tbuckley/cabot-search huggingface dataset:
Abstract 3643: Molecular pathogenesis of lung cancer associated with interstitial pneumonia
Authors: Daisuke Mizuno, Kazuhiko Shien, Atsushi Matsuoka, Masayoshi Ohki, Shuta Tomida, Ryo Yoshichika, Tomoaki Higashihara, Fumiaki Mukohara, Naohiro Hayashi, Tomohiro Habu, Mao Yoshikawa, Ken Suzawa, Hiromasa Yamamoto, Daisuke Ennishi, Shinichi Toyooka
Journal: Cancer Research (2024)

Abstract Background: Interstitial pneumonia (IP) is known to be associated with a high risk of developing lung cancer. While common mechanisms have been reported to be involved in the pathogenesis of IP and lung cancer, including genetic and epigenomic alterations or specific signaling pathway activations, many of the molecular mechanisms of lung cancer development in IP lesions remain unknown. Methods: To clarify the detailed mechanisms of the pathogenesis of lung cancer associated with IP, we performed spatially resolved transcriptomics on lung cancer specimens obtained from usual interstitial pneumonia (UIP) associated lung cancer patients. In a total of 10 patients, including five lung cancers that developed inside the UIP and five lung cancers that originated outside the UIP, regions of interest (ROIs) were selected in the tumoral tissues and their adjacent non-tumor tissues. Then, gene expression profiles were comprehensively analyzed by using GeoMx digital spatial profiler in each ROI. Results: In the UIP lesions adjacent to lung cancer, increased gene expressions associated with pulmonary fibrosis, such as COL1A1, COL3A1, and APOE, were observed, and gene set enrichment analysis (GSEA) revealed that they were associated with autoimmunity-related pathways. When we compared the tumor lesions developed inside the UIP with outside the UIP, increased gene expressions related to IP mortality were observed in the tumor cells developed inside the UIP. Interestingly, GSEA revealed that the gene set for neutrophil extracellular trap (NETs) formation was found to be upregulated in the tumor cells developed inside the UIP, suggesting that NETs plays an important role in the pathogenesis of lung cancer developed in IP lesion. Conclusions: In our study, spatially resolved transcriptomics revealed a novel pathway related to the pathogenesis of lung cancer associated with IP. Citation Format: Daisuke Mizuno, Kazuhiko Shien, Atsushi Matsuoka, Masayoshi Ohki, Shuta Tomida, Ryo Yoshichika, Tomoaki Higashihara, Fumiaki Mukohara, Naohiro Hayashi, Tomohiro Habu, Mao Yoshikawa, Ken Suzawa, Hiromasa Yamamoto, Daisuke Ennishi, Shinichi Toyooka. Molecular pathogenesis of lung cancer associated with interstitial pneumonia [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 3643.
Abstract 6489: Paradoxical activation of kinases occurs directly with ATP-competitive kinase inhibitors and is observable biochemically at physiologically relevant drug concentrations
Authors: Christian M. Loch, Mia Eason, Shuguang Liang, Alison Goupil, Anthony Acinapura, Jamie Purcell, Maia Domiguez
Journal: Cancer Research (2024)

Abstract We sought to screen all FDA approved, cancer-indicated, kinase targeting drugs using the gold standard radiometric biochemical activity assay (HotSpot) against the largest collection of kinases in the world (&amp;gt;100 drugs against 735 total kinases including 395 wild type and 340 mutants). One of these drugs, mitapivat, is an activator of Pyruvate Kinase. Here, we show mitapivat-driven biochemical inhibition of several, but not all, mutants of c-KIT. We also observed the equal and opposite phenomenon whereby many ATP-competitive kinase inhibitors demonstrate biochemical activation of certain kinases, several of which seem particularly susceptible to the effect. Previous work by other investigators (at Genentech and the Rosen lab, MSKCC) demonstrated that PLX4720 (precursor to Vemurafenib) paradoxically activated wild type BRAF, but not BRAF mutants, by driving dimerization of the kinase in drug concentrations insufficient to inhibit both members of the dimerized pair. Our data suggests this phenomenon may be more widespread than previously appreciated and fully observable in vitro. Such paradoxical activation could be driving both toxicities and inefficacy against cancers expressing some of these activatable kinases. This information could suggest novel opportunities for combination therapy and improve outcomes by contraindicating certain medication from use based on tumor expression profile. Citation Format: Christian M. Loch, Mia Eason, Shuguang Liang, Alison Goupil, Anthony Acinapura, Jamie Purcell, Maia Domiguez. Paradoxical activation of kinases occurs directly with ATP-competitive kinase inhibitors and is observable biochemically at physiologically relevant drug concentrations [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 6489.
Abstract 1350: KD6001: A promising new anti-CTLA-4 human monoclonal antibody for cancer therapy
Authors: Yi Chen, Peng Li, Guobo Fang, Heng Wu, Chi Zhang, Zeling Cai
Journal: Cancer Research (2024)

Abstract Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that negatively regulates T cell activation. Inhibiting this negative regulation through CTLA-4 blockade has emerged as a promising therapeutic strategy against cancer. Herein, we present the preclinical pharmacology study of KD6001, a novel anti-CTLA-4 IgG1 kappa human monoclonal antibody with superior properties compared to ipilimumab, a currently approved anti-CTLA-4 mAb. Surface plasmon resonance (SPR) analysis revealed that KD6001 exhibits a higher affinity for CTLA-4 compared to ipilimumab (KD = 0.57 nM vs 1.20 nM). Competition ELISA experiments demonstrated that KD6001 is significantly more potent than ipilimumab in disrupting CTLA-4 interactions with CD80 (IC50 = 16 ng/mL vs 93 ng/mL) and CD86. Further, amino acid point mutation analysis indicated that two specific residues following the CD80/CD86 binding site (99MYPPPY104) are critical for ipilimumab binding, whereas mutation of the two residues had minimal impact on KD6001's CTLA-4 binding activity. These findings suggest that KD6001 and ipilimumab bind distinct epitopes on CTLA-4. In vitro experiments demonstrated that KD6001 enhances the production of IL-2 and IFNγ in PHA-activated human lymphocytes and exhibits synergistic anti-tumor effects when combined with anti-PD-1/L1 antibodies. Moreover, in vivo studies utilizing syngeneic murine tumor models established in human CTLA-4 gene knock-in mice revealed that KD6001 effectively inhibits or delays tumor growth in colon cancer MC38, melanoma B16, and hepatocellular carcinoma Hepa1-6 models. Additionally, KD6001 demonstrated synergistic anti-tumor effects when combined with a mouse anti-PD-1 antibody or ibuprofen. Toxicity evaluation in cynomolgus monkeys revealed that KD6001 was generally well-tolerated at doses ranging from 1 mg/kg to 10 mg/kg administered intravenously once weekly for four weeks. The primary pathological changes observed were lymphocyte/monocyte infiltration or increased lymphocyte/monocyte infiltration in several organs, consistent with KD6001's mechanism of action. Notably, the similar affinity of KD6001 for human and cynomolgus monkey CTLA-4 suggests that the toxicity profile observed in monkeys accurately reflects the dose-toxicity relationship in human. The promising preclinical data presented herein support the further clinical development of KD6001 as a potential therapeutic agent for cancer treatment. Currently, clinical trials evaluating KD6001 in patients with advanced melanoma are ongoing. Citation Format: Yi Chen, Peng Li, Guobo Fang, Heng Wu, Chi Zhang, Zeling Cai. KD6001: A promising new anti-CTLA-4 human monoclonal antibody for cancer therapy [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 1350.
Abstract 499: Enhancing neoantigen cancer vaccine efficacy with a self-assembling peptide conjugates nanoparticle platform
Authors: Yangfan Wu, Jian-Dong Huang
Journal: Cancer Research (2024)

Abstract Tumor neoantigens, arising from genomic mutations during cancer cell proliferation, are absent in normal tissues, making them ideal immunotherapy targets. Predicting neoantigen peptide sequences using artificial neural networks (ANNs) like NetMHCpan offers a promising approach to developing personalized peptide cancer vaccines. However, limitations such as low affinity, short half-life, and weak immunogenicity hinder their efficacy. To address these challenges, we propose loading neoantigens into nanoparticles for protection and slow release within the body. We used ANN prediction to determine neoantigen peptide sequences for various cancer cell lines and engineered these peptides by conjugating them with Toll-like receptor 7 agonist (TLR7a) adjuvants, forming a self-assembling peptide conjugates nanoparticle (SPCN) platform. To assess the immunogenicity of the SPCN platform, we conducted enzyme-linked ELISpot assays and evaluated the activation of antigen-presenting cells (APCs) in draining lymph nodes using flow cytometry analysis. The therapeutic efficacy of the SPCN platform was determined by monitoring tumor growth curves in mouse models. The SPCN platform demonstrated broad applicability, carrying different neoantigens in vivo, resulting in robust and safe systemic anti-tumor responses. The SPCN enhanced immunogenicity, stimulating splenocytes to produce more interferon gamma and facilitating efficient absorption by antigen-presenting cells (APCs). Moreover, SPCNs loaded with neoantigens targeted different cancer models, including B16OVA, MB49, and RIL175. In conclusion, our self-assembling peptide conjugates nanoparticle platform enhances APC activation and neoantigen immunogenicity, leading to improved anti-tumor efficacy, offering valuable insights for developing synthetic peptide cancer vaccines. Citation Format: Yangfan Wu, Jian-Dong Huang. Enhancing neoantigen cancer vaccine efficacy with a self-assembling peptide conjugates nanoparticle platform [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 499.
Abstract 6479: Metastases in uveal melanoma patients: Trends and risk factors
Authors: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza
Journal: Cancer Research (2024)

Abstract Purpose: Uveal melanoma has a high tendency to metastasize. Due to its rarity, there has not been large population studies that have demonstrated the effect of demographic variables on a patient’s risk to have metastases. Methods: The Nationwide Emergency Department Sample was queried from the last quarter of 2015 to 2019 to identify patients with a diagnosis of uveal melanoma. Multivariable logistic regression, with patient- and hospital-level characteristics as covariates, was used to identify factors associated with a higher chance of developing a metastasis and specific metastasis locations. Results: From the last quarter of 2015 to 2019, there were 7,561 ED encounters with a diagnosis of uveal melanoma. Of these patients, 5.8% had at least one metastasis. Most patients with a metastasis were at least 65 years of age (47.1%), male (54.4%), a Medicare beneficiary (45.2%), and belonged to a family in the highest income quartile (29.7%). The median age of these patients was 61 years (IQR: 32-74). Most patients presented to hospitals in the South (40.7%), with a Trauma Level I designation (56.1%), and to a metropolitan teaching hospital (72.9%). The most common sites of metastasis were liver (17.0%), brain (5.3%), and bone (2.0%). Multivariable logistic regression identified the following factors to be associated with increased risk of developing a metastasis: private insurance (odds ratio [OR]=1.62; p=0.012), highest income quartile (OR=2.30; p&amp;lt;0.001), and 2nd highest income quartile (OR=1.78; p=0.002). The following factors were associated with higher odds of developing a liver metastasis specifically: no-charge/charity work (OR=15.8; p=0.012), highest income quartile (OR=1.99; p=0.003), and second highest income quartile (OR=1.66; p=0.035). Presenting to a Trauma Level I hospital was associated with decreased risk of developing a liver metastasis (OR=0.57; p=0.016). Belonging to the highest income quartile was associated with a higher chance of developing a brain metastasis (OR=2.13; p=0.023) or a bone metastasis (OR=2.74; p=0.045). Among patients with a metastasis, the in-hospital mortality rate was 8.3%. Conclusion: Metastasis is an important complication to monitor in uveal melanoma patients. In this study, we have demonstrated that income and insurance status are factors that are associated with higher rates of metastases. Physicians should place special attention to these groups to ensure that metastases are minimized. Citation Format: Alice A. Beneke, Kamil Taneja, Lauren Ladehoff, Kevin Root, Eric Toloza. Metastases in uveal melanoma patients: Trends and risk factors [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 6479.
Abstract 6966: STAT3 integration of inflammatory signals and cellular stress promote tumor initiation and progression through the expression of integrin β3
Authors: Alejandro D. Campos, Ryan Shepard, Ingrid Heumann, Justin Lam, Sara M. Weis, David Cheresh
Journal: Cancer Research (2024)

Abstract STAT3 represents an oncogene whose transcriptional regulation is known to drive tumor initiation, progression, and drug resistance. Although STAT3 can regulate many genes, it remains unclear which genes are critical for STAT3-mediated cancer progression. Here, we report that inflammatory cytokines and cellular stress induce STAT3 activation leading to tumor initiation and progression, which we show depends on its ability to drive transcription of the β3 integrin gene leading to αvβ3 expression. Specifically, CRISPR KO of either STAT3 or integrin β3 in pancreatic cancer cells, is sufficient to impede their tumor initiating capacity in mice, while ectopic STAT3 or β3 expression in STAT3 KO cells rescues their tumor initiation capacity. Mechanistically, STAT3 activation induces β3 expression based on its ability to engage enhancer regions that modulate β3 gene expression. These findings implicate integrin αvβ3 as a critical downstream effector of STAT3, thereby contributing to its role as a driver of tumor initiation and progression. Citation Format: Alejandro D. Campos, Ryan Shepard, Ingrid Heumann, Justin Lam, Sara M. Weis, David Cheresh. STAT3 integration of inflammatory signals and cellular stress promote tumor initiation and progression through the expression of integrin β3 [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 6966.
Abstract 6530: TREM1 inhibition: A novel approach to suppress tumor growth and enhance immune checkpoint therapy
Authors: Ashwin Ajith, Kenza Moamouni, Daniel D Horuzsko, Anatolij Horuzsko
Journal: Cancer Research (2024)

Abstract In the context of cancer, inflammation is a multifaceted contributor to tumorigenesis. The Triggering Receptor Expressed on Myeloid Cells 1 (TREM1) is recognized for its role in amplifying inflammatory responses, yet its specific pro-tumorigenic mechanisms have remained elusive. This study employs Trem1-deficient mice and a novel inhibitor, VJDT, to explore the therapeutic potential of targeting TREM1 in cancer. Both genetic silencing and pharmacological inhibiton of Trem1 led to remarkable reductions in tumor growth in mouse models of melanoma (B16F10) and fibrosarcoma (MCA205). In-depth analysis using single-cell RNA sequencing unveiled that TREM1 deficiency resulted in a decrease in the frequency and suppressive capabilities of myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment, concomitant with an increase in cytotoxic CD8+ T cells and enhanced T cell activation. Furthermore, TREM1 inhibition not only curtailed tumor growth but also potentiated the effectiveness of anti-PD-1 therapy, primarily by mitigating MDSC frequency and reversing T cell exhaustion. Notably, in melanoma xenografts from patient samples, pharmacological TREM1 inhibition via VJDT treatment significantly downregulated critical oncogenic pathways linked to cell proliferation, migration, and survival. This research underscores the pivotal role of TREM1, expressed both within cancer cells and the tumor microenvironment, in driving cancer progression. Consequently, targeting TREM1 for therapeutic intervention holds promise for reshaping the immunosuppressive tumor milieu and augmenting the success of immune checkpoint therapy. Citation Format: Ashwin Ajith, Kenza Moamouni, Daniel D Horuzsko, Anatolij Horuzsko. TREM1 inhibition: A novel approach to suppress tumor growth and enhance immune checkpoint therapy [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 6530.
Abstract 6527: Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T cells
Authors: S. W. Fung, Sally K. Y. To, A. A. Hassan, Phillip P.C. Ip, Alice S. T. Wong
Journal: Cancer Research (2024)

Abstract Emerging evidence suggests that aberrant glycosylation in cancer impact on various stages in the disease progression including immunomodulation, but the underlying mechanisms remain poorly understood. Our previous data demonstrated that fucosyltransferase 5 (FUT5), a glycosyltransferase responsible for the terminal step in synthesizing Lewis antigens, may contribute to peritoneal metastasis of ovarian cancer. In this study, using clinical samples of high grade serous ovarian cancer (HGSOC), the most common subtype, we found that high expression of FUT5 is associated with a worse outcome. By employing multiplex immunohistochemistry (IHC) to examine T cell subsets, we found a significant decrease in CD3+CD4−CD8− (double negative, DN) T cells in FUT5high (n=10) compared to FUT5low samples (n=10), while there is no difference in the abundance of CD8+ cytotoxic T cells, CD4+ helper T cells or CD4+Foxp3+ regulatory T cells. Tumor-infiltrating DN T cells has been shown to mediate potent anti-tumor response. In addition to their cytotoxic capabilities, DN T cells largely exhibit modulatory functions on other T cell subsets. To further investigate, we performed additional IHC staining and observed a significant increase in proliferating (Ki67+) CD8+ tissue resident memory cells, which are known to be important for cancer immunity. In addition, we observed a decrease in metastases in the FUT5 knockdown group, accompanied by an increase in DN T cells in ascites and omental metastatic tumors in humanised mice, as revealed by flow cytometry, confirming a direct immunomodulatory role of FUT5. Together, these findings reveal a novel role of FUT5 in promoting immune evasion by suppressing anti-tumor DN T cells, which could provide novel insights for immunotherapy in HGSOC, which has a low response rate to immune checkpoint inhibitors (This research is supported by RGC SRFS2223-7S05, HMRF 08192286 and LSCCB under the Health@InnoHK Program launched by ITC, HKSAR). Citation Format: S. W. Fung, Sally K. Y. To, A. A. Hassan, Phillip P.C. Ip, Alice S. T. Wong. Fucosyltransferase 5 promotes immune evasion in ovarian cancer by suppressing double negative T 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 6527.
Abstract 6513: Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical models
Authors: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Zhengyao Zou, Xiaoqiang Kong, Haibo Chen, Yongqing Sun, Ying Zhao, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Hong Lan, Lieming Ding, Quan Zhou, Hao Wu, Jiabing Wang
Journal: Cancer Research (2024)

Abstract KRAS mutations are one of the most common oncogenic drivers for multiple cancers. KRASG12X mutations are identified in approximately 25% of lung cancer, 24% of colorectal (CRC), and 79% of pancreatic ductal adenocarcinoma (PDAC). Although the approval of Sotorasib in 2021 by the FDA partially addressed the needs of patients with KRASG12C mutant, other mutations, such as G12D and G12V, still lack effective target therapies. Here, we report RD0255359, a proteolysis targeting chimera (PROTAC) KRASG12C/D/V degrader with highly potent cell viability and KRASG12C/D/V degradation ability. In vitro, RD0255359 exhibited a remarkable KRAS degradation property in NCI-H358 (G12C), AGS (G12D), and SW620 (G12V) cell lines at concentrations below 10 nM. RD0255359 suppressed the proliferation of these cells with nanomolar IC50 without affecting the viability of KRASWT or KRAS-independent cell lines. Meanwhile, using protease inhibitor MG132 or corresponding ligand pretreatment and VHLKD-AGS cell experiment confirmed that RD0255359-induced KRAS degradation was VHL and UPS dependent. In vivo, weekly IV injection of 1-10 mg/kg RD0255359 led to tumor growth suppression or tumor regression in PK-59 PDAC xenograft model. The in vivo PK/PD demonstrated that durable KRAS degradation could be achieved with once- weekly IV injection. Notably, after injection, the drug can distribute into tumor tissue rapidly and abundantly, and maintaining a high concentration till the next administration. Taken together, RD0255359 is a highly potent and selective KRASG12C/D/V degrader with favorable PK properties. It exhibits a promising therapeutic index in preclinical studies. Citation Format: Zhengqing Li, Renqi Xu, Xiaofeng Yang, Zhengyao Zou, Xiaoqiang Kong, Haibo Chen, Yongqing Sun, Ying Zhao, Jing Guo, Cheng Yang, Han Han, Xiaoyun Liu, Hong Lan, Lieming Ding, Quan Zhou, Hao Wu, Jiabing Wang. Discovery and characterization of a KRASG12C/D/V degrader with potent anti-tumor activity in KRASmut-driven preclinical 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 6513.