tbuckley/cabot-search huggingface dataset:
Abstract 5196: Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells
Authors: Jae-Jun Kim, Gi-Eun Yang, Tae Hwan Shin, Sun-Hee Leem
Journal: Cancer Research (2024)

Abstract Bladder cancer (BC) is one of the most prevalent genitourinary tumors worldwide, with approximately 573,000 new cases reported. Approximately 80% of BC patients are diagnosed with non-muscle-invasive bladder cancer (NMIBC) with a high five-year survival rate, while the remaining 20% are diagnosed with muscle-invasive bladder cancer (MIBC). Although the surgical operation has been utilized to BC, patients with NMIBC frequently experience disease recurrence, of which about 20% progress to MIBC. However, the response rate of MIBC patients to gemcitabine treatment has been shown to be limited to less than 40% efficacy, and only a small number of patients have potential benefits.Chemotherapy resistance is an obstacle to cancer therapy and is considered a major cause of recurrence. Thus, understanding the mechanisms of chemoresistance is critical to improving the prognosis of patients. Here, we have established a stepwise gemcitabine-resistant T24 bladder cancer cell line to understand the molecular mechanisms of chemoresistance within cancer cells. The characteristics of the stepwise chemoresistance cell line were divided into 4 phases (parental, early, intermediate, and late phases). These four phase cells showed increasingly aggressive phenotypes in vitro and in vivo experiments with increasing phases and revealed the molecular properties of the biological process from parent cells to phased gemcitabine-resistant cell line (GRC). Taken together, through the analysis of gene expression profile data, we have characterized gene set of each phase indicating the response to anticancer drug treatment. Specifically, we identified a multigene signature (23-genes including GATA3, APOBEC3G, NT5E, MYC, STC1, FOXD1, SMAD9) and developed a chemoresistance score consisting of that could predict eventual responsiveness to gemcitabine treatment. We suggest that our findings improve prognosis by predicting to acquiring of chemotherapy resistance in bladder cancer patients. Citation Format: Jae-Jun Kim, Gi-Eun Yang, Tae Hwan Shin, Sun-Hee Leem. Stepwise molecular mechanisms involved in chemoresistance in bladder cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5196.
Abstract 2718: A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety
Authors: Ye Chen, Fei You, Chenchen Zhu, Yao Xiong, Li Li, Nana Luo, Shuaixiang Zhou, Fushuai Wang, Chenyang Xu, Fan Fei, Chang Li, Jianglu Wang, Jinling Xu, Huizhong Xiong
Journal: Cancer Research (2024)

Abstract Immune stimulating antibody conjugates (ISACs) are a unique class of ADC in which antibodies recognizing tumor antigens are conjugated with immune agonists. ISACs target tumor tissue and specifically activate intra-tumoral myeloid cells, unleashing downstream immune response. Like the other immune agonists, balance between efficacy and safety remains a challenge for ISACs. Here we describe a potential first-in-class TROP2 ISAC with rationally selected antibody and TLR7/8 agonist linker-payload. The anti-TROP2 antibody elicited robust ADCP of TROP2+ tumor cells by macrophages. In-vitro, TROP2 ISAC mildly activated myeloid cells only in the presence of TROP2+ tumor cells. In-vivo, the molecule potently suppressed tumor growth in different TROP2+ xenograft tumors, and effectively enhanced killing of an ADC. In terms of safety, the ISAC was tolerated in both WT and hTROP2KI mice, and, importantly, in monkeys. Taken together, our data demonstrate a novel TROP2 ISAC with outstanding efficacy and manageable safety profile, which may benefit patients with TROP2+ tumors. Citation Format: Ye Chen, Fei You, Chenchen Zhu, Yao Xiong, Li Li, Nana Luo, Shuaixiang Zhou, Fushuai Wang, Chenyang Xu, Fan Fei, Chang Li, Jianglu Wang, Jinling Xu, Huizhong Xiong. A novel TROP2-targeted immune stimulating antibody conjugate (ISAC) with potent anti-tumoral activtiy and accpetable safety [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 2718.
Abstract 7219: Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin for treatment of cervical cancer
Authors: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Rotem Engelman, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg M. Palmer, Angeles Alvarez Secord
Journal: Cancer Research (2024)

Abstract Introduction: Cervical cancer, although largely preventable, continues to be a significant health concern. Early-stage treatment is commonly surgery; while advanced, recurrent, or metastatic disease often requires systemic therapy. Chemotherapy, mainly cisplatin is the backbone of first-line therapy. TTFields are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression. In other tumor types, TTFields applied with cisplatin has exhibited benefit. This in vitro study assessed the preclinical efficacy of TTFields for cervical cancer and explored efficacy for concurrent use with cisplatin. Methods: Effects on cell count in cervical cancer cell lines exposed to TTFields (0.5 V/cm for Ca Ski cells, 1 V/cm RMS for HeLa and SiHa cells; 72 h) across a range of frequencies (100-400 kHz) were evaluated. TTFields (200 kHz) were then applied with varying cisplatin doses followed by cell count, colony formation, and apoptosis assays. Overall effect was calculated as the product of percent reductions in cell count and colony formation. TTFields-treated cells were evaluated for formation of the DNA damage marker γH2AX using fluorescent microscopy; and for the expression of Fanconi Anemia (FA)-BRCA pathway proteins through Western blotting. Results: TTFields treatment reduced cell count in all cervical cancer cell lines tested. Cisplatin exhibited dose-response effects, which were enhanced when TTFields were co-applied. TTFields led to downregulated expression of FA-BRCA pathway proteins, which are involved in repairing cisplatin-induced DNA damage, resulting in increased DNA damage. Conclusions: These preclinical results suggest that TTFields should be further explored as a potential treatment for cervical cancer. TTFields-induced downregulation of the FA-BRCA pathway possibly explains the enhanced efficacy when TTFields are applied together with cisplatin, providing mechanistic insight. Citation Format: Roni Frechtel-Gerzi, Daria Gerasimova, Einav Zeevi, Roni Monin, Hila Fishman, Inbar Schlachet-Drukerman, Helena Mumblat, Antonia Martinez-Conde, Rotem Engelman, Eyal Dor-On, Itai Tzchori, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti, Greg M. Palmer, Angeles Alvarez Secord. Preclinical investigations of concomitant tumor treating fields (TTFields) with cisplatin for treatment of cervical 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 7219.
Abstract 2361: A PD1-antibody-attenuated IL-2 fusion protein activates immune cells leading to the inhibition of tumor growth in ex vivo human 3D tumor models
Authors: Ronit Satchi-Fainaro, Opal Avramoff, Anshika Katyal, Eilam Yeini, Anne Krinsky, Yulia Liubomirski, Shai Dulberg, Galia Tiram, Ayelet Kaminitz, Jason Gill, Jessica Pedersen, Dana Bar-On, Ayala Tamir, Paul Ayton, Tetsuya Taura, David Wilson, Asaf Madi
Journal: Cancer Research (2024)

Abstract IL-2 has been prescribed to effectively treat malignancies, mainly melanoma, for decades. Its use has waned in recent years due to significant toxicity and a narrow therapeutic index. To overcome the limitations of systemic administration of IL-2, we have generated a modified IL-2 (IL2Att) with specific substitutions to reduce the binding affinity with the IL-2R. The attenuated cytokine was fused to a high-affinity anti-PD1 antibody that does not block PD-1 binding with its ligands (PD-L1 and PD-L2). The resulting antibody-cytokine fusion, anti-PD1-IL2Att, allows selective delivery of IL-2 to tumor-reactive PD1+ T cells, with limited potential to activate PD1− cells. To evaluate the effect of anti-PD1-IL2Att in a human tumor microenvironment (TME), we established a unique human 3D multi-cellular cancer system. This model system includes neoplastic and somatic cells that make up the TME, further supplemented with peripheral blood mononuclear cells (PBMC). We found that the anti-PD1-IL2Att reduced tumor cell survival more effectively in several types of these 3D cancer models (melanoma, glioblastoma, ovarian and colon cancer) than standard immune checkpoint inhibitors pembrolizumab or nivolumab. Combination treatments of anti-PD1-IL2Att with either of these agents resulted in improved immune activation and tumor cell killing. Our findings suggest that tumor-targeted attenuated cytokines such as IL-2 can promote robust tumor killing while minimizing systemic toxicity. Citation Format: Ronit Satchi-Fainaro, Opal Avramoff, Anshika Katyal, Eilam Yeini, Anne Krinsky, Yulia Liubomirski, Shai Dulberg, Galia Tiram, Ayelet Kaminitz, Jason Gill, Jessica Pedersen, Dana Bar-On, Ayala Tamir, Paul Ayton, Tetsuya Taura, David Wilson, Asaf Madi. A PD1-antibody-attenuated IL-2 fusion protein activates immune cells leading to the inhibition of tumor growth in ex vivo human 3D 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 2361.
Abstract 7234: The second-generation high-fidelity base editor AccuBaseTM (ceBE) can proficiently modify multiple genes within a human primary T cell while minimizing Off-target effects
Authors: Han Ying, Guanglei Li, Liling Wang, Chunju Lu, Qi Lai, Chao Yao, Fenghua Lv, Shiguo Zhu, Tianhong Xu
Journal: Cancer Research (2024)

Abstract Off target mutations, chromosomal rearrangements and Indels are the biggest limitation to the use of gene editing tools today. Base editing system provides an efficient method to modify the genome without double strand breaks (DSB). The biggest problem for base editing is the sgRNA-independent off-target. We utilize synthetic biology strategies to create a novel base editor AccuBaseTM (ceBE) that has the highest editing efficiency in the industry, with zero off target events. This was achieved by strategically inserting deaminases into Cas9 at specific, tolerance-verified sites, a process guided by an extensive transposon-based genetic screening, protein engineering, and direct evolution approach. AccuBaseTM protein forms a complex with the sgRNA, but it has not yet engaged with the target DNA and is not in contact with any non-targeting dsDNA. This mechanism avoids guide RNA independent indiscriminate off-target mutations that was a common problem of the first generation base editing tool. Upon guided by sgRNA, the AccuBaseTM protein associates with the target double-stranded DNA, triggering structural alterations within the AccuBaseTM protein. This results in the outward exposure of the deaminase domain, facilitating the editing of the target base. AccuBaseTM (ceBE) substantially reduces off-target effects while maintaining on-target editing when compared to BE4max. This improvement has been confirmed in multiple human cell lines, mouse cell lines, human primary T and NK cells, human embryonic stem cells, and in animal embryos. In this study, we apply AccuBaseTM to achieve multiplex gene modifications in primary human T cells, demonstrating its capacity for highly efficient multiplex gene disruption without inducing off-target effects. Importantly, the multiplex base-edited T cells exhibit enhanced ex-vivo cell expansion and do not exhibit the double-strand break-induced translocations observed in T cells edited with Cas9 nuclease. Citation Format: Han Ying, Guanglei Li, Liling Wang, Chunju Lu, Qi Lai, Chao Yao, Fenghua Lv, Shiguo Zhu, Tianhong Xu. The second-generation high-fidelity base editor AccuBaseTM (ceBE) can proficiently modify multiple genes within a human primary T cell while minimizing Off-target effects [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 7234.
Abstract 6311: From bench to bedside: GMP manufacturing and testing of an LGR5-targeting CAR-T against colorectal cancer
Authors: Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Timona Tylis, Emma Thompson, Stuart Mills, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry
Journal: Cancer Research (2024)

Abstract Colorectal cancer is the third most diagnosed cancer worldwide, and is responsible for the second largest number of cancer related deaths, warranting the need for new treatments. The successful use of chimeric antigen receptor T (CAR-T) cells against B-cell malignancies has inspired the search for CAR-T cell therapies against solid tumours such as colorectal cancer. Cancer stem cells (CSC) are a small population of cells within a tumour with the capacity to self-renew, differentiate, and initiate new tumours. CSC are resistant to chemotherapy and radiotherapy and are enriched in residual disease. Targeting CSC is a strategy to reduce the tumours’ ability to generate new cells. Leucine-rich G protein-coupled receptor 5 (LGR5) is a marker of CSC and LGR5+ cancer cells are implicated in tumour progression and metastasis in colorectal cancer. We designed and tested a chimeric antigen receptor (CAR) targeting the extracellular domain of LGR5. LGR5-targeting CAR-T cells showed significant antigen-specific cytotoxicity and IFNγ release against colorectal cancer (CRC) cell lines in vitro, and in vivo efficacy in a CRC xenograft mouse model. We confirmed the specificity and safety of the LGR5 targeting CAR-T cells by testing against normal human tissues. A GMP ready protocol for clinical scale manufacture of LGR5-targeting CAR-T cells have been developed using CD3+ T-cells from healthy donors. We have successfully tested this protocol using CRC patient-derived CD3+ T-cells and were able to generate clinically relevant cell numbers (80-fold expansion) with high CAR expression. Cells manufactured using this GMP protocol expressed markers of self-renewing naïve-like and central memory phenotype and showed very low percentage of cells that were triple-positive for PD1, TIM3 and LAG3. This protocol has been successfully tested and validated in a GMP manufacturing facility for the production of LGR5 targeting CAR-T cells, in preparation for an FDA approved first in man clinical trial against metastatic colorectal cancer, starting in 2023 (NCT05759728). Citation Format: Veronika Bandara, Batjargal Gundsambuu, Silvana Napoli, Jade Foeng, Dylan McPeake, Timona Tylis, Emma Thompson, Stuart Mills, Allison Cowin, Claudine Bonder, Timothy Sadlon, Shaun McColl, Simon Barry. From bench to bedside: GMP manufacturing and testing of an LGR5-targeting CAR-T against 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 6311.
Abstract 6067: Identification of selective CBP degraders with robust preclinical PK, PD, efficacy and safety across solid tumor indications
Authors: Darshan Sappal, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudia Dominici, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Qianhe Zhou, Mark Zimmerman, Laura La Bonte
Journal: Cancer Research (2024)

Abstract CREB binding protein (CBP) and E1A binding protein (EP300) are paralog histone acetyltransferases involved in many cellular processes via their activity as transcription factor co-activators. Dysregulation of one or both proteins has been implicated in various cancer types, and functional genomic screens have revealed a bidirectional synthetic lethal relationship between these two paralogs in tumor cells. Due to the high homology between CBP and EP300, identifying selective chemical matter that selectively disrupts the activity of CBP has proven challenging. Small molecule inhibitors targeting the HAT or bromodomain of CBP/EP300 have been developed, however these agents exhibit hematopoietic toxicity resulting from dual inhibition, which limits their therapeutic window. Herein, we describe the PK, PD, and efficacy of selective, potent CBP degraders across various EP300-mutant cancer xenograft models. Our results show deep and sustained CBP degradation, leading to significant tumor growth inhibition in solid tumors. This anti-tumor activity was not associated with significant body weight loss or hematopoietic toxicity. Our CBP-selective protein degraders have the potential to be a first-in-class therapeutic option for patients with tumors harboring EP300 mutations. Citation Format: Darshan Sappal, Ammar Adam, Hafiz Ahmad, Benjamin Adams, Ketaki Adhikari, Wesley Austin, Breanna Bullock, Julie Di Bernardo, Thomas Dixon, Danette Daniels, Claudia Dominici, GiNell Elliot, Brian Ethell, Anais Gervais, Md Imran Hossain, David Huang, Dave Lahr, Mei Yun Lin, David Mayhew, Karolina Mizeracka, Solymar Negretti, Tyler Nguyen, Olga Prifti, Shawn Schiller, Brenna Sherbanee, David Terry, Nihan Ucisik, Elizabeth Wittenborn, Qianhe Zhou, Mark Zimmerman, Laura La Bonte. Identification of selective CBP degraders with robust preclinical PK, PD, efficacy and safety across solid tumor indications [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 6067.
Abstract 4686: Identification of ART3 as a novel synthetic lethal partner of the BRCA1 mutation in breast cancer
Authors: Hannah Neiger, Xinyu Pei, Anh Nguyen, Wenjia Wang, Emily L. Siegler, James Zhou, Kristie Lau, Alexandra Tan, Yihui Shi
Journal: Cancer Research (2024)

Abstract Breast cancer (BC), the most prevalent malignancy in women, ranks fourth in cancer mortality as of 2022. Mutations in the BRCA genes significantly elevate BC risk and are associated with markedly reduced survival compared to non-carriers. These genes are crucial in homologous recombination, a mechanism essential for error-free DNA repair. Despite advancements, treatment options for BRCA mutation-driven cancers remain limited. Synthetic lethality (SL) has emerged as a promising strategy, with poly(ADP-ribose) polymerase inhibitors (PARPi) being the first developed drugs based on this principle. However, PARPi's effectiveness is limited, as nearly 40% of BRCA-mutated BCs are unresponsive, and resistance often develops in initial responders. Therefore, novel mutation-specific targeted therapies are urgently needed. In this study, we employed the novel computational method 'Mining Synthetic Lethals (MiSL)' to analyze TCGA pan-cancer primary tumor data, identifying ART3 as a potential SL partner of the BRCA1 germline mutation. Our approach focused on the intersection of genetic interactions and cancer vulnerabilities, providing a unique insight into SL relationships. siRNA-mediated silencing of ART3 in BRCA1-mutated cells consistently led to decreased cell viability, apoptosis induction, and G2/M cell cycle arrest. Following stable transfection with an inducible ART3 shRNA construct, we confirmed significant reduction in cell viability in BRCA1-deficient cells through colony formation assays. RNA sequencing of ART3 knockdown cells revealed transcriptional changes in genes involved in cell cycle progression, apoptosis, and growth and proliferation pathways compared with control cells. Immunofluorescent staining revealed increased DNA damage foci with decreased DNA repair in ART3 knockdown BRCA1-deficient cells. In conclusion, our study identifies ART3 as a novel SL partner of the BRCA1 mutation in BC. This discovery paves the way for developing new therapeutic strategies for BRCA1-mutated breast cancers and novel chemoprevention approaches for individuals carrying germline BRCA1 mutations. Future research will focus on further elucidating the molecular mechanisms underlying this SL interaction and exploring its therapeutic potential in clinical settings. Citation Format: Hannah Neiger, Xinyu Pei, Anh Nguyen, Wenjia Wang, Emily L. Siegler, James Zhou, Kristie Lau, Alexandra Tan, Yihui Shi. Identification of ART3 as a novel synthetic lethal partner of the BRCA1 mutation in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4686.