Target For Cancer Treatment Research Articles

Abstract 6362: The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate tumors

Abstract Cancer immunotherapy with 4-1BB agonists has faced limitations in further clinical development due to dose-limiting toxicity. PSMA, highly expressed in normal prostate tissue and prostate cancer, is a clinically validated target for prostate cancer treatment. In this study, we developed a bispecific antibody (BsAb), KA-3002, targeting PSMA and human 4-1BB, with the aim of restricting 4-1BB stimulation to the interior of tumors. KA-3002 was developed based on our nanobody antibody discovery platform. KA-3002, in IgG1 format, features mutations in the Fc domain to eliminate ADCC, ADCP, and CDC activity. It contains two identical nanobodies at the C-terminal against 4-1BB to stimulate 4-1BB signaling in T cells and binds to PSMA with two Fabs at the N-terminal. KA-3002 exhibits high avidity binding to prostate tumor cells expressing PSMA (EC50<1nM) and also binds to 4-1BB expressed on 293T cells and activated human T cells. In the presence of a low concentration of CD3 antibody to stimulate T cell activation, co-culture of tumor cells expressing PSMA with primary T cells isolated from human PBMC enhances T cell activation and proliferation. In PBMC humanized immunodeficient mouse tumor models, KA-3002 effectively suppresses the growth of 22Rv1 tumors, which highly express PSMA. The antibody also demonstrates a half-life of more than five days in the blood of Balb/c mice. Finally, we assessed the developability of this antibody with different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature. KA-3002 shows neither aggregation nor degradation. In conclusion, the BsAb KA-3002, developed with our nanobody antibody discovery platform, emerges as a promising pre-clinical candidate drug for the treatment of prostate cancer. Citation Format: Guojin Wu, Jiabei Liang, Hao Peng, Feng Hao, Tongtong Liu, Jinying Ning. The bispecific antibody KA-3002, targeting PSMA and 4-1BB, specifically enhances T cell activity within prostate 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 6362.

Abstract 7098: Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics

Abstract The aim of the study is to conduct translational research of crucial breast cancer prognostic genes with functional proteomics. We have collected 61 breast cancer core biopsy samples, which were used for targeted sequencing for genetic variant analysis, mass-spectrometry analysis for protein expression and stain with H&E for whole slide image with Aperio Scanncer. After analysis of variant (ANOVA) of LC-MS/MS data, we found 17 proteins with highly differential expression between these 5 molecular subtypes from 61 patients. We then search for the protein-protein interaction (PPI) network from STRING database and found the strong network including 6 proteins namely Collagen Type II Alpha 1 Chain (COL2A1), Collagen alpha-1(XI) chain (COL11A1), Collagen alpha-1(VI) chain (COL6A1), Collagen alpha-2(VI) chain (COL6A2), Thrombospondin 1 (THBS1) and Lumican (LUM). To further investigate on the expression of these 6 target proteins in literature, we used Oncomine for data mining to query their mRNA expression profiles. Intriguingly, we discovered the mRNA expression of these targets are intensively distributed in many cancer types. This finding suggested the high potency of COL2A1, COL11A1, COL6A1, COL6A2, THBS1 and LUM as potential targets in breast cancer treatment. Our study has the potential contributing to the knowledge of breast cancer susceptibility, early detection, surveillance, and potential actionable targets, developing optimized screening programs and treatment protocols for distinct molecular subtypes. Citation Format: Chi-Cheng Huang, Wei-Chi Ku, Chi-Jung Huang, Ling-Ming Tseng. Identifying of potential therapeutic targets of Taiwanese breast cancer by functional proteomics [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 7098.

Abstract 3630: Measuring EGFr on extracellular vesicles in human plasma samples

Abstract Introduction: Extracellular vesicles (EVs), secreted extracellularly by almost all types of cells, play a pivotal role in intercellular communication and have emerged as valuable indicators in disease progression. Their potential for cancer diagnostics and monitoring is particularly noteworthy. Epidermal growth factor receptor (EGFr) is a major driver of several cancers and serve as an important target or co-target in cancer treatment. The purpose of this study was to develop an assay for measuring EGFr on EVs directly in plasma samples. Additionally three assays were developed to measure the total concentration of plasma EVs. Methods: Recognizing the expected low concentrations of EGFr on EVs, the immunoassays were developed using Single molecule array (Simoa) technology, which has shown up to a 1000-fold improvement in sensitivity as compared to conventional immunoassay approaches. Commercial available calibrator material and antibodies against surface markers (EGFr, CD9, CD63 and CD81) were used to develop four assays: CD81-EGFr, CD81-CD9, CD81-CD63, and CD9-CD63. Plasma samples from healthy individuals (n=13) and small cohorts of various cancer patients (n=30, lung, colorectal, ovarian) were used for development, validation and testing. Results: Each assay was tested for dilution linearity, limit of detection, analytical variation and pre-analytical stability of EVs. EGFr on EVs was lower in cancer patients (median: 489 × 106 EVegfr/mL) compared with healthy individuals (median: 663 × 106 EVegfr/mL). Conversely, total EV concentrations were markedly higher in plasma from cancer patients compared with healthy individuals (CD81-CD9: 9157 vs 4088, CD81-CD63: 3634 vs 1582, CD9-CD63: 9538 vs 1210, median values x106 EV/mL). Positive correlations were observed among the total EV assays (r=0.6, p<0.0001). Conclusion: The developed assays allow measurement of EGFr on EVs and total EVs in human plasma samples. Notable, total EV concentrations were highly increased in cancer as compared with healthy individuals. The assays are now ready for a comprehensive validation using large cohorts of cancer samples. Citation Format: Dorte Aa. Olsen, Torben F. Hansen, Ivan Brandslund, Jonna S. Madsen. Measuring EGFr on extracellular vesicles in human plasma 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 3630.

Abstract 2922: Sensory innervation as a novel driver of ovarian cancer progression

Abstract One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment. Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Suyeon Ryu, Jamie Moon, Dave Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. Sensory innervation as a novel driver of ovarian cancer progression [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 2922.

Abstract 1635: Inhibition of FANCA Suppresses Breast Cancer Development by Regulating Cell Cycle Progression

Abstract FANCA is one of the 22 known Fanconi anemia (FA) pathway genes that are involved in interstrand crosslink (ICL) repair. We have also shown that and FANCA plays a role in double strand break repair by promoting strand annealing and exchange. In this report, we describe that FANCA expression in breast cancer is significantly elevated within TCGA databases and in patient tumors-derived sections on both transcription and translation levels and this elevation is associated with poor outcomes of the breast cancer patients. Importantly, we have found that overexpressing FANCA in breast cancer cell line MDA-MB-231 promotes tumor growth both in vitro and in vivo. We have also demonstrated that FANCA inactivation by knocking out or knocking down inhibits growth of MDA-MB-231 in vitro and in vivo by causing cell cycle arrest at G1 phase resulting from hypophosphorylation of Rb protein. Our RNA-seq data has indicated that E2F targets are also downregulated in FANCA knockout (KO) cells compared to the wildtype (WT) MDA-MB-231 cells, which is consistent with the G1/S cell cycle arrest and Rb hypophosphorylation. Intriguingly, heterozygous FANCA KO in a breast cancer mouse model MMTV-PyMT model has shown reduction of breast tumor formation and volume. Our goal is to elucidate the role of FANCA in breast cancer development and to evaluate the potential of FANCA as a target for breast cancer treatment. Citation Format: Liang Luo, Wenjun Liu, Fenghua Yuan, Fang Li, Anna Palovcak, Daniel Calkins, Karoline Briegel Briegel, Yan Li, Christian Mason, Zhao-Jun Liu, Sylvia Daunert, Yanbin Zhang. Inhibition of FANCA Suppresses Breast Cancer Development by Regulating Cell Cycle Progression [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 1635.

Abstract 3629: Prevalence of claudin18.2 expression in gastric/gastroesophageal junction adenocarcinoma among patients in TranStar101 and TranStar102 clinical trials

Abstract Background: Claudin18.2 (CLDN18.2) is a tight junction protein highly specific to gastric mucosa, and a validated target for gastric cancer (GC) treatment. Immune checkpoint therapy targeting PD-1 combined with chemotherapy has been approved as the first line therapy of GC. Understanding the expression profiles of CLDN18.2 and PD-L1 could guide the development of combination therapies to maximize the benefits of these two agents. This study investigated the prevalence of CLDN18.2 expression in gastric/gastroesophageal junction adenocarcinoma (G/GEJC) screening samples from studies Transtar101 (NCT04396821 in US) and TranStar102 (NCT04495296 in China), and its correlation with various clinical characteristics and PD-L1 expression. Methods: CLDN18.2 expression in formalin-fixed, paraffin-embedded (FFPE) G/GEJC tissue samples was prospectively detected by an immunohistochemistry-based LDT using an in-house anti-CLDN18.2 antibody (Clone14G11) on the Leica Bond III stainer. CLDN18.2 expression was assessed by scoring the staining intensity (0, 1+, 2+, 3+) and the percentage of positive tumor cells. Positive CLDN18.2 expression is defined as the cutoff at ≥10% of tumor cell with ≥1+ staining intensity for this evaluation. PD-L1 expression was assessed by combined positive score (CPS) using Agilent’s PD-L1 IHC 28-8 pharmDx. Both assays were conducted in CAP/CLIA certified LabCorp central lab. Results: 547 G/GEJC patient samples had CLDN18.2 results as part of the screening procedures for the clinical trials. Of these patients (454 GC/93 GEJC), 439 (80%) were Asian, 29 (5%) were Caucasian, 2 (0.4%) were other ethnic group, and 77 (14%) were not recorded; 434 (79%) were primary tumors and 113 (21%) were metastasis; 201 (37%) were core needle biopsies (CNB), 108 (20%) were surgical resections (SR) and 238 (44%) had no information. 311 (57%) samples had positive CLDN18.2 expressions (≥10%/≥1+). No significant difference in CLDN18.2 positive rates were found between TranStar101 and TranStar102 studies (p=0.801), Asian and Caucasian (p=0.612), GC and GEJC (p=0.373), primary and metastatic specimens (p=0.055) or CNBs and SRs (p=0.715). Out of 83 TranStar102 specimens that had both CLDN18.2 and PD-L1 results, 15 (18%) had PD-L1 CPS≥5, 59 (71%) had positive CLDN18.2, and 10 (15%) had both positive CLDN18.2 and PD-L1 CPS≥5. No correlation (p=0.393) was observed between PD-L1 scores (CPS<5 or CPS≥5) and CLDN18.2 expression (≥10%/≥1+ or <10%/≥1+). Conclusions: Data suggested CLDN18.2 expression levels were independent of PD-L1 status, and support the use of Transcenta 14G11 antibody for CLDN18.2 detection regardless of sample collection methods, location, and patient demographics. An anti-CLDN18.2 companion diagnostic device based on 14G11 is being developed (CLDN18.2 IHC 14G11 pharmDx, Agilent Technologies, Inc.). Citation Format: Li Shen, Carol Mao, Alan Lin, Ying Gu, Jenny Milata, Lijuan Zhang, Chuan Qi, Jenny Yao, Steven Yu, Changjun Yue, Lin Shen, Yelena Janjigian, Xueming Qian, Wen-I Chang, Caroline Germa. Prevalence of claudin18.2 expression in gastric/gastroesophageal junction adenocarcinoma among patients in TranStar101 and TranStar102 clinical trials [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 3629.

Abstract 3105: Computational integration with phage library to optimize clones of DEFB4A antibodies for cancer diagnostics and therapeutics

Abstract DEFB4A, a human beta-defensin, functions as a potential cancer biomarker, with elevated expression observed in various cancers, making it a candidate for diagnostic and prognostic applications. Additionally, its role in immune modulation suggests that DEFB4A may hold promise as a target for novel cancer treatments, particularly in the context of immunotherapy. This study aimed to develop a stable and high-affinity DEFB4A antibody for clinical and pre-clinical use. To achieve this, a combination of high-diversity phage libraries and computation-assisted analysis was employed to generate single-chain variable fragments (ScFv) clones specifically targeting DEFB4A. This research presents a robust approach for the generation of DEFB4A-targeting single-chain variable fragments (ScFv) from a phage library characterized by a high diversity of 109 unique clones and high titer of 1013 cfu/mL. Computational optimization was then applied to enhance the affinity, stability, and expression of these candidates through rational design and virtual mutagenesis programs. The binding activity of the optimized mutants was validated using biophysical methods such as surface plasmon resonance (SPR) and thermal stability assays. The process showed a remarkable 100-fold increase in affinity and stability. Additionally, the selected ScFv clone was further employed in immunohistochemistry (IHC) to detect DEFB4A in breast, prostate, and gastric cancers, showing higher expression levels compared to initial clones. This study highlights the synergy of high-diversity phage libraries and computational methods in crafting DEFB4A antibodies with enhanced affinity, stability, and expression. The findings advance the field of antibody engineering, emphasizing the crucial integration of experimental and computational approaches. This work lays the groundwork for the development of high-performance biologics with diagnostic and prognostic applications across diverse cancer types. Furthermore, it demonstrates the possibility of integrating computational approaches in antibody development, offering the promise of expediting the process in the future. Citation Format: Yichen Guo, Jina Yom, Andy (Xi) Han, Zhaoying Guo, Eden Zewdu, Rachel Gonzalez, Tianli Qu, Bailey Gilmore, Xuan Liu, Wei Fu, Xiaomin Hu. Computational integration with phage library to optimize clones of DEFB4A antibodies for cancer diagnostics and therapeutics [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 3105.

Abstract 1781: Elucidation of glutathione related dipeptide metabolism in cancer

Abstract There is a long-standing belief that supplementation with antioxidants could potentially treat diseases like cancer. Recent year studies showed, however, that they can behave like a double-edged sword and can also increase tumor proliferation and metastatic progression. The exact mechanism behind antioxidants' impact on tumors is poorly understood. Glutathione (GSH), the most abundant antioxidant in mammalian cells, is a tripeptide containing glutamate, cysteine, and glycine. GSH levels are reported to be significantly elevated within the extracellular space of the tumor. Our preliminary findings show that the breakdown of extracellular GSH can support tumor cell survival under cystine-free conditions. Extracellular GSH catabolism releases cysteinylglycine, which can enter the cell through a dipeptide transporter and be further broken down to supply cysteine and glycine to cells. Alternatively, cysteinylglycine can also be broken down extracellularly into cysteine and glycine, allowing for the uptake of these individual peptides. The molecular mechanisms surrounding the utilization of GSH-breakdown products by the tumor cell are largely unknown. We hypothesize that the proteins responsible for the supply of cysteinylglycine to the tumor cell are required for tumor growth and survival. To test this, we will use unbiased genetic and pharmacologic screening approaches to elucidate the proteins involved in cysteinylglycine processing. Preliminarily, we have found that inhibitors of dipeptidases prevent the ability of cysteinylglycine to support tumor cell survival under cystine starvation, suggesting that tumors require downstream utilization of GSH products. By identifying the mechanisms involved in cysteinylglycine breakdown and supply to tumor cells, we will potentially reveal novel therapeutic targets for cancer treatment, including those not relied upon by normal tissues. Further, our studies will potentially provide a better understanding of how antioxidants impact tumor growth and progression. Citation Format: Fatemeh Alimohammadi, Fabio Hecht, Marco Zocchi, Emily Tuttle, Gloria Asantewaa, TashJae Scales, Nathan Ward, Gina DeNicola, Isaac Harris. Elucidation of glutathione related dipeptide metabolism in 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 1781.

Abstract 7185: Long acting injectable FHD-609 micro-suspension: A potent BRD9 degrader with comparable efficacy, reduced frequency of dosing in preclinical models

Abstract Bromodomain-containing protein 9 (BRD9) is a unique component of the non-canonical Brahma-associated factor (ncBAF) complex, essential for cancer cells relying on this complex for survival. This makes it an attractive target for cancer treatment. In synovial sarcoma (SS), SS18-SSX fusion protein drives disease progression and integrates into BAF complexes, promoting tumor growth. Targeting BRD9 degradation is a potential therapeutic approach for SS tumors, as it depletes the essential SS18-SSX fusion protein upon which cancer cells depend for survival within the BAF complex. FHD-609, a potent heterobifunctional degrader of BRD9, has been administered intravenously (IV) in medical facilities twice weekly during clinical trials. In order to facilitate less frequent and more convenient patient-centric dosing, a long acting injectable formulation was developed that allows subcutaneous (SC) or intramuscular (IM) dosing every 4 weeks in preclinical studies. The formulation is an aqueous microsuspension containing the drug along with a polymer and surfactant which provides sustained release of FHD-609 upon injection. We compared the long acting injectable formulation dosed once every 4 weeks to the IV formulation dosed twice a week for the pharmacokinetic and pharmacodynamic properties, as well as the efficacy of the long in xenograft models of different sensitivities, including cell line-derived xenografts (CDX) and patient-derived xenografts (PDX). Our results showed that a single dose of the injectable suspension formulation was well-tolerated in mice and exhibited a significantly flatter PK profile than IV injection with a lower peak to trough ratio and detectable compound concentrations 4 weeks post dose. Moreover, it demonstrated comparable in vivo efficacy and BRD9 protein degradation to the standard intravenous (IV) administration. The long acting FHD-609 injectable formulation has the potential to offer better patient compliance and acceptance in clinical settings than IV dosing. The long acting injectable formulation provides a promising and effective drug delivery option for various protein degraders that are not orally bioavailable. Citation Format: Meiyun Lin, Ammar Adam, Abira Pyne Ramakrishnan, Hafiz Ahmad, Xiaohuan Wu, Brandon Antonakos, Chong-Hui Gu, Ashish Ramani, Victoria Amaral, Claudia Dominici, Qianhe Zhou, Mike Collins, Jessica Piel, Sal Topal, Brian Ethell, Kelly McKiernan, Scott Innis. Long acting injectable FHD-609 micro-suspension: A potent BRD9 degrader with comparable efficacy, reduced frequency of dosing in 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 7185.

Abstract 1893: OBI-992, a novel TROP2 targeting antibody-drug conjugate, displayed excellent antitumor efficacy in various animal models

Abstract Background: TROP2 is a validated therapeutic target for cancer treatment. OBI-992 is an antibody-drug conjugate (ADC) derived from a novel TROP2 antibody linked with a topoisomerase 1 inhibitor payload, exatecan, through conjugation with an enzyme-cleavable linker. Upon binding to TROP2 on the surface of cancer cells, OBI-992 is internalized into the cell and trafficked to lysosomes where the linker is cleaved by cathepsin B, releasing the payload exatecan to kill the cancer cells. This study aims to evaluate the antitumor efficacy of OBI-992 in vitro and in vivo, including cell-based cytotoxicity, cell line-derived xenografts (CDX), and patient-derived xenografts (PDX) models. Methods: The cytotoxicity of OBI-992 was evaluated in cell lines with different levels of TROP2 expression. In vivo efficacy was evaluated using CDX and PDX models of various cancer types. Bystander killing effect of OBI-992 was examined in a xenograft model containing a premixture of TROP2 positive and TROP2 negative cancer cells. Moreover, the impact of overexpression of P-glycoprotein (Pgp) or breast cancer resistance protein (BCRP) on the antitumor efficacy of TROP-2 ADCs was evaluated. OBI-992 in combination with PARP inhibitors such as olaparib and talazoparib was examined for potential synergistic effects in a homologous recombination deficiency (HRD) xenograft model. Results: The cytotoxicity of OBI-992 was positively associated with the TROP2 RNA levels in different cell lines. In various CDX and PDX models, a single dose of OBI-992 at 3 or 10 mg/kg exhibited remarkable tumor growth inhibition. Notably, the antitumor efficacy of OBI-992 surpassed that of datopotamab deruxtecan (Dato-DXd) across different CDX and PDX models. OBI-992 demonstrated a bystander killing effect as OBI-992 was able to kill TROP2-negative xenografts in the presence of nearby TROP2-positive cells. OBI-992 showed superior efficacy to Dato-DXd in the CDX model overexpressing Pgp or BCRP. These findings suggest that OBI-992 was not affected by the Pgp- and BCRP-mediated multidrug resistance. In the HRD CDX model at suboptimal doses, combination of OBI-992 with olaparib or talazoparib displayed remarkable synergistic effects. Conclusions: OBI-992 exhibited excellent antitumor efficacy and outperformed the benchmark Dato-DXd in CDX and PDX models of various cancer types. A strong bystander killing effect indicated that OBI-992 will be effective for tumors with heterogenous expression of target antigen. OBI-992 retained its antitumor effect upon overexpression of Pgp and BCRP, suggesting that OBI-992 may overcome the multidrug resistance. Outstanding synergistic effect with the combination of OBI-992 with PARP inhibitors was observed. These results warrant further studies of OBI-992 in the clinical setting. Citation Format: Wan-Fen Li, Ming-Feng Chiang, Hao-Cheng Weng, Jhih-Jie Yang, Hsin-Shan Wu, Chun-Jung Lin, Ping-Tzu Chiu, Ming-Tain Lai. OBI-992, a novel TROP2 targeting antibody-drug conjugate, displayed excellent antitumor efficacy in various animal 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 1893.

Abstract 1897: Preclinical development of MGC028, an ADAM9-targeted, glycan-linked, exatecan-based antibody-drug conjugate for the treatment of solid cancers

Abstract Introduction: Antibody-drug conjugates (ADCs) seek to increase the therapeutic window of potent cytotoxic agents by linking them with monoclonal antibodies (mAbs) to selectively deliver cytotoxic payloads to tumor cells. The effectiveness and safety of ADCs rely on both the mAb specificity, and the linker-payload employed. Several approved ADCs using microtubule inhibitor payloads are impacted by ocular adverse events that have been observed both preclinically and in patients. A class of linker-payloads incorporating topoisomerase 1 inhibitors (TOP1i) has emerged recently as an effective alternative to tubulin inhibitor-based ADCs. To date, TOP1i ADCs have not been associated with dose-limiting ocular toxicity seen with microtubule inhibitor payloads. Here we report the preclinical development of an ADAM9 (a disintegrin and metalloprotease domain 9)-targeted ADC that incorporates a novel glycan-linked TOP1i. ADAM9, a member of the ADAM family of multifunctional type 1 transmembrane proteins, plays a role in tumorigenesis and cancer progression and is overexpressed in multiple cancers, making it an attractive target for cancer treatment. Methods: MGC028 incorporates the cleavable linker-payload, bicyclononyne carbamoyl sulfamide Val-Ala-PABC exatecan (SYNtecan E™), site-specifically conjugated at asparagine 297 of the heavy chain through enzymatic glycan remodeling and metal-free click chemistry using Synaffix’s GlycoConnect™ technology. In vivo efficacy studies were performed in immunodeficient mice with ADAM9-expressing human tumor cell-line (CDX) or patient-derived (PDX) xenografts. A non-human primate toxicology study was conducted in which MGC028 was administered by 15-minute IV infusion every two weeks at dose levels of 22.5 and 55 mg/kg for a total of two doses. Results: MGC028 exhibited specific, dose-dependent in vivo antitumor activity toward ADAM9-positive CDX models representing gastric, lung, pancreatic and colorectal cancer, and head and neck squamous cell carcinoma. Furthermore, MGC028 demonstrated antitumor activity toward ADAM9-positive PDX models of lung and pancreatic cancer, and cholangiocarcinoma. MGC028 was well tolerated in a repeat-dose non-human primate toxicology study, up to 55 mg/kg, the highest dose level tested. Observations were limited to mild, reversible increases in liver enzymes, without microscopic correlates, and decreased lymphoid cellularity in the thymus. In particular, ocular toxicities were not observed. Conclusions: MGC028 exhibited potent antitumor activity in in vivo models representing various solid cancer indications and was well tolerated in non-human primates at exposure levels exceeding those required for antitumor activity. Our findings support continued investigation of MGC028 as an ADC therapeutic for the treatment of ADAM9-expressing solid cancers. Citation Format: Juniper A. Scribner, Jennifer G. Brown, Thomas Son, Linda Jin, Carroll McKenzie, Viktoriya Nam, Curtis Bush, Dienis Quinonez, Delta Ford, Verlene Gonzalez, James Tamura, Sergey Gorlatov, Hua Li, Shelley Butler, Ezio Bonvini, Deryk Loo. Preclinical development of MGC028, an ADAM9-targeted, glycan-linked, exatecan-based antibody-drug conjugate for the treatment of solid cancers [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 1897.

Abstract 628: RNA binding protein Matrin3 acts as a tumor suppressor by inhibiting microtubule nucleation

Abstract Introduction: Microtubule-associated proteins (MAPs) regulate microtubule dynamics, which is critical for controlling cell division, proliferation, migration, and intracellular transport. Due to their critical role in maintaining cellular integrity, microtubules have served as potent therapeutic targets for cancer treatment. Here, we report “Matrin 3 (MATR3)” as a novel MAP that interacts with β- tubulin and γ-tubulin, which constitutes microtubule organizing center (MTOC) essential for proper spindle formation and chromosomal segregation. Methods: Breast cancer cell lines (MDA-MB-231, MDA-MB-468, SKBR3, MCF7, BT549, HMEC, and MCF10A) were purchased from the American Type Culture Collection and cultured in standard medium. Breast cancer cells were transfected either with MATR3 overexpression plasmid or siRNA specific to MATR3. These overexpression/knockdown breast cancer cells were analyzed for cell viability, migration, invasion, colony formation, cell cycle, apoptosis assays, RNA sequencing, RT-qPCR, western blotting, RNA immunoprecipitation, and in vivo tumor xenograft study. Results: Our findings show that MATR3 binds to RNA encoding MAPs including β-tubulin and γ-tubulin, and regulate their stabilization. MATR3 also interacted with β-tubulin protein. Our data demonstrate that MATR3 functions as a tumor suppressor, as its overexpression inhibits cancer growth, while its depletion increased tumor growth in vivo. Mechanistic studies confirmed that MATR3 mediates its tumor suppressor role by regulating the expression of the MTOC-associated protein-encoding gene MZT2B (Mitotic Spindle Organizing Protein 2B), which is overexpressed in cancers and promotes cancer growth. Further, loss of MATR3 expression or function results in dysregulated microtubule dynamics and uncontrolled expression of the oncogenic proteins including MZT2B. Conclusions: In conclusion, our data strongly suggests that MATR3 serves as a novel RNA-binding protein with tumor suppressor properties. This discovery holds significant importance as MATR3 becomes the second protein, following Adenomatous Polyposis Coli (APC), to be identified for its binding to both MAP RNA and protein. Citation Format: Panneerdoss Subbarayalu, Subapriya Rajamanickam, Santosh Timilsina, Saif Nirzhor, Daisy Medina, Shahad Abdulsahib, Pitta V Prabhakar, Deepika Singh, Fu-Yang Li, Pooja Yadav, Esha Reddy, Krishna Evani, Vijay Eedunuri, Trong Phat Do, Benjamin C. Onyeagucha, Tabrez A. Mohammad, Jae-Hoon Ji, Yidong Chen, Nourhan Abdelfattah, Nicholas Dybdal-Hargreaves, Li-Ju Wang, Yu-Chiao Chiu, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi, Manjeet K. Rao. RNA binding protein Matrin3 acts as a tumor suppressor by inhibiting microtubule nucleation [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 628.

Abstract 7149: Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers

Abstract Harnessing synthetic lethality offers an innovative approach to targeted cancer treatment. USP1, a specific deubiquitinating enzyme, has gained attention as a potential synthetic lethality target for BRCA-mutated cancers. At AIGEN Sciences, Inc., we've integrated the advanced capabilities of our human-in-the-loop (HITL) AI drug discovery platform, AIGEN ChemTailor. This cutting-edge platform thrives on continuous learning enhanced by expert feedback, refining our approach to drug discovery. Using AIGEN ChemTailor, we synthesized a specific USP1 inhibitor. Its inhibitory capabilities were validated through the Ubiquitin-rhodamine 110 assay. Notably, our inhibitor presented remarkable anti-proliferative effects on BRCA1 mutant cells (MDA-MB-436) while showing no activity against BRCA wild-type cells (HCC1954), highlighting its specificity. The efficacy of our inhibitor was enhanced when combined with PARP inhibitors, such as olaparib or AZD5305, especially in UWB1.289 cells. Impressively, the USP1 inhibitor also effectively targeted PARPi-resistant cell lines, including A2780-ola, UWB1.289-nir, HCC38-ola, MDA-MB-468-ola, U251MG-ola, and OVCAR8-ola. Clonogenic assays with MDA-MB-436 and MCF-10A emphasized our inhibitor's selectivity towards BRCA mutant phenotypes. Subsequent studies demonstrated the compound's mechanism: inducing replication stress by impairing of DNA synthesis and activating DNA damage pathways via ATR signaling. Preclinical mouse studies highlighted favorable pharmacokinetics and involved the assessment of anti-tumor effects in animal models. In summation, our USP1 inhibitor, developed using AIGEN ChemTailor and advanced molecular modeling techniques, stands out as a potent therapeutic against BRCA-mutated cancers and PARP inhibitor-resistant strains. Citation Format: Jihye Kim, Sunkyu Kim, Sejeong Park, Sanghoon Lee, Kiwoong Yoo, Ho-Jeong Lee, Jaewoo Kang, Kwang-Ok Lee. Discovery of a novel USP1 inhibitor: Targeted therapy for BRCA-mutated and PARPi-resistant cancers [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 7149.

Abstract 5468: Pediatric Preclinical In Vivo Testing (PIVOT) data portal enables access to 15 years of retrospective treatment study data in support of prospective study design

Abstract The PIVOT program (https://preclinicalpivot.org) is a National Cancer Institute (NCI) funded initiative in support of the RACE Act that funds collaborations between academic centers and industry partners to test the efficacy of targeted cancer treatments developed for adult oncology for potential application in diverse pediatric cancers, including cancers of the central nervous system, leukemia, osteosarcoma, sarcoma, and neuroblastoma. In support of the PIVOT program, we have harmonized more than 15 years of data collected during two previous preclinical pediatric testing programs. To disseminate the data and results of these programs broadly we designed and implemented the PIVOT Data Portal. The PIVOT Data Portal is an R Shiny App that makes treatment efficacy data from PIVOT accessible on the web. The data are harmonized which supports comparison of treatment results across different cancer types. The data from the portal are freely available and downloadable. The portal includes study summaries within and across cancer models, statistical reports, tables, and tools for the visualization of treatment results. Data summary tables include entries for objective response measures (ORM), mean outcome, number of tumor studies, and p-value as appropriate. Visualizations include relative tumor volume plots for solid tumors; CD45 plots for leukemia; and survival curves to compare survival time across treatment groups. Treatment study visualizations and data summaries with their related metadata can be generated and downloaded within the Shiny App, allowing researchers to perform further downstream analysis. The portal collectively contains data for 52 agents, 45 drug targets, 34 drug classes (including ADCs, small molecular inhibitors, protein degraders, BiTEs, etc.), and 167 models, with a total of 245,926 data points. Currently, 44% of agents have been tested on 2 or more cancer types. Among the solid tumor models tested, 10 had at least one treatment that resulted in an ORM of maintained complete response (MCR), while 29 leukemia models had an ORM of MCR. Similarly, 48% of agents tested had an ORM of MCR for at least one cancer type. The PIVOT Data Portal makes pediatric cancer model treatment data available without restriction to support retrospective analyses and design of prospective studies. We are working to link cancer model data within the portal to molecular data. Merging outcome data with genomics data will facilitate computational approaches for molecular target identification, personalized treatment, and treatment optimization. Citation Format: Saul E. Acevedo, Tim M. Stearns, Phillip Webster, Vivek Philip, Michael W. Lloyd, Anuj Srivastava, Steven Neuhauser, Dale Begley, Debbie Krupke, Emily L. Jocoy, Carol J. Bult, Jeffrey H. Chuang, Dennis A. Dean. Pediatric Preclinical In Vivo Testing (PIVOT) data portal enables access to 15 years of retrospective treatment study data in support of prospective study design [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 5468.

Abstract 3132: A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity in solid tumor models

Abstract Antibody-drug conjugates (ADCs) are emerging therapeutic agents for targeted cancer treatment with remarkable clinical success. However, tumor heterogeneity and microenvironment complexity are still the major factors contributing to drug resistance, recurrence, and metastasis, which cannot be resolved with a mono therapy strategy. We’ve developed a novel dual drug ADC (BiADC), BR113, by conjugating an anti-hTrop2 antibody with a drug linker of a Topoisomerase I inhibitor payload, and another drug linker of an immune stimulator. Our studies show that the homogeneous ADC containing two distinct payloads is a new promising drug class, with two different anti-tumor MOAs, synergistic antigen-specific cell killing potency, desirable pharmacokinetic profiles, and minimal toxicity at therapeutic doses. In the cancer cells and human PBMC co-culture assay, BR113 exerts significantly more potent killing on cancer cells than two individual single-drug ADCs and the combination of two single-drug ADCs, which suggested a synergy on anti-tumor effects of this dual-drug ADC. In the xenograft mouse model studies, BR113 exhibits greater treatment effect and survival benefit than the combo of two single-drug ADCs at various doses. This robust superior anti-tumor activity is further confirmed in a hTrop2-MC38 syngeneic model with a prolonged anti-tumor protection against the tumor re-challenge. Finally, the novel BiADC, BR113, is well tolerated in hTop2 humanized mice after repeated administration. Our findings highlight the therapeutic potential of the BiADC format for treating refractory advanced solid tumors. The outstanding anti-tumor activity across various CDX tumor models and its favorable safety profile in mice support further evaluation of the innovative BiADC, BR113. Citation Format: Jie Zhu, Xiaobei Zhao, Eileen Li, Hong Xu, Lei Nie, Gang Chen, Haibing Wang. A novel dual drug antibody-drug conjugate targeting hTrop2 has synergetic anti-tumor activity in solid tumor 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 3132.

Abstract 7121: The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers

Abstract Previous studies have demonstrated that WEE1 inhibitors (WEE1i) are a promising cancer therapeutic through synthetic lethality with Cyclin E overexpression. One challenge for two of the leading WEE1i, AZD1775 and ZN-c3, has been the observed off-targeting of PLK family members, namely, PLK1, PLK2 and PLK3. In addition, the therapeutic application of these inhibitors in clinical trials has been limited by adverse hematological effects, including anemia. Herein, we describe the testing of a novel WEE1i (APR-1051) that, based on preclinical studies: 1) demonstrates reduced off-targeting of PLK1, PLK2 and PLK3, and 2) has the ability to suppress the growth of CCNE1-overexpressing xenografted tumors while causing little impact on red blood cell and reticulocyte levels. APR-1051 has an IC50 of 2.2 nM for WEE1 in vitro and has shown the ability to limit the proliferation of various cancer cell lines in culture. Interestingly, the genotoxicity of APR-1051 is suppressed by increasing concentrations of PLK1 inhibitors, suggesting that off-targeting of PLK1 by other WEE1i may compromise efficacy of this targeted cancer treatment in addition to the risk of producing PLK1i-associated adverse effects. APR-1051 demonstrated effectiveness in suppressing the growth of Cyclin E-overexpressing breast and ovarian cancer cells lines, thus pinpointing Cyclin E as a potential biomarker for APR-1051 treatment. Importantly, dose and scheduling of APR-1051 that causes significant suppression of CCNE1-amplified high-grade serious ovarian cancer tumors in mice is well tolerated, with red blood cell and platelet counts remaining within non-pathogenic ranges after a 28-day treatment period. In addition, inhibition WEE1 by APR-1051 occurs at an IC50 that is 200-fold lower on average than the IC50 of hERG potassium channel inhibition, implying that APR-1051 will potentially exhibit low cardiotoxicity. APR-1051 is now progressing through IND-enabling studies. Together, these findings underscore the potential of APR-1051 as a novel WEE1i for the treatment of Cyclin E-overexpressing cancers. Citation Format: Molly M. Hansbarger, Stephen J. Rocca, Sonia Ritzmann, Joseph Vacca, Bridget Tokiwa, Jonathan Weinstein, Henry Zabierek, Justin Frye, Michael Carleton, Eric J. Brown, Oren Gilad. The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers [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 7121.

Abstract 4681: Unlocking the anticancer potential of calix[4]arene-based Cu(I) ionophores in vitro and in vivo

Abstract Introduction: Cuproptosis is a novel programmed cell death pathway triggered by increased intracellular Copper (Cu) levels. This process offers promising avenues for cancer therapy and underscores the pivotal role of Cu-targeting molecules, such as chelators and ionophores. Despite the progress made, there is still a critical need for novel molecules capable of disrupting copper homeostasis within cancer cells. Methods: We developed and patented a novel class of Cu(I) ionophores characterized by calix[4]arene structures. The anticancer effects of these compounds were evaluated through proliferation assays (IC50), cell cycle assays, and the mechanisms of cell death were explored, including apoptosis, senescence, autophagy, and cuproptosis. To elucidate the mechanisms of action, we conducted proteomic and phosphoproteomic analyses in three different lung adenocarcinoma cell lines (A549, H322, and PC9). Intracellular concentrations of Zn, Fe, and Cu were determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Animal experiments were conducted on nude mice bearing subcutaneous A549 lung cancer xenografts. Results: Our lead compound, Cuphoralix, demonstrated potent cytostatic effect across a panel of 60 cancer cell lines. This effect was attributed to an early and irreversible blockade of the cell cycle initiation at 24 hours post-treatment. Cuphoralix treatment did not induce senescence or apoptosis. Proteomic analyses confirmed the differential regulation—both upregulation and downregulation—of over 500 proteins and phosphopeptides following treatment with Cuphoralix. Notably, Cuphoralix treatment resulted in decreased expression levels of proteins implicated in cell cycle progression and DNA replication. We discovered that Cuphoralix induced cuproptosis and autophagy, as evidenced by the overexpression of LC3B-II. Intracellular Cu level was significantly increased after treatment with Cuphoralix, suggesting the initiation of cuproptosis. In vivo, the toxicity of liposomal Cuphoralix was assessed following three intravenous injections/week for 4 weeks. Animal weights remained stable, with no observed toxicity or signs of neurological or functional impairment. The anticancer efficacy of Cuphoralix, both alone and in combination with other treatments, was corroborated in vivo by measuring the volumes of subcutaneous xenografts. Conclusions: Our novel Cu(I) ionophore, Cuphoralix, has demonstrated significant potential in inducing cuproptosis and disrupting copper homeostasis, presenting a novel approach to cancer therapy. The compound's capacity to initiate an early and irreversible cell cycle blockade and to modulate the expression of key proteins underscores its therapeutic promise. The profound in vitro and in vivo anticancer effects observed encourage further development and investigation of cuproptosis as a targeted cancer treatment strategy. Citation Format: Pierre Lelievre, Cyril Nogier, Nathan Renier, Jean-Luc Coll, Ivan Jabin, Lucie Sancey, Hennie Valkenier, Aurelien Deniaud, Benoit Busser. Unlocking the anticancer potential of calix[4]arene-based Cu(I) ionophores in vitro and in vivo [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 4681.

Population-enriched innate immune variants may identify candidate gene targets at the intersection of cancer and cardio-metabolic disease.

Both cancer and cardio-metabolic disease disparities exist among specific populations in the US. For example, African Americans experience the highest rates of breast and prostate cancer mortality and the highest incidence of obesity. Native and Hispanic Americans experience the highest rates of liver cancer mortality. At the same time, Pacific Islanders have the highest death rate attributed to type 2 diabetes (T2D), and Asian Americans experience the highest incidence of non-alcoholic fatty liver disease (NAFLD) and cancers induced by infectious agents. Notably, the pathologic progression of both cancer and cardio-metabolic diseases involves innate immunity and mechanisms of inflammation. Innate immunity in individuals is established through genetic inheritance and external stimuli to respond to environmental threats and stresses such as pathogen exposure. Further, individual genomes contain characteristic genetic markers associated with one or more geographic ancestries (ethnic groups), including protective innate immune genetic programming optimized for survival in their corresponding ancestral environment(s). This perspective explores evidence related to our working hypothesis that genetic variations in innate immune genes, particularly those that are commonly found but unevenly distributed between populations, are associated with disparities between populations in both cancer and cardio-metabolic diseases. Identifying conventional and unconventional innate immune genes that fit this profile may provide critical insights into the underlying mechanisms that connect these two families of complex diseases and offer novel targets for precision-based treatment of cancer and/or cardio-metabolic disease.

Targeting human progesterone receptor (PR), through pharmacophore-based screening and molecular simulation revealed potent inhibitors against breast cancer

Breast cancer, the prevailing malignant tumor among women, is linked to progesterone and its receptor (PR) in both tumorigenesis and treatment responsiveness. Despite thorough investigation, the precise molecular mechanisms of progesterone in breast cancer remain unclear. The human progesterone receptor (PR) serves as an essential therapeutic target for breast cancer treatment, warranting the rapid design of small molecule therapeutics that can effectively inhibit HPR. By employing cutting-edge computational techniques like molecular screening, simulation, and free energy calculation, the process of identifying potential lead molecules from natural products has been significantly expedited. In this study, we employed pharmacophore-based virtual screening and molecular simulations to identify natural product-based inhibitors of human progesterone receptor (PR) in breast cancer treatment. High-throughput molecular screening of traditional Chinese medicine (TCM) and zinc databases was performed, leading to the identification of potential lead compounds. The analysis of binding modes for the top five compounds from both database provides valuable structural insights into the inhibition of HPR for breast cancer treatment. The top five hits exhibited enhanced stability and compactness compared to the reference compound. In conclusion, our study provides valuable insights for identifying and refining lead compounds as HPR inhibitors.

Identification of CAF-related lncRNAs at the pan-cancer level represents a potential carcinogenic risk.

Cancer-associated fibroblasts (CAFs) are increasingly recognized as playing a crucial role in regulating cancer progression and metastasis. These cells can be activated by long non-coding RNAs (lncRNAs), promoting the malignant biological processes of tumor cells. Therefore, it is essential to understand the regulatory relationship between CAFs and lncRNAs in cancers. Here, we identified CAF-related lncRNAs at the pan-cancer level to systematically predict their potential regulatory functions. The identified lncRNAs were also validated using various external data at both tissue and cellular levels. This study has revealed that these CAF-related lncRNAs exhibit expression perturbations in cancers and are highly correlated with the infiltration of stromal cells, particularly fibroblasts and endothelial cells. By prioritizing a list of CAF-related lncRNAs, we can further distinguish patient subtypes that show survival and molecular differences. In addition, we have developed a web server, CAFLnc (https://46906u5t63.zicp.fun/CAFLnc/), to visualize our results. In conclusion, CAF-related lncRNAs hold great potential as a valuable resource for comprehending lncRNA functions and advancing the identification of biomarkers for cancer progression and therapeutic targets in cancer treatment.