tbuckley/cabot-search huggingface dataset:
Abstract 1916: Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid tumors
Authors: Jill M. Carton, Chris Dower, Michael Miller, John Wheeler, Sean Heron, Hillary J. Millar, David Walker, Daniel J. Perry, Andriana Lebid, Luis Cocka, Dae Hwan Kim, Barry Morse, Buddha Gurung, Maisha Harris, Annalise Jethon, Michael Naso, Hy Levitsky
Journal: Cancer Research (2024)

Abstract Century Therapeutics is developing a Nectin4-targeting IPSC-derived cell therapy for the treatment of Nectin4 expressing solid tumors. The Nectin proteins (Nectin1, Nectin2, Nectin3 and Nectin4) are members of the calcium independent immunoglobulin superfamily of cell adhesion molecules (CAMs) involved in adhesive processes that help in the growth and development of tissues. Nectin 1, 2 and 3 are normally found in adult tissue whereas Nectin4 is mainly found in normal placental and embryonic tissue. Nectin4 is also expressed in different types of cancer including urothelial, ovarian, lung and head/neck cancers. Nectin4 is established as a biomarker for worse prognosis in cancers and is linked with carcinogenesis and disease severity. These features establish Nectin4 as a promising target for anti-tumor drug development. Enfortumab vedotin, an antibody drug conjugate targeting Nectin4 positive tumors, has demonstrated benefit in clinical trials and is FDA approved for treatment of advanced bladder cancer. We have identified novel single-domain antibodies (VHH) that bind to multiple epitopes on Nectin4 extracellular domain. The VHH antibodies were engineered into chimeric antigen receptor (CAR) formats and characterized for expression, cell activation through antigen engagement, and cytotoxicity activity in primary T-cells. Selected binders demonstrated efficacy in multiple CAR formats in primary T-cells in a mouse xenograft model using OVCar-3 tumor cells. The lead CARs engineered into primary T-cells demonstrated tumor inhibition similar to a reference CAR using the ASG-5ME antibody (Enfortumab) as the Nectin4 binder. The CARs were engineered into our IPSC-derived iNK and iT cells and demonstrated cytotoxicity activity against a panel of cell lines with a range of cell surface expression of Nectin4. Based on these studies, Century Therapeutics is advancing the lead Nectin4 binder for development of an IPSC-derived cell therapy to treat Nectin4 positive solid tumors. Citation Format: Jill M. Carton, Chris Dower, Michael Miller, John Wheeler, Sean Heron, Hillary J. Millar, David Walker, Daniel J. Perry, Andriana Lebid, Luis Cocka, Dae Hwan Kim, Barry Morse, Buddha Gurung, Maisha Harris, Annalise Jethon, Michael Naso, Hy Levitsky. Discovery of a novel Nectin4 IPSC-derived cell therapy for the treatment of solid 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 1916.
Abstract 4979: Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location
Authors: Muhammet Ozer, Suleyman Y. Goksu, Busra Bacik Goksu, Nina N. Sanford, Amy Jones, Nilesh Verma, Syed Kazmi
Journal: Cancer Research (2024)

Abstract Background: Here, we describe analyses towards identifying and comparing genetic variations between the primary and metastatic sites in early-onset metastatic colorectal cancer patients. Methods: We selected patients with early-onset metastatic colorectal cancer (under 50 years old) using data from the American Association for Cancer Research Project GENIE (version 14.1). We used the Fisher exact test to compare genetic mutations between the primary tumor and metastatic sites, complemented by the Benjamini-Hochberg adjustment method. Results: In a total of 1,791 patients with early-onset metastatic colorectal cancer, 27.1% had tumor samples from metastatic sites, while the majority, 72.9%, were from the primary tumor location. The most common mutations found were in the TP53 gene (77.6%), followed by APC (76.0%), KRAS (42.4%), and PIK3CA (19.0%). Notably, the metastatic samples had a significantly higher occurrence of SMAD4 mutations compared to their primary site counterparts (20.8% vs. 14.0%, p&amp;lt;0.001, q&amp;lt;0.001). Conversely, the primary tumor samples exhibited higher frequencies of TCF7L2 and ARID1A mutations (16.9% vs. 10.6%, p&amp;lt;0.001, q&amp;lt;0.001, and 13.0% vs. 6.4%, p&amp;lt;0.001, q&amp;lt;0.001, respectively). Conclusion: Determining the specific genes responsible for the formation of metastatic tumors is crucial for a deeper understanding of the disease's underlying biology in early-onset metastatic colorectal cancer. Such genomic details are crucial to pave the way to the discovery of potential biomarkers for diagnosis and the development of new cancer therapeutics. Citation Format: Muhammet Ozer, Suleyman Y. Goksu, Busra Bacik Goksu, Nina N. Sanford, Amy Jones, Nilesh Verma, Syed Kazmi. Genomic profiling of early-onset metastatic colorectal cancer based on tumor sample location [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 4979.
Abstract 6727: QL335, a novel T cell engager with enhanced safety profile targeting MSS colorectal cancer
Authors: Shenda Gu, Guangjie Guo, Helena Yee, Hieu V. Tran, Shihao Chen, Chuanzeng Cao, Ke Liu, Chunyan Jin, Weihua Lun, Ruixue Ma, Lele Ren
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the fourth leading cause of death in the world with a global mortality rate of over 700,000 annually. While recent advancement in diagnosis and prevention has reduced the overall number of deaths, the lack of effective and durable treatment has not significantly improved survival rate. Emerging modalities in immunotherapy such as T cell engagers have paved new ways for disease management. However, a common challenge to advancing T cell engagers in the clinic is poor target specificity and high toxicity associated with non-specific T cell activation and cytokine release. To overcome these shortcomings, we have developed QL335, a bispecific antibody bridging LY6G6D antigen on tumor cells and CD3 on T cells. LY6G6D or Lymphocyte Antigen 6 Family Member G6D, is a GPI-anchored membrane protein that, according to TCGA RNAseq data, is highly expressed in microsatellite stable (MSS) colorectal cancer but not in normal tissues. We analyzed LY6G6D expression by IHC in over 200 CRC patient tumors and 40+ normal tissue samples from different organs, confirming its highly restricted CRC expression pattern. We constructed our bispecific antibody in a 2+1 format, comprising two high affinity LY6G6D binding domains and one reduced affinity CD3 binding domain. Such format allows for higher tumor accumulation while mitigating non-specific T cell activation in the periphery. In vitro evaluation showed that QL335 induced potent yet highly specific T cell activation and killing of only target cells expressing LY6G6D. QL335 demonstrated robust anti-tumor efficacy in vivo against human colon cancer xenograft models with human PBMC reconstitution. Importantly, QL335 was well tolerated in cynomolgus monkeys dosed up to 50 mg/kg, supporting the enhanced safety profile by design of this therapeutic candidate. QL335 is currently being evaluated in a phase 1 clinical trial. Citation Format: Shenda Gu, Guangjie Guo, Helena Yee, Hieu V. Tran, Shihao Chen, Chuanzeng Cao, Ke Liu, Chunyan Jin, Weihua Lun, Ruixue Ma, Lele Ren. QL335, a novel T cell engager with enhanced safety profile targeting MSS colorectal 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 6727.
Abstract 1121: Targeting the DNA damage response in high-risk medulloblastoma
Authors: Alexandria DeCarlo, Carolina Fernandes da Silva, Lily Shen, Vijay Ramaswamy, Uri Tabori
Journal: Cancer Research (2024)

Abstract Medulloblastoma (MB) is the most common malignant pediatric brain tumour and is currently treated with surgery, external beam radiation and chemotherapy however, current treatments are woefully inadequate, with survival of only 50% but morbidity approaching 100%. A very-high risk group of SHH-activated MB harboring TP53 mutations (TP53mut-SHH) account for a substantial proportion of treatment failures after radiotherapy with a uniformly fatal outcome. Through optimizing radiation as a selection pressure and employing a functional genetic approach through whole-genome CrisprCas-9 dropout screening, the present study aims to identify drivers of radiation resistance and uncover unique vulnerabilities to sensitize these tumours to therapy. The dropout screen was conducted across a panel of established in vitro models of sporadic murine TP53mut-SHH, which resemble the human disease with profound radio-resistance. Initial results reveal that targeting the DNA damage response confer radiation sensitization. However, consistent hits across all models demonstrate non-homologous end-joining (NHEJ) as being synthetically lethal with radiation specifically in TP53mut-SHH. Genetic knockout experiments confirm genes encoding main proteins involved in NHEJ are synthetically lethal in combination with radiation. A small molecule drug screen targeting NHEJ revealed such vulnerabilities may be therapeutically exploited in TP53mut-SHH and are able sensitize these tumours to radiation. Using our unique approach of leveraging newly established models of TP53mut-SHH with a combination of functional genetic screening and small-molecule drug screening, this study highlights the genetic mechanisms of treatment resistance and reveals novel approaches for radiation sensitization. Here, we develop a novel approach to identify targets that are synthetically lethal with radiotherapy and identify multiple synthetically lethal targets at the genetic level which can be therapeutically targeted, allowing the development of new treatments to overcome current barriers. Citation Format: Alexandria DeCarlo, Carolina Fernandes da Silva, Lily Shen, Vijay Ramaswamy, Uri Tabori. Targeting the DNA damage response in high-risk medulloblastoma [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 1121.
Abstract 766: Effects of supplemental calcium and vitamin D on circulating biomarkers of gut barrier function in colorectal adenoma patients: A randomized controlled trial
Authors: Sangji Lee, Veronika Fedirko, Roberd M. Bostick, Bradley Pearce, Elizabeth L. Barry, Robin E. Rutherford, March E. Seabrook
Journal: Cancer Research (2024)

Abstract Introduction: Recent experimental evidence shows that intestinal barrier disruption initiates colon inflammation, which may promote colorectal carcinogenesis. In experimental models, vitamin D and calcium improved gut barrier function; however, this has not been assessed in humans. Method: To test the effects of supplemental calcium and vitamin D3 on circulating biomarkers of intestinal mucosal damage (intestinal fatty-acid binding protein, IFABP) and exposure to bacterial products due to impaired gut barrier (lipopolysaccharide-binding protein, LBP), we conducted an “adjunct biomarker study” to a larger 11-center, randomized, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial, the Vitamin D/Calcium Polyp Prevention Study. Participants were randomized into four different treatment groups: placebo, 1,200 mg/day calcium, 1,000 IU/day vitamin D3, and 1,200 mg/day calcium plus 1,000 IU/day vitamin D3. Circulating concentrations of LBP and IFABP were measured at baseline and 1-year follow-up using the Meso Scale Discovery electrochemiluminescence assays in a subset of 118 participants included in the adjunct biomarker study. Result: Following one year of vitamin D3 treatment, in the vitamin D3 plus calcium and vitamin D3 groups versus placebo and calcium groups, LBP decreased 10% (316 ng/ml; P=0.23) and IFABP 18% (77 ng/ml; P=0.06). A similar decrease of 20% (P=0.10) was observed for IFABP, but not LBP, in the vitamin D3 plus calcium versus the calcium group. There were no appreciable biomarker changes with calcium treatment. In stratified analyses, we found possible effect modifications by baseline serum 25-OH-vitamin D, total calcium intake, body mass index, and interleukin 6 (IL-6) concentration on estimated vitamin D3 treatment effects on LBP and/or IFABP. Conclusion: These preliminary results are consistent with vitamin D’s potential protective effects on intestinal mucosal barrier and support further research of vitamin D against gut barrier disruption and colorectal neoplasms. Citation Format: Sangji Lee, Veronika Fedirko, Roberd M. Bostick, Bradley Pearce, Elizabeth L. Barry, Robin E. Rutherford, March E. Seabrook. Effects of supplemental calcium and vitamin D on circulating biomarkers of gut barrier function in colorectal adenoma patients: A randomized controlled trial [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 766.
Abstract 2581: Measuring interstitial fluid flow to predict and optimize spatial CAR-T dynamics in the clinic
Authors: Ryan T. Woodall, Cora Esparza, Christine C. Brown, Jennifer M. Munson, Russell C. Rockne
Journal: Cancer Research (2024)

Abstract Interstitial fluid flow dynamics in brain tumors are known to be an important indicator for tumor invasion into healthy tissue, as cancerous cells follow the interstitial flow towards tumor-stimulating chemokines. These flow gradients not only carry tumor-stimulating chemokines, but also carry cytokines secreted by immune response. CAR-T cells are known to also depend highly on the cytokines present in the CSF and serum. For these reasons, we have developed a novel method, Localized Convolutional Function Regression (LCFR) for measuring interstitial fluid flow, perfusion, and diffusion using dynamic contrast-enhanced MRI. LCFR works by applying the known physics of contrast agent transport, and fitting the observed contrast agent dynamics to the known physics. From LCFR, we can recover standard Tofts-Kety perfusion dynamics, including Ktrans and Vp, and also recover the underlying flow field and diffusivity. These new measurements allow for the prediction of where tumors invade, and allow for us to model how CAR-T cells move within a tumor. In a case study, we model the spatial distribution of CAR-T cells and glioblastoma cells over time, assuming that the fluid velocity field drives CAR-T spread throughout the tumor. Using multiple delivery locations, we identify the optimal catheter placement to optimally distribute CAR-T cells through the tumor, improving the 50% kill rate of simulated tumor cells by over 25% from a naive delivery strategy. Further, we collect longitudinal cytokine levels from patients undergoing CAR-T therapy, allowing us to understand how interstitial flow, CAR-T dynamics, and tumor dynamics interact with each other. We report a case study wherein a patient is longitudinally followed through their treatment with CAR-Ts. Perfusion imaging reveals that the patient experienced a steady increase in perfusion and decrease in fluid leakage into surrounding tissue. VEGF and IL12 levels are observed to increase as tumor volume increases. To better understand this patient's dynamics, we use the fluid velocity field measured by LCFR to simulate the development of CAR-T cells within the tumor, using the cytokine profile as a surrogate measurement of CAR-T population. These results demonstrate the importance of fluid flow and cytokines in understanding how brain tumors develop and respond to treatment. Citation Format: Ryan T. Woodall, Cora Esparza, Christine C. Brown, Jennifer M. Munson, Russell C. Rockne. Measuring interstitial fluid flow to predict and optimize spatial CAR-T dynamics in the clinic [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 2581.
Abstract 1839: Proteomic and glycoproteomic differences associated with prostate cancer in urine
Authors: Nikhiya Shamsher, Fernando Garcia-Marques, Abel Bermudez, Mark R. Flory, Sharon J. Pitteri
Journal: Cancer Research (2024)

Abstract Background and Aims: Prostate cancer is one of the most common cancers affecting men in the United States, with ~288,300 new cases and 34,700 deaths in 2023 alone. Prostate-specific antigen (PSA), the most widely used prostate cancer biomarker, lacks specificity and sensitivity, leading to unnecessary biopsies, overdiagnosis, and overtreatment. There is an urgent unmet clinical need to find new biomarkers that can distinguish patients with benign disease from those with prostate cancer. Urine is an attractive source for these biomarkers as prostate-derived proteins are more highly concentrated in urine than in blood. To better understand both global proteomic and glycoproteomic molecular signatures that could lead to improved diagnostics for prostate cancer, we analyzed urine samples from unaffected men, men with benign prostatic hyperplasia (BPH), and men with prostate cancer. Methods: Urine samples (N = 58 total) were collected from unaffected men (N = 17), men with BPH (N = 24), and men with prostate cancer (N = 17). Samples were digested with trypsin and analyzed with high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS) for shotgun proteomics analysis. Association with cancer was determined through supervised analysis using Pearson correlation. For glycoproteomics analysis, intact glycopeptides were enriched using strong anion exchange-electrostatic repulsion hydrophilic interaction chromatography, fractionated using high pH reversed-phase chromatography, and analyzed with LC-MS/MS. Association with the three conditions was determined through several rounds of supervised analysis using Pearson correlation. Results: In total, 3542 human proteins were identified, and 78 proteins (p &amp;lt; 0.01) were significantly associated with prostate cancer. The glycolysis pathway and lysosome pathway were enriched in samples from men with prostate cancer. In the glycoproteomics analysis, 36 proteins (p &amp;lt; 0.05) had altered glycan diversity in one of the three conditions, and the complement and coagulation cascade pathway and the lysosome pathway were highly enriched. Six proteins (p &amp;lt; 0.05) had significantly increased glycan diversity in the cancerous samples than in the BPH and normal samples. Conclusions: This study identifies a set of interesting proteomic and glycoproteomic differences in urine from men with prostate cancer compared to BPH and non-cancer samples, which warrant further investigation in additional sample cohorts as potential novel biomarkers. Citation Format: Nikhiya Shamsher, Fernando Garcia-Marques, Abel Bermudez, Mark R. Flory, Sharon J. Pitteri. Proteomic and glycoproteomic differences associated with prostate cancer in urine [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 1839.
Abstract 2436: In-depth analysis of microRNA signature in breast cancer derived extracellular vesicles: A potential biomarker repository for breast cancer diagnosis
Authors: Jee Ye Kim, Min Woo Kim, Young Kim, Sol Moon, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim
Journal: Cancer Research (2024)

Abstract Breast cancer remains one of the leading causes of cancer-related mortality among women worldwide. With the rising incidence of breast cancer, early and accurate diagnosis is pivotal in improving survival rates and patient outcomes. Our study addresses to identify vesicles associated with breast cancer in scope of miRNA signature. We focused on isolating breast cancer-derived extracellular vesicles (BEVs) from the bloodstream with immune affinity capture techniques. Then, we analyzed the miRNA profiles of BEVs in plasma samples from 120 breast cancer patients, 46 individuals with benign tumors, and 45 healthy controls. In this study, we analyzed to discover miRNA candidates for diagnosis of breast cancer with The Gene Expression Omnibus (GEO) database and found 379 down-regulated and 584 up-regulated differentially expressed miRNAs (DEMs) in tissue samples across 5 GEO datasets, and 28 down-regulated and 80 up-regulated DEMS in blood samples. Subsequently, we measured the expression levels of these 10 candidate miRNAs in BEVs from breast cancer cells and compared them with EVs from human mammary cells (MCF10a), using our BEV isolation method. The expression profiles of these miRNAs in BEVs were significantly elevated, supporting their potential as surrogate markers for breast cancer diagnosis. When comparing the AUC values of 10 candidate miRNAs through ROC analysis, 5 EV miRNAs (miR-21, miR-106b, miR-181a, miR-484, and miR-1260b) showed a high AUC values above 0.8. Subsequently, we verified a distinct signature of 5 EV miRNAs that effectively differentiate breast cancer patients from normal controls with 57.14% of sensitivity and 95% of specificity. Overall, our study not only complements existing diagnostic methods with high accuracy but also provides a deeper understanding of the molecular aspects of breast cancer, heralding a significant advancement in precision medicine and personalized cancer care. Citation Format: Jee Ye Kim, Min Woo Kim, Young Kim, Sol Moon, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim. In-depth analysis of microRNA signature in breast cancer derived extracellular vesicles: A potential biomarker repository for breast cancer diagnosis [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 2436.