEP70 and SKY92. The higher CGS score of patients is significantly associated with poor response to dexamethasone, a commonly used drug for MM treatment. Conclusions: In summary, we proposed a computational framework that only requires gene expression data to identify clonal gene signatures for prognosis prediction. The CGS provides a useful biomarker for improving prognostic stratification in MM, especially for the identification of patients with the highest risk. The computational framework used for defining this signature provides a useful tool, which can be readily applied to many other cancer types. Citation Format: Jian-Rong Li, Christiana Wang, Chao Cheng. Identification of high-risk patients in multiple myeloma using a clonal gene signature [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 7663.
Abstract 2620: BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity
Authors: Zhenyan Han, Chengzhang Shang, Yifu Zhang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang
Journal: Cancer Research (2024)

Abstract 5T4 is a highly expressed tumor-associated antigen associated with adverse clinical outcomes in solid tumors, and is an attractive therapeutic target due to low expression on normal adult tissues. While several therapeutic agents targeting 5T4 antigen are currently being evaluated in human clinical trials, none have yet entered the market. Another target, MUC1, is currently under clinical investigation, with most drugs in clinical trials showing limited efficacy due to shedding of the target antigen MUC1-N. 5T4 and MUC1 are commonly co-expressed in various solid tumors, including lung, breast, colorectal and pancreatic cancers, suggesting that targeting both antigens with a single drug could be a promising therapeutic strategy. We previously identified and evaluated antibodies targeting human 5T4 and MUC1-C (cleaved MUC1) using RenLite® fully human common light chain mice. Here, selected antibodies were constructed into 5T4 × MUC1 bispecific antibodies (bsAb). The 5T4-MUC1 bsAb demonstrated high avidity in multiple human tumor cell lines by flow cytometry. Notably, the parental 5T4 antibody also binds strongly to many tumor cell lines. Internalization assays demonstrate that the internalization of 5T4-MUC1 bsAb in breast cancer cells was enhanced compared to the parental anti-5T4 and anti-MUC1 monoclonal antibodies, as measured by Incucyte® live cell imaging. Subsequently, the 5T4-MUC1 bsAb was then conjugated with monomethyl auristatin E (MMAE) to generate 5T4 x MUC1 bsADC (BCG016). Cytotoxicity assays indicate that BCG016 improved tumor cell killing in vitro compared to benchmark ADCs, and in vivo efficacy studies showed superior anti-tumor efficacy of BCG016 in patient-derived NSCLC xenografts compared to benchmark ADCs and parental ADC combination therapy. In summary, we have generated a novel bispecific ADC targeting 5T4 and the cleaved MUC1-C protein, which remains membrane-bound on tumor cells. The 5T4-MUC1 bsADC showed superior anti-tumor efficacy in PDX models and has the potential to be a novel therapeutic for 5T4 and MUC1 co-expressing tumors. Citation Format: Zhenyan Han, Chengzhang Shang, Yifu Zhang, Gao An, Chaoshe Guo, W. Frank An, Yi Yang. BCG016, a first-in-class bispecific antibody-drug conjugate targeting 5T4 and MUC1, demonstrates potent preclinical anti-tumor activity [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 2620.
Abstract 2635: An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast cancer
Authors: You-Zhe Lin, Wan-Rong Wu, Feng-Chi Chung, Yi-Chun Shen, Chuan-Chun Lee, Hong-Wei Li, Guang-Jan Lin, Wei-Chung Chengx, Shao-Chun Wang
Journal: Cancer Research (2024)

Abstract T cell exhaustion is a state of dysfunctional T cell response characterized by prolonged antigen exposure and diminished effector functions, a significant cause of tumor tolerance, and poor response to immune checkpoint blockade (ICB) therapy. T cell exhaustion is a highly dynamic process involved with a network of genetic and epigenetic regulation that program the T cell functions. Epigenetic regulation by microRNAs targets multiple genes involved in T cell function and is expected to be a major contributor to the functional programming of tumor-associated T cells. However, the underlying causal mechanisms remain to be determined. Here, we show that the microRNA miR-379-5p is a critical epigenetic regulator for promoting T cell function and suppressing exhaustion induced by chronic stimulation. The microRNA is identified by integrating bioinformatic interrogation of the miRNA databases cross-referencing with the TCGA database for genes involved in T cell functioning and their correlation with clinical outcomes, coupled with molecular profiling of miRNAs in experimental T exhaustion. Notably, the expression levels of miR-379-5p in tumor tissues, which encompass cancer cells and the surrounding stromal components, including immune cells, are closely associated with favorable prognosis of various cancer types. Further molecular and cellular characterization of miR-379-5p entailing cell culture, animal models, and patient-derived tumor organoids shows that it exerts suppressive effects by targeting specific sequences in the 3’ untranslated region (UTR) of critical immune checkpoint genes in T cells, thereby enhances the effector functions of cytotoxic T cells for tumor clearance. Ectopic expression of miR-379-5p shifts the evolution of primary T cells toward memory-like effector cells while silencing miR-379-5p induces exhaustion and abrogates the cytotoxic activity of primary T cells. We further demonstrate that transcriptional downregulation of miR-379-5p in T cells by a nuclear receptor transcription factor which is responsible for initiating the exhausting process impairs the tumor suppression function of T cells. Our studies indicate that miR-379-5p can function as a tumor suppressor by protecting T cells from exhaustion and bears the potential for developing novel strategies to improve the response to ICB therapy in breast cancer. Citation Format: You-Zhe Lin, Wan-Rong Wu, Feng-Chi Chung, Yi-Chun Shen, Chuan-Chun Lee, Hong-Wei Li, Guang-Jan Lin, Wei-Chung Chengx, Shao-Chun Wang. An epigenetic regulation targeting inhibitory receptors and attenuates CD8 T cell exhaustion in breast 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 2635.
Abstract 2639: Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response
Authors: Irene Fischetti, Botti Laura, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P. Colombo, Elena Jachetti
Journal: Cancer Research (2024)

Abstract Castration resistant prostate cancer (CRPC) is a fatal disease. Androgen receptor pathway inhibitors, like enzalutamide, are initially effective but resistance eventually occurs, often associated to the emergence of aggressive neuroendocrine variants (NEPC). Even immunotherapy induced limited results in prostate cancer, governed by an immunosuppressive microenvironment. Therefore, effective therapies are needed. We here investigate in preclinical models a new approach aimed to revert castration resistance and simultaneously turn the immune milieu from “cold” to “hot”, through the combination between enzalutamide and the drug GSK-126, which inhibits the epigenetic modulator EZH2. We show that enzalutamide and GSK-126 can synergize to restrain the growth of CRPC in vitro and in vivo. Moreover, this therapeutic combination efficiently reduced NEPC differentiation, in both subcutaneous and autochthonous in vivo models, increasing the rate of cured mice with regressed lesions. The antitumor efficacy observed in immunocompetent mice bearing subcutaneous syngeneic CRPC tumors was lost in immunodeficient mice, indicating a contribution of immune cells. Additional experiments in the TRAMP spontaneous mouse model revealed that the combination of enzalutamide and GSK-126 significantly induced cytotoxic activity and IFNγ production by tumor-specific CD8+ T cells, otherwise tolerant, and increased IL-17 production by CD4+ T cells. The two drugs did not directly modulate T cell activity in vitro, suggesting the importance of microenvironment accomplices in triggering these effects. These results promote the combined use of enzalutamide and GSK-126 to restrain CRPC growth and NEPC differentiation, and, simultaneously, to awake antitumor T cell response, opening new possibilities for immunotherapy in prostate cancer. Citation Format: Irene Fischetti, Botti Laura, Roberta Sulsenti, Valeria Cancila, Claudia Enriquez, Renata Ferri, Marco Bregni, Filippo Crivelli, Claudio Tripodo, Mario P. Colombo, Elena Jachetti. Combined therapy targeting AR and EZH2 restrains the growth of castration resistant prostate cancer by enhancing antitumor T cell response [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 2639.
Abstract 2950: CRISPR/saCas9 and CRISPR/spCas9 systems for combinatorial genetic screens (CRISPR-KO, CRISPRa, CRISPRi)
Authors: Nadya Isachenko, Gayane Aleksanyan, Paul Diehl, Donato Tedesco
Journal: Cancer Research (2024)

Abstract This study explores the utilization of orthogonal CRISPR-based gene editing/modulation systems for combinatorial genetic screens using CRISPR knockout (CRISPR-KO), CRISPR activation (CRISPRa), and CRISPR interference (CRISPRi) functionalities. S. aureus (sa)Cas9 is an alternative nuclease to S. pyogenes (sp)Cas9 in scenarios where the latter cannot be used, or when multiple independent CRISPR systems need to be simultaneously expressed in the same cell. In this study we set out to explore the feasibility of utilizing different combinations of saCas9 and spCas9 CRISPR systems to achieve the simultaneous inactivation (via CRISPR-KO or CRISPRi) and transactivation (via CRISPRa) of different target genes in the same host cell. For this purpose, a complete set of tools for CRISPR/saCas9 gene editing and gene modulation was developed, compatible with CRISPR/spCas9 co-expression. Specifically, we developed and validated optimized saCas9 and sg(sa)RNA lentiviral and AAV vectors, dual expression (sp)/(sa)sgRNA lentiviral library vectors, as well as (sa)CRISPR-KO, (sa)CRISPRi, (sa)CRISPRa fluorescence-based activity kits for the functional validation of saCas9 expressing cell lines. Results demonstrating the feasibility of the orthogonal screens will be presented, with different combinations of CRISPR-KO, CRISPRa, and CRISPRi systems in multiple cell lines. Citation Format: Nadya Isachenko, Gayane Aleksanyan, Paul Diehl, Donato Tedesco. CRISPR/saCas9 and CRISPR/spCas9 systems for combinatorial genetic screens (CRISPR-KO, CRISPRa, CRISPRi) [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 2950.
Abstract 1947: Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations
Authors: Xiaobing Lv, Min Xu, Yong Hu, Lanjiao Zhao, Xiuquan Chen, Youqin Chen, Chen Yang, Jizhi Li, Chen Chen
Journal: Cancer Research (2024)

Abstract RAS mutations are the most common oncogene in human cancers and KRAS has the highest frequency in non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC). KRAS G12C inhibitors have been approved to treat NSCLC patients. However, drug-resistance is eventually developed for these treatments. Preclinical studies suggested MAPK pathway reactivation is one possible mechanism. Among many MEK inhibitors in clinical development, CH5126766 binds to MEK1 inactive conformation and blocks its phosphorylation and activation. We believe this compound should prevent MAPK “paradoxical activation” commonly observed in most RAF and MEK inhibitors such as vemurafenib and cobimetinib. We studied this compound in various in vitro assays and found its potential in combating the paradoxical activation, which might be the cause of drug-resistance for MAPK signal pathway inhibitors, including RAS-, RAF- MEK- and ERK-inhibitors, as a single agent or in combination with above-mentioned inhibitors. In addition, we are developing a series of compounds based on CH5126766, by improving the inhibition of MEK1/2 kinase activity in addition to its activation. In summary, studies on the pMEK inhibitor demonstrated that this class of compounds might mitigate the MAPK pathway reactivation and prolong drug efficacies in clinical. Detailed research results will be discussed. Citation Format: Xiaobing Lv, Min Xu, Yong Hu, Lanjiao Zhao, Xiuquan Chen, Youqin Chen, Chen Yang, Jizhi Li, Chen Chen. Studies on pMEK inhibitors for the treatment of RAS-mutant cancers as a single agent or combinations [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 1947.
Abstract 2634: CRISPR <i>in vivo</i> screen utilizing removable Cas9 system to identify epigenetic immune response modulators in antigen-sensitive mouse syngeneic models
Authors: Yuan He, Yafei Liu, Xiao Wang, Xianyi Li, Wenle Dong, Tongrui Hao, Chenyang Zhu, Wenrong Zhou, Zhengang Peng
Journal: Cancer Research (2024)

Abstract The application of CRISPR-Cas9 screen in tumor immunology research has promoted the discovery of potential therapeutic targets and provided a deeper understanding of the mechanisms of immunotherapy resistance. Mouse syngeneic tumor model based CRISPR in vivo screen revealed significant features of immunotherapy by better approaching the tumor immune interaction. However, the immunogenicity of CRISPR-Cas9 has been widely observed in a variety of syngeneic models, which greatly limited for the application of CRISPR in vivo screen. Herein, we used two strategies for cancer cell gene editing, Cas9 protein electroporation and loxP-flanked Cas9 with Cre recombinase, to reduce the immunogenicity of CRISPR-Cas9 in CT26 subcutaneous and Renca orthotropic syngeneic models. Encouragingly, we found out that compared with constitutive Cas9-expressing All-In-One based cell pool models, both CT26 subcutaneous model and Renca orthotropic model showed a parental cell tumor comparable growth kinetics and immune checkpoint blockade ICB response by PD-1 antibody treatment. Further immuno-profiling of tumor immune microenvironment indicated limited changes from the parental cell model, which helped the data interpretation of in vivo screen outcome. We then performed a CRISPR in vivo screen by using a focused library against mouse epigenetic regulators in these two models and will discuss the hits from the screen in future. Citation Format: Yuan He, Yafei Liu, Xiao Wang, Xianyi Li, Wenle Dong, Tongrui Hao, Chenyang Zhu, Wenrong Zhou, Zhengang Peng. CRISPR in vivo screen utilizing removable Cas9 system to identify epigenetic immune response modulators in antigen-sensitive mouse syngeneic models [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 2634.
Abstract 1941: AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer
Authors: Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Katayama, Kei Kunimasa, Takaaki Sasaki, Makoto Nishida, Satoshi Watanabe, Shinsuke Shiotsu, Hisanori Uehara, Koichi Takayama
Journal: Cancer Research (2024)

Abstract Background: KRAS is the most frequent targetable oncogene in non-small cell lung cancer (NSCLC). Recently, novel KRAS inhibitor have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, it is difficult to achieve complete remission of tumor. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. In this study, we focused on the mechanisms underlying adaptive resistance to KRAS G12C inhibitors and therapeutic strategies required to overcome them. Methods: We used KRAS G12C-mutated NSCLC cell lines to evaluate the adaptive response to KRAS G12C inhibitors in vitro and in vivo. We also investigated the correlation between AXL expression in pre-treated tumors and clinical outcomes with sotorasib for KRAS G12C-mutated NSCLC patients. Results: We revealed that AXL signaling leads to the adaptive resistance to KRAS G12C inhibitors in KRAS-G12C mutated NSCLC, activation of which is induced by GAS6 production via transcriptional coactivator YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or the combination after acquired resistance to KRAS G12C inhibitor. AXL was highly expressed in clinical specimens of KRAS G12C-mutated lung cancers and its high expression was associated with a low treatment response to sotorasib. Conclusions: These results indicated pivotal roles for AXL activation and its inhibition in the intrinsic resistance to KRAS G12C inhibitor. Citation Format: Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Katayama, Kei Kunimasa, Takaaki Sasaki, Makoto Nishida, Satoshi Watanabe, Shinsuke Shiotsu, Hisanori Uehara, Koichi Takayama. AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung 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 1941.