tbuckley/cabot-search huggingface dataset:
Abstract 5087: ILB-3101, a novel B7H3-targeting ADC with Eribulin as payload, demonstrates strong tumor killing activities and favorable PK/TOX profile in preclinical evaluation
Authors: Yushuan Shang, Junzhuan Qiu, Yanfei Xin, Min Zhao, Qiang Liu, Zhengsheng Wang, Xiaojing Gong, Yan Xu, Yan Li, Mingde Xia, Rulei Chen
Journal: Cancer Research (2024)

Abstract B7H3, a B7 family member of immune checkpoint proteins, is overexpressed in a broad spectrum of malignant tumors. It has become an attractive target for cancer therapies in recent years. ILB-3101, a potential best-in-class ADC, was constructed by conjugating a potent mitotic inhibitor Eribulin to a proprietary anti-B7H3 mAb through a proprietary linker. This ADC molecule has been developed and preclinically evaluated as both the 1st line ADC treatment with B7H3 expressed patients in Eribulin sensitive cancer types and the later line treatment for patients whose cancer are B7H3 positive but TopoI inhibitor resistant. The humanized antibody of ILB-3101 is IgG1 type and shows high affinity to both human and monkey B7H3 proteins. It also shows better internalization than benchmark antibodies such as that of DS-7300 analog. The DAR value of ILB-3101 is 3.5. ILB-3101 has potent and dose-dependent cytotoxicity to B7H3-positive tumor cells and shows better activities than DS-7300 analog as positive control. In vivo studies based on xenograft tumor models reveal that ILB-3101 has potent anti-tumor activities in various tumor types including TNBC, sarcoma, ovarian cancer and AML etc., which are superior or comparable to DS-7300 analog. Furthermore, ILB-3101 shows strong anti-tumor activity on Dxd based ADC resistant tumors in xenograft tumor models. The PK study of ILB-3101 in cynomolgus monkeys shows dose-dependent exposure and desirable PK profile. ILB-3101 was well tolerated in cynomolgus monkeys with HNSTD at 6 mg/kg. No serious adverse events were observed, and the main safety findings were limited and reversible hematological and immunological effects, which are consistent with the safety profile of Eribulin as an approved chemotherapy. The in vitro and in vivo preclinical results above demonstrate that ILB-3101 has good efficacy and safety profile and it is a promising and potentially best-in-class B7H3 targeting ADC drug candidate. ILB-3101 is worthy of further translational research and clinical trials. Its IND application has been submitted in China, followed by US FDA filing soon. Citation Format: Yushuan Shang, Junzhuan Qiu, Yanfei Xin, Min Zhao, Qiang Liu, Zhengsheng Wang, Xiaojing Gong, Yan Xu, Yan Li, Mingde Xia, Rulei Chen. ILB-3101, a novel B7H3-targeting ADC with Eribulin as payload, demonstrates strong tumor killing activities and favorable PK/TOX profile in preclinical evaluation [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 5087.
Abstract 5999: Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors
Authors: Seong Yu, Heesu Lee, Jeong Mu Shin, Na-Young Song
Journal: Cancer Research (2024)

Abstract Oral squamous cell carcinoma (OSCC) is the most common type of head and neck cancers. It has been reported that the composition of the oral microbiome was shifted in OSCC patients compared to healthy subjects. In particular, Pseudomonas aeruginosa is one of the most abundant oral microbes in OSCC patients. Bitter taste receptors (taste 2 receptors, TAS2Rs), known as G protein-coupled receptors (GPCRs), can recognize P. aeruginosa-derived quorum sensing molecules, such as N-(3-oxododecanoyl)-L-homoserine lactone (oxo-C12). Therefore, we explored the role of TAS2Rs in oral dysbiosis and cancers. Herein, we observed that TAS2Rs, such as TAS2R4, TAS2R14, and TAS2R38, mediated both pyroptosis and apoptosis, two distinct types of programmed cell death, in human OSCC HSC3 cells exposed to oxo-C12. Unexpectedly, TAS2Rs provoked pyroptosis and apoptosis in a GPCR-independent manner. Instead, TAS2Rs seemed to recruit NLRP3 inflammasome and subsequently activate caspase-8 in response to oxo-C12, implying the TAS2Rs-NLRP3-caspase-8 axis. Notably, the immunofluorescence staining showed considerable expression of TAS2Rs and NLRP3 in oxo-C12-treated HSC3 cells as well as human OSCC tissues, further supporting the presence of the alternative activation pathway of TAS2Rs. Moreover, siRNA knockdown of MyD88 diminished oxo-C12-induced NLRP3 activation, caspase-8 cleavage and cell death marker expression, which implies that MyD88 is involved in activation of the TAS2Rs-NLRP3-caspase-8 axis. This also suggests that TAS2Rs might function as potential pattern recognition receptors, similar to toll-like receptors responsible for recognition of pathogen and their molecules. Based on The Cancer Genome Atlas analysis, downregulation of TAS2Rs was correlated with poor prognosis in OSCC patients. Taken together, TAS2Rs might trigger the host defense mechanism against microbial dysbiosis-induced cancer development. Thus, TAS2Rs could be promising chemotherapeutic targets for OSCC treatment, particularly via disconnecting interkingdom molecular links between microbial alterations and carcinogenesis. Citation Format: Seong Yu, Heesu Lee, Jeong Mu Shin, Na-Young Song. Bitter taste receptors trigger pyroptosis and apoptosis through NLRP3 activation in oral cancer cells in response to a dysbiotic bacterial molecule: A possible role as pattern recognition receptors [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 5999.
Abstract 672: Small molecule NSC59984 stimulates mitochondria-dependent ferroptosis and overcomes integrated stress response pro-survival signaling in pre-clinical pancreatic and colorectal cancer models
Authors: Praveen R. Srinivasan, Arielle J. De La Cruz, Maximilian Pinho-Schwermann, Andrew George, William J. MacDonald, Shengliang Zhang, Wafik S. El-Deiry
Journal: Cancer Research (2024)

Abstract Pancreatic and colorectal cancer are leading causes of cancer deaths worldwide. Resistance to current therapeutics is a significant challenge in treating these cancers. Ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by overwhelming lipid peroxidation, has emerged as a potential strategy to overcome drug resistance. Our lab previously identified the small-molecule NSC59984 as a p53 pathway restoring compound that induces reactive oxygen species, requires p73, and targets mutant p53 for ubiquitin-mediated proteolysis involving MDM2 and HSP90. In pre-clinical models of pancreatic and colorectal cancer, we now show that the small-molecule NSC59984 induces lipid peroxidation and causes reactive oxygen species-dependent apoptosis as monotherapy. However, when combined with ferroptosis inducers or cystine deprivation, NSC59984 potently induces ferroptosis in a mitochondrial complex III-dependent manner. Using CRISPR/Cas9 in pancreatic cancer cells, we further show that HRI, an EIF2-alpha kinase responsible for the cellular response to mitochondrial stress, induces the integrated stress response (ISR) upon treatment with NSC59984 or ferroptosis inducers. The ISR serves as a mechanism for resistance to cell death induced by NSC59984 or ferroptosis inducers, causing upregulation of key anti-oxidative stress and anti-ferroptosis proteins, including the cystine importer SLC7A11 and the GPX4-stabilizing protein HSPA5/BIP/GRP78. The combination therapy overcomes the ISR to induce potent cell death. Our work demonstrates the importance of the interplay between mitochondria and the ISR during ferroptosis induction in pancreatic and colorectal cancer cells. Citation Format: Praveen R. Srinivasan, Arielle J. De La Cruz, Maximilian Pinho-Schwermann, Andrew George, William J. MacDonald, Shengliang Zhang, Wafik S. El-Deiry. Small molecule NSC59984 stimulates mitochondria-dependent ferroptosis and overcomes integrated stress response pro-survival signaling in pre-clinical pancreatic and colorectal cancer 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 672.
Abstract 5738: Repurposing disulfiram for cancer: A drug delivery and population-based approach
Authors: Devon Heroux, Ada W. Leung, Roger Gilabert-Oriol, Marcel B. Bally
Journal: Cancer Research (2024)

Abstract Purpose: Disulfiram was approved by the FDA for treatment of alcohol abuse in 1951, although for over 40 years there has been evidence supporting disulfiram’s use as an anti-cancer drug. Upon administration, disulfiram is hydrolyzed to form two molecules of DDC, which upon binding Cu forms Cu(DDC)2, the proposed active form against cancer. It was our goal to formulate the water-insoluble Cu(DDC)2 in liposomes to facilitate its repurposing for breast and colon cancers. In addition, we also initiated an ongoing population-based study assessing the protective and treatment effects of disulfiram with cancer. Methods: Cu(DDC)2 liposomes were generated by the thin-film hydration method followed by extrusion, using DSPC and cholesterol (55:45 molar ratio). DDC and CuSO4 were added to the liposomes forming Cu(DDC)2, which was transported inside the liposomes. Anti-tumor activity was evaluated in tumor-bearing mice with or without competent immune systems, and immune system activation was assessed via a cancer vaccination model and the expression of markers of immunogenic cell death (ICD). A study was also initiated for cancer cases and controls in British Columbia (BC Cancer) with at least one prescription of disulfiram from 1996-2022 (PharmaNET), patients treated with immune-modulating therapies (BC Cancer), and outcome of death (Vital Statistics). Results: Liposomes encapsulating Cu(DDC)2 had a size of 100 nm and polydispersity of 0.1, and caused a 40% reduction in tumor burden in a MDA-MB-231 xenograft model. In a syngeneic tumor model of breast cancer the response with immune-competent mice was greater than mice lacking immune function, and a cancer vaccination model and the presence of ATP, HMBG1 and surface-exposed calreticulin indicated the presence of ICD. Conclusions: Cu(DDC)2 was formulated in liposomes facilitating its parenteral administration, and its anti-cancer activity was found to be due in part to activation of the adaptive immune system through ICD. A case-control study is currently being employed to examine the clinical potential of disulfiram, as a protectant and as an adjuvant with immune-activating therapies such as checkpoint inhibitors and anthracyclines to potentially improve efficacy through induction of ICD. Citation Format: Devon Heroux, Ada W. Leung, Roger Gilabert-Oriol, Marcel B. Bally. Repurposing disulfiram for cancer: A drug delivery and population-based approach [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 5738.
Abstract 3488: Decoding splicing isoforms and adaptive evolution in melanoma brain metastases through single cell long-read RNA sequencing
Authors: Lina Lu, Cheng-Kai Shiau, Kazutaka Fukumura, Hsiaoyun Lin, Yueying He, Timothy Pan, Lisa Norberg, Jennifer Ritchie, Jason T. Huse, Ruli Gao
Journal: Cancer Research (2024)

Abstract Melanoma brain metastasis (MBM) is the third most common origin of metastasis to the brain, with a median overall survival of 8.9 months. Alternative splicing plays a critical role in cancer pathogenesis through altered protein coding complexity in tumor cells, which however has been poorly studied in MBM due to technical limitations. Long-read single cell RNA sequencing has the unique strength of measuring transcript isoforms and mutations simultaneously in individual cells due to its capacity of measuring full-length transcripts. In this study, we employed high throughout single cell long-read RNA sequencing (scNanoRNAseq) onto patient-matched MBM and extracranial metastasis (ECM) tumor pairs to evaluate the extent to which splicing isoforms impact adaptive clonal evolution in MBM. Our results showed that MBM tumors had distinct genetic alterations and ecological cellular compositions compared to matched ECM tumors, indicating that tumor clones were adaptively expanded in brain microenvironment. Comparative isoform analysis revealed that hundreds of genes expressed different combinations of isoforms (DCIs) involved in glucose and lipid metabolic pathways. Interestingly, our data demonstrated that ~10% of splicing related genes themselves were alternatively spliced including both spliceosome members and splicing activators. Furthermore, we calculated temporal changes of isoform usages along with tumor cell evolutionary lineages to quantify their impact on adaptive clonal expansion in MBM. Taken together, our work improves the understanding of transcriptional and splicing dynamics inherent in the adaptive evolution of MBM, providing evidence for developing new therapeutics targeting tumor cell-specific and MBM-specific splicing isoforms. Citation Format: Lina Lu, Cheng-Kai Shiau, Kazutaka Fukumura, Hsiaoyun Lin, Yueying He, Timothy Pan, Lisa Norberg, Jennifer Ritchie, Jason T. Huse, Ruli Gao. Decoding splicing isoforms and adaptive evolution in melanoma brain metastases through single cell long-read RNA sequencing [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 3488.
Abstract 29: A genetically modified tumor-infiltrating lymphocytes product (GT216) enhanced anti-tumor efficacy against solid tumor by fine-tuning multiple negative immune regulators
Authors: Jingwei Sun, Yiyang Tan, Jiahui Jin, Jingman Wang, Lingyun Chen, Fengbiao Guo, Yongchao Tan, Zhao Xu, Yarong Liu
Journal: Cancer Research (2024)

Abstract Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising clinical benefits for patients with solid tumors. However, the large-scale expansion during manufacture may drive hypofunction or exhaustion status of the final TIL product, leading to impaired anti-tumor efficacy and persistence post infusion. Grit Biotechnology designed a genetically engineered TIL product (GT216) to overexpress an intracellular protein that is induced by antigen-specific T cell response and mediates the degradation of multiple immunoregulatory molecules, which releases the therapeutic potential of TIL with enhanced cytotoxicity as well as persistence in vitro and in vivo. Multiple vector construct designs of GT216 were compared and the best design was selected based on stable and efficient expression of surrogate marker in TILs. GT216 could be successfully manufactured by Grit’s StemTexp® and StaViral® platforms with good memory phenotype and no signs of overactivation or exhaustion. In vitro functional analysis showed that GT216 demonstrated significantly increased cytotoxicity and cytokine production when cocultured with tumor cells and better tumor control ability during a serial killing assay than conventional TILs. Notably, GT216 TILs eradicated tumor growth with low IL-2 support in NOG mice inoculated with HLA-matched tumor cells while conventional TILs showed limited tumor control with high IL-2, corelated with their better infiltration and persistence in tumor and periphery. In summary, GT216 demonstrated enhanced anti-tumor efficacy and persistence as well as reduced IL-2 dependency in vitro and in vivo, supporting the clinical evaluation of GT216 as a next-generation TIL therapy in treatment of refractory solid tumors. Citation Format: Jingwei Sun, Yiyang Tan, Jiahui Jin, Jingman Wang, Lingyun Chen, Fengbiao Guo, Yongchao Tan, Zhao Xu, Yarong Liu. A genetically modified tumor-infiltrating lymphocytes product (GT216) enhanced anti-tumor efficacy against solid tumor by fine-tuning multiple negative immune regulators [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 29.
Abstract 5924: RNAi mediated inhibition of beta-catenin demonstrates anti-tumor efficacy and immune microenvironment modulation in preclinical hepatocellular carcinoma models
Authors: Tulin Dadali, Spencer Miller, Gaurav Saawant, Stephen Abbott, Mikyung Yu, Svetlana Morskaya, Brandon Lehrich, Satdarshan Monga, Gloria Lau, Martin Maier, Wendy Broom
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) is the fifth most common solid tumor worldwide, and the third most common cause of cancer-related deaths. For the 40% to 50% of HCC patients who are candidates for systemic therapies, the landscape has evolved significantly in the last 10 years, with most recently, immunotherapies such as combination of atezolizumab and bevacizumab emerging as the current first-line systemic therapy for patients with intermediate or advanced disease. However, there are no predictive biomarkers for patients with HCC to enable selection of those most likely to benefit from these therapies and this remains a disease with high unmet medical need. Activation of the WNT pathway via mutational events or indirect pathway activation is implicated in many cancers including up to 50% of HCC patient tumors. High expression of beta-catenin, encoded by the CTNNB1 gene, has been shown to correlate with decreased survival and more rapid disease progression in HCC patients. In addition, WNT/beta-catenin pathway activation has been shown to result in immune exclusion and resistance to immunotherapy in HCC. ALN-BCAT comprises a chemically modified siRNA encapsulated in a lipid nanoparticle formulation which generates robust and highly specific reductions of CTNNB1 mRNA, downstream biomarkers and tumor cell proliferation in in vitro model systems. Anti-tumor activity has been demonstrated in multiple in vivo orthotopic HCC mouse models, in both early and late treatment settings as measured by liver to body weight ratio. Reductions in tumor burden were orthogonally confirmed by histology analysis and shown to be associated with changes in CTNNB1-related biomarkers. Finally, ALN-BCAT treatment results in changes in the tumor microenvironment in a mouse syngeneic HCC model, with increases in CD4+ and CD8+ T cells and reductions in M2 macrophages, consistent with a shift to a more immune stimulatory anti-tumor microenvironment. Here, we demonstrate that ALN-BCAT provides a novel approach to the inhibition of the WNT pathway as a therapeutic approach for treatment of HCC patients and WNT pathway activated tumors. Citation Format: Tulin Dadali, Spencer Miller, Gaurav Saawant, Stephen Abbott, Mikyung Yu, Svetlana Morskaya, Brandon Lehrich, Satdarshan Monga, Gloria Lau, Martin Maier, Wendy Broom. RNAi mediated inhibition of beta-catenin demonstrates anti-tumor efficacy and immune microenvironment modulation in preclinical hepatocellular carcinoma 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 5924.
Abstract 7559: Multi-state gene cluster switches determining the adaptive mitochondrial and metabolic landscape of breast cancer
Authors: Michela Menegollo, Robert Bentham, Neill Patani, Robert C. Stein, Mariia Yuneva, Gyorgy Szabadkai
Journal: Cancer Research (2024)

Abstract Adaptive metabolic switches are proposed to underlie conversions between cellular states during normal development as well as in cancer evolution, where they represent important therapeutic targets. However, the full spectrum, characteristics and regulation of existing metabolic switches are unknown. We propose that metabolic switches can be recognised by locating large alternating gene expression patterns and associate them with specific metabolic states. We developed a method to identify interspersed genesets by massive correlated biclustering (MCbiclust) and to predict their metabolic wiring. Testing the method on major breast cancer transcriptome datasets we discovered a series of gene sets with switch-like behaviour, predicting mitochondrial content, activity and central carbon fluxes in tumours associated with different switch positions. The predictions were experimentally validated by bioenergetic profiling and metabolic flux analysis of 13C-labelled substrates and were ultimately extended by geneset analysis to link metabolic alterations to cellular states, thus predicting tumour pathology, prognosis and chemosensitivity. The method is applicable to any large and heterogeneous transcriptome dataset to discover metabolic and associated pathophysiological states. Citation Format: Michela Menegollo, Robert Bentham, Neill Patani, Robert C. Stein, Mariia Yuneva, Gyorgy Szabadkai. Multi-state gene cluster switches determining the adaptive mitochondrial and metabolic landscape of 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 7559.