bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6463: Highly frequent gene mutations and co-occurring genes analysis in colorectal cancer
Authors: Zha Qinqin , Scarpa Frank , Rengaraj Madhu , Juncker-Jensen Anna 
Published: March 2024

Abstract
Background: Colorectal cancer (CRC) is the second most leading cause of cancer-related deaths worldwide. Understanding the molecular alterations that drive CRC is critical for improving patient outcomes. Next-generation sequencing (NGS) has revolutionized CRC molecular profiling by simultaneous analysis of multiple genes with high accuracy and sensitivity. In this study, we analyzed a cohort of CRC formalin-fixed paraffin-embedded (FFPE) samples to identify highly frequent gene mutations and co-occurring genes in CRC.
Methods: FFPE samples from CRC patients tested from January 2020 to May 2023 were analyzed using NeoTYPE® Colorectal Tumor Profile. This profile analyzes 44 biomarkers through a combination of NGS focusing on a panel of 36 genes known to be frequently mutated in CRC, as well as 3 FISH and 3 IHC biomarkers. Gene mutation frequency, co-occurring mutation genes and clinical significance were explored and analyzed. In addition, immunotherapy markers, Microsatellite Instability (MSI) and Tumor Mutation Burden (TMB) were assessed.
Results: A total of 2,920 patients (1,577 men and 1,343 women) with CRC were included in this study. Average sequence coverage was 2386X with mean minor allelic frequency of 30%. A higher average number of variant allele frequency were observed in metastatic versus primary colorectal cancer (P &lt; .001). We found that APC, TP53, KRAS, PIK3CA and ARID1A were the most frequently mutated genes. APC truncated mutation p. R1450* were the most common mutations. KRAS, PIK3CA and TP53 missense mutations are the prevalent consequence. Notably, a subset of patients exhibited high microsatellite instability (MSI-H) or TMB high, indicating potential eligibility for immune checkpoint inhibitor therapy. In addition, we found APC mutations co-occurring with TP53 or KRAS mutations (p &lt;.001) in our cohort.
Conclusion: Our results provide insight into the genetic landscape of CRC and highlight the importance of understanding co-occurring mutations in this disease. Specifically, APC mutations frequently coincide with TP53 mutations, jointly contributing to the onset of CRC. TP53 often play a role in promoting genomic instability and evading mechanisms that regulate cell growth. The identification of highly frequent mutations and co-occurring genes may have important implications for the development of targeted therapies and personalized treatment approaches for CRC patients.
Citation Format: Qinqin Zha, Frank Scarpa, Madhu Rengaraj, Anna Juncker-Jensen. Highly frequent gene mutations and co-occurring genes analysis in 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 6463.
Abstract 6493: CRISPR-directed prime editing sensitizes EGFR inhibitor by correcting oncogenic KRAS mutants In NSCLC
Authors: Fang Qingxiao , Yang Chao , Huang Chongbiao , Wang Hongwei , Yu Jun , Hao Jihui 
Published: March 2024

Abstract
EGFR inhibitor has been demonstrated with huge therapeutic potential in advanced non-small cell lung cancer (NSCLC), while the patients carrying KRAS mutation had poor response to EGFR inhibitor. KRAS mutation is the most frequent molecular alteration found in advanced NSCLC, which is associated with a poor prognosis without available targeted therapy. Previous research showed that CRISPR-directed prime editor could induce unconstrained correction for KRAS mutants (KRASG12D, KRASG12C, KRASG12V). Accordingly, it would be a promising strategy to combine PE-based genetic therapy with EGFR inhibitor for enhanced therapy in NSCLC. Here,we selected several PE variants with reported highly efficient reverse transcriptase, among which eEc48-based PE6a showed the highest editing efficiency toward KRAS mutation. The lentivirus-mediated PE6a editing inhibited cell proliferation and invasion in vitro and in vivo. After that, EGFR inhibitor combined with PE6a was employed in patient-derived organoid (PDO) model carrying diverse KRAS mutants. We found that PE6a editing significantly inhibited PDO proliferation compared to EGFR inhibitor alone and control. Correspondingly, the transcriptome sequencing also showed that the cell apoptosis, cell growth and cell motility signaling were inhibited upon PE6a editing. Our findings demonstrated that the PE-directed genetic therapy could sensitize EGFR inhibitor in NSCLC, providing an alternative choice for NSCLC patients carrying KRAS mutant.
Citation Format: Qingxiao Fang, Chao Yang, Chongbiao Huang, Hongwei Wang, Jun Yu, Jihui Hao. CRISPR-directed prime editing sensitizes EGFR inhibitor by correcting oncogenic KRAS mutants In NSCLC [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 6493.
Abstract 6583: Developing a selective cancer chemotherapy by small molecule-based targeting of PCNA protein
Authors: Jossart Jennifer , Gu Long , Haratipour Pouya , Li Caroline , Lingeman Robert , Hickey Robert , Malkas Linda , Perry John J. 
Published: March 2024

Abstract
Proliferating cell nuclear antigen (PCNA) is a proliferation biomarker in a variety of human tumors and has critical cellular functions in DNA replication and repair. We previously identified a unique cancer-associated isoform of the protein, termed caPCNA, which allows for structure-based drug discovery studies to develop inhibitors for selective therapeutic targeting of cancer cells. Distinct strategies have been used to develop caPCNA targeting agents, which includes peptide and small molecule-based compounds, although the success in developing therapeutically tractable compounds has been limited so far. Here, we present the crystal structures and corresponding biochemical characterizations of our novel small molecule-based caPCNA inhibitors, which bind into the PIP-box binding pocket of PCNA. Our lead compound selectively kills cancer cells, and it appears to induce replication stress, apoptosis and increase cancer cell sensitivity to genotoxic agents, while these effects are not observed in non-malignant cell controls. This caPCNA inhibitor is orally administrable, metabolic stable and it suppresses tumor growth as a monotherapy or as a combination treatment and is now an investigational new drug in Phase 1 clinical trials. PCNA plays a critical role enabling the replication fork to proceed from transcription replication conflict sites, by temporarily dislodging RNA polymerase II. Thus, structure-based drug discovery against caPCNA may open a novel therapeutic avenue for the development of selective chemotherapeutics, through targeting a cancer cell’s vulnerability to unresolved transcription replication conflicts.
Citation Format: Jennifer Jossart, Long Gu, Pouya Haratipour, Caroline Li, Robert Lingeman, Robert Hickey, Linda Malkas, John J. Perry. Developing a selective cancer chemotherapy by small molecule-based targeting of PCNA protein [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 6583.
Abstract 6612: Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress
Authors: Li Melvin , Amend Sarah R. , Pienta Kenneth J. 
Published: March 2024

Abstract
Therapy resistance is responsible for 90% of cancer-related deaths. We identified a novel mechanism of therapy resistance in which cancer cells enter an endocycling cell state, undergoing repeated S and G phases without dividing. As a result, resistant endocycling cells are 40 times larger than mitotic cancer cell controls. Interestingly, we observed that these non-proliferative endocycling cells can eventually give rise to proliferative progeny weeks after chemotherapy is removed, modeling cancer recurrence. We hypothesize that this endocycling cancer cell state is a critical driver of therapy resistance and cancer lethality.
We evaluated oxidative stress in endocycling cells that survived the days and weeks following chemotherapy treatment using DCF-DA staining. We found increased levels of reactive oxygen species (ROS) in endocycling prostate cancer cells compared to untreated mitotic cells when normalized to cell size. Given that mitochondria are major producers and regulators of ROS, we hypothesize that cells surviving in this resistant state alter mitochondrial structure and function in response to increased oxidative stress. We performed immunofluorescence and confocal microscopy on mitochondria in untreated cells and cells following chemotherapy treatment to observe their morphology. Surviving endocycling cells had increased mitochondrial fragmentation when compared to the untreated group, a result that was further supported by reduced expression of phospho-DRP1 Ser637 via western blot.
To assess changes in glucose metabolism, we then utilized isotope tracing-based metabolomics with [U-13C]glucose on untreated and surviving endocycling cells following chemotherapy. Endocycling cells had decreased labeling of 13C in TCA cycle metabolites, suggesting a decrease in mitochondrial function when compared to untreated cells. Ongoing work involves further studying metabolic reprogramming as cells enter this resistant state with parallel labeling experiments using [1,2-13C]glucose and [U-13C]glutamine to perform mathematical modeling-based 13C-metabolic flux analysis. In addition, we engineered a cell line to track mitochondria in real-time to quantify mitochondrial dynamics underlying the morphology observed in untreated and surviving cells.
Our goal is to characterize how this therapy-resistant cell state alters its mitochondrial structure and function to survive therapeutic stress. Identifying vulnerabilities of this phenotype will enable new approaches for eliminating drug resistance in cancer.
Citation Format: Melvin Li, Sarah R. Amend, Kenneth J. Pienta. Therapy-resistant endocycling cancer cells alter mitochondrial structure and metabolism to survive therapeutic stress [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 6612.
Abstract 668: Enhancing chemosensitivity of lung adenocarcinoma via Y-box binding protein 1 (YB-1) inhibition
Authors: Lee Jee Min , Tailor Dhanir , Garcia-Marques Fernando J. , Bermudez Abel , Pitteri Sharon , Malhotra Sanjay V. 
Published: March 2024

Abstract
Background: Y-box binding protein 1 (YB-1, YBX1) is a multifunctional nucleic acid binding protein that regulates the expression of various genes by binding to their mRNA and stabilizing them. In over 20 cancer types, including lung adenocarcinoma (LUAD), YBX1 expression is significantly elevated in tumor samples compared to normal tissue. Within cancer cells, YB-1 promotes the expression of genes involved in tumorigenesis and chemoresistance. Consequently, elevated YBX1 expression in tumor is associated with poor clinical outcomes and significantly reduced overall survival in LUAD patients. Therefore, YB-1 emerges as a promising therapeutic target for LUAD treatment. Utilizing a small molecule YB-1 inhibitor, CET056, we performed a series of in vitro and in vivo analyses to assess the therapeutic efficacy of YB-1 inhibition and unravel YB-1’s role in tumorigenesis and disease progression in LUAD.
Methods: Four human and one mouse LUAD cell lines were treated with CET056 and/or chemotherapeutic drugs and analyzed for the in vitro therapeutic activity of CET056. Using xenograft and syngeneic LUAD mouse models, the preclinical therapeutic efficacy of CET056 on disease progression of LUAD was also tested.
Results: CET056 was shown to effectively decrease YB-1 expression in both human and mouse LUAD cell lines and exert inhibitory effects on LUAD in vitro and in vivo. This treatment delayed tumor progression and metastasis in CMT-64 syngeneic mouse model. Proteomics analysis revealed that translational machinery-associated pathways were down-regulated in LUAD cells after CET056 treatment whereas apoptosis and cell death-associated pathways were up-regulated. In alignment with this finding, CET056 treatment in combination with cisplatin showed chemo-sensitizing effect on LUAD in vitro and in vivo.
Conclusion: Our studies suggest that YB-1 could be a promising target for combating chemoresistance in LUAD. Inhibition of YB-1 with a small molecule drug as a monotherapy or combination therapy could an effective strategy to treat LUAD.
Citation Format: Jee Min Lee, Dhanir Tailor, Fernando J. Garcia-Marques, Abel Bermudez, Sharon Pitteri, Sanjay V. Malhotra. Enhancing chemosensitivity of lung adenocarcinoma via Y-box binding protein 1 (YB-1) inhibition [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 668.
Abstract 6686: The mechanism of gut microbiome-mediated immune activation on the clinical efficacy of PD-1 blocking treatment in solid tumors
Authors: Lin Nina Yi-Tzu , Fukuoka Shota , Motooka Daisuke , Shigeno Yuko , Irie Takuma , Tourlousse Dieter M. , Murotomi Kazutoshi , Sekiguchi Yuji , Tamaki Hideyuki , Shindo Mariko , Tsuji Takahiro , Wake Hiroaki , Goto Koichi , Doi Toshihiko , Shitara Kohei , Watanabe Keisuke , Maeda Yuka , Nakamura Shota , Benno Yoshimi , Nishikawa Hiroyoshi , Koyama Shohei 
Published: March 2024

Abstract
Gut microbiota is associated with antitumor efficacy of immune checkpoint blockade therapies, yet the mechanism is not largely understood. Here, we show that a novel bacterial strain of Ruminococcaceae isolated from the feces of patients who respond to PD-1 (programmed cell death 1) blockade efficiently primes/activates tumor-specific CD8+ T cells through effective stimulation/maturation of CD103+ dendritic cells (DCs) during migration from the gut to the tumor microenvironment (TME). The administration of this bacteria strain with PD-1 blockade significantly inhibited tumor growth, even when adding them to fecal transplantation of non-responder patients in animal models. Mechanistically, the bacterial strain promoted the IRF8-driven differentiation of CD103+ DCs by stimulating multiple Toll-like receptors and the accumulation of these DCs in tumors and tumor-draining lymph nodes. These CD103+ DCs prolonged engagement with cognate antigen-specific CD8+ T cells, which induced the activation of CD8+ T cells specific for a wide variety of tumor antigens and fostered their PD-1 expression through enhanced T-cell activation signals with NFATc1 nuclear translocation, thereby leading to abundant PD-1+CD8+ T cells, a key effector cell population in PD-1 blockade, with a broader T-cell receptor repertoire in the TME. Our findings with novel single bacterium isolated from feces of responder patients demonstrate the mode of action by gut microbiota to augment antitumor immunity.
Citation Format: Nina Yi-Tzu Lin, Shota Fukuoka, Daisuke Motooka, Yuko Shigeno, Takuma Irie, Dieter M. Tourlousse, Kazutoshi Murotomi, Yuji Sekiguchi, Hideyuki Tamaki, Mariko Shindo, Takahiro Tsuji, Hiroaki Wake, Koichi Goto, Toshihiko Doi, Kohei Shitara, Keisuke Watanabe, Yuka Maeda, Shota Nakamura, Yoshimi Benno, Hiroyoshi Nishikawa, Shohei Koyama. The mechanism of gut microbiome-mediated immune activation on the clinical efficacy of PD-1 blocking treatment in 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 6686.
Abstract 6692: Intermittent fasting-remodeled gut microbiota improves anti-tumor immunity in pancreatic cancer
Authors: Li Le , Chandra Vidhi , Le Roux Olivereen , Howell Rian Morgan , Tahan Virginia , Putluri Nagireddy , Petrosino Joseph , Sreekumar Arun , Kolls Jay K. , White James , McAllister Florencia 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has become the third leading cause of cancer-related death in the United States with high resistance to therapies, presentation at late stages and aggressive biology. Immunotherapy has revolutionized cancer therapy by offering survival benefit in many solid malignancies, however, it is still not effective in pancreatic cancer. Host factors are crucial modulators of responses to immunotherapy. The roles of gut microbiome in modulating the immune system and determining cancer outcomes have been well established. Eating patterns can alter the gut microbiota and metabolic output, both of which affect anti-tumor immune responses. Intermittent fasting (IF), a form of dietary restriction which is characterized by limited feeding with unlimited calorie consumption during a certain time window. IF has been shown to affect gut microbiota composition, modulate immunity, and metabolic processes. Despite the well-known beneficial role of fasting in pancreatic conditions, including pancreatitis and diabetes, its effect in the treatment of pancreatic cancer has not been explored. Our study found that IF reverses immunotherapy resistance in PDAC. IF can reshape gut microbiota composition and reprogram the metabolism of host. We found that IF improves anti-tumor immunity through modulating gut microbiota. Depletion of gut microbiota can abrogate the beneficial effect of IF on anti-tumor response, while fecal microbiota transplantation from mice exposed to IF can sensitize the anti-tumor effects of immunotherapy. Using 16S rRNA sequencing, metabolic profiling and transcriptomic sequencing, our findings elucidate the mechanism of IF-remodeled gut bacteria influencing metabolic molecules which drive immune cells activation. Our study suggests that IF-based interventions have potential utility for the prevention and treatment of PDAC.
Citation Format: Le Li, Vidhi Chandra, Olivereen Le Roux, Rian Morgan Howell, Virginia Tahan, Nagireddy Putluri, Joseph Petrosino, Arun Sreekumar, Jay K. Kolls, James White, Florencia McAllister. Intermittent fasting-remodeled gut microbiota improves anti-tumor immunity in pancreatic 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 6692.
Abstract 6707: IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological tumors
Authors: Greiner Sarah Maria , Mauermann Jonas , Lutz Martina , Hagelstein Ilona , Tobias Engler , Koch André , Andreas Hartkopf , Sara Brucker , Zekri Latifa , Märklin Melanie 
Published: March 2024

Abstract
Ovarian cancer is characterized by late stage disease and a poor prognosis. Endometrial cancer is a heterogeneous disease with different prognoses depending on the molecular subtype. Novel treatment strategies are needed to improve patient survival in both entities.
T cell-based immunotherapy has significantly improved the treatment options for many malignancies. B7-H3 (CD276) is an interesting target for immunotherapeutic approaches because it is overexpressed on a wide range of tumor entities and has characteristics of immune checkpoint molecules. Its expression not only on tumor cells but also on the tumor vasculature allows improved infiltration of immune effector cells into the tumor to overcome the major limitation of T cell-based therapy of solid tumors, which is the access of immune cells to the tumor site. A novel bispecific antibody in an IgG-based format called CC-3 with B7-H3xCD3 specificity has already been shown to efficiently induce T cell responses against gastrointestinal malignancies.
Here we show that B7-H3 is highly expressed on endometrial and ovarian cancer cell lines. Treatment with CC-3 induced T cell activation and degranulation as well as secretion of IL-2, IFNy and perforin. These results demonstrate CC-3 induced T cell reactivity against ovarian and endometrial cancer cells. In addition, CC-3 induced efficient T cell proliferation and formation of T cell memory subsets. This resulted in potent target cell lysis.
Taken together, our results underscore the potential of CC-3, which is currently in GMP manufacturing, to enable clinical evaluation for the treatment of gynecologic malignancies.
Citation Format: Sarah Maria Greiner, Jonas Mauermann, Martina Lutz, Ilona Hagelstein, Engler Tobias, André Koch, Hartkopf Andreas, Brucker Sara, Latifa Zekri, Melanie Märklin. IgG based B7-H3xCD3 bispecific antibody for treatment of gynecological 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 6707.
Abstract 6721: AI-guided generation of novel GUCY2C-targeting T-cell engagers for the treatment of colorectal cancer
Authors: Tian Liang , Hou Jinxiu , Su Chenpeng , Xu Xiaoou , Chen Xiaoqian , Liu Dandan , Tian Jiyuan , Shen Rui , Pan Yi , Yuan Yuan , Dong Lisha , Gu Tingting , Peng Jian 
Published: March 2024

Abstract
Colorectal cancer (CRC) ranks as one of the most lethal cancers worldwide. Given the advances in immunotherapy and targeted therapy, the survival time in CRC has been improving recently. However, the development of novel and effective therapies for CRC still remains an unmet medical need. Guanylyl cyclase C (GUCY2C) is a transmembrane receptor expressed on the surface of intestinal epithelial cells. Recent studies have demonstrated that GUCY2C is causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. To this end, GUCY2C has emerged as a promising target for immunotherapy and a diagnostic marker of primary and metastatic cancer. Here we describe the discovery and optimization of a novel panel of GUCY2C-targeting T cell engagers (TCEs) developed via our streamlined AI-guided TCE development platform. We have identified a number of anti-GUCY2C antibodies with various binding epitopes on GUCY2C, and subsequently generated a panel of novel GUCY2C-targeting multispecific antibodies with favorable developability and functionalities via our AI-driven engineering technology. Our data demonstrate that a biparatopic GUCY2C x CD3 TCE engineered as an asymmetric ‘1+2’ format can recognize two distinct epitopes on GUCY2C. This biparatopic GUCY2C x CD3 TCE shows enhanced tumor cell binding affinity and superior T cell-mediated cytotoxicity compared to the ‘1+1’ GUCY2C x CD3 TCE and ‘1+2’ bivalent GUCY2C x CD3 TCE where the two GUCY2C targeting arms can only bind to an identical epitope on GUCY2C. In addition, we have engineered a novel GUCY2C × CD3 x CD28 trispecific TCE, in which the CD3-targeting arm in tandem with the co-stimulating CD28-targeting arm mediate the interaction with T cells. This anti-GUCY2C trispecific TCE induces favorable synergistic T cell activation and tumor cell killing in vitro compared to the bispecific counterparts. In vivo anti-tumor activity assessments of these multispecific TCE molecules in various tumor xenograft mouse models are currently ongoing.
Citation Format: Liang Tian, Jinxiu Hou, Chenpeng Su, Xiaoou Xu, Xiaoqian Chen, Dandan Liu, Jiyuan Tian, Rui Shen, Yi Pan, Yuan Yuan, Lisha Dong, Tingting Gu, Jian Peng. AI-guided generation of novel GUCY2C-targeting T-cell engagers for the treatment of 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 6721.