tbuckley/cabot-search huggingface dataset:
Abstract 7122: A novel USP1 inhibitor coupled with a novel proteomic response biomarker for precision oncology therapy
Authors: Iris Alchanati, Andrew Morley, Avital Hay-Koren, Fabrizio Fierro, Galina Otonin, Shay Herman, Alon Shtrikman, Yonatan Katzenelenbogen, Gali Arad, Barr Tivon, Kirill Pevzner, Eran Seger
Journal: Cancer Research (2024)

Abstract Ubiquitin-specific protease 1 (USP1) is a well-characterized deubiquitinating enzyme (DUB) that plays a critical role in DNA damage repair (DDR). It was shown to regulate various key repair processes, most notably proliferating cell nuclear antigen (PCNA) in the Translesion Repair (TLS) pathway and FANCD2/FANCI in the Fanconi Anemia (FA) repair pathway. Research indicates that USP1 deficiency leads to a decrease in cell survival and disruption of genomic stability, suggesting that USP1 inhibitors (USP1i) may hold promise in treating DDR deficient tumors. Through the integration of computational and medicinal chemistry approaches, we discovered a novel, potent inhibitor of USP1, showing anti-USP1 activity in both cell-free enzymatic assay and in measurement of PCNA-ubiquitination change upon USP1 inhibition in cells. We demonstrate anti tumor activity in DDR-related and other indications. By utilizing our platform to analyze the basal proteomics of resistant and sensitive cell lines treated with USP1i, we revealed a distinctive proteomic biomarker signature for USP1i response. This data demonstrates the potential of our novel USP1 inhibitor to serve as a potent therapeutic agent for DDR-deficient and other biomarker-positive cancer patients. Citation Format: Iris Alchanati, Andrew Morley, Avital Hay-Koren, Fabrizio Fierro, Galina Otonin, Shay Herman, Alon Shtrikman, Yonatan Katzenelenbogen, Gali Arad, Barr Tivon, Kirill Pevzner, Eran Seger. A novel USP1 inhibitor coupled with a novel proteomic response biomarker for precision oncology therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7122.
Abstract 2382: KY-CLC-mouse: a common light chain bispecific antibody discovery platform
Authors: Hao Peng, Guojin Wu, Feng Hao, Feng He, Yi Gu, Jinying Ning
Journal: Cancer Research (2024)

Abstract Bispecific antibodies (BsAbs) have emerged as a potent therapeutic tool in cancer treatment, gaining increasing centrality in therapeutic applications. However, the development of bispecific antibodies is hindered by the mispairing of light and heavy chains. In response to this challenge, our company developed the KY-CLC-mouse, featuring an identical κ light chain without the expression of the λ light chain. This mouse shows great promise in bispecific antibody development, as the identical κ light chain, modified from a frequently occurring light chain in mice, pairs with multiple heavy chains. The advantages of such a light chain include good solubility and stability, as well as ease of humanization without post-translational modifications in the complementary-determining regions (CDRs). Furthermore, the CDRs were modified to reduce immunogenicity. This KY-CLC-mouse platform has facilitated the identification of antibodies that specifically target over a dozen antigens, such as PD-1, LAG33, MET, PSMA, and CD28, with KD ranging from 0.1 nM to 10 nM. We apply the knob-in-hole technology to assemble bispecific antibodies, targeting two antigens or different epitopes of the same antigen, following their humanization. Prime examples include fully humanized BsAbs PD1xLAG-3, PDL1xEGFR, PSMAxCD28, and EGFRxB7H3. These bispecific antibodies have an identical light chain and were developed with knob-into-hole technology. With different treatments such as high concentration, low pH, repeated freezing and thawing, and high temperature, the BsAbs show neither aggregation nor degradation, suggesting good developability of these antibodies. Additionally, these BsAbs have a half-life of more than five days in the blood of both mice and monkeys. In conclusion, our common light chain KY-CLC-mouse is a powerful bispecific antibody discovery platform. Citation Format: Hao Peng, Guojin Wu, Feng Hao, Feng He, Yi Gu, Jinying Ning. KY-CLC-mouse: a common light chain bispecific antibody discovery platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2382.
Abstract 1648: RB represses cohesin-dependent loop formation and activates E2F-independent transcription
Authors: Hanjun Lee, Ioanna-Maria Gkotinakou, Badri Krishnan, Nicholas J. Dyson, Michael S. Lawrence, Ioannis Sanidas
Journal: Cancer Research (2024)

Abstract The retinoblastoma protein (RB) suppresses the activity of the E2F transcription factor family, controlling cellular proliferation. Recent studies, however, indicate that RB's role in chromatin organization, which is not yet fully understood, might be distinct from this E2F-dependent regulation. Employing chromosome conformation capture at a single nucleosome resolution, we identified RB as a cell cycle-regulated repressor of cohesin-dependent loop formation at topologically associating domain (TAD) boundaries. RB depletion increased the number and size of cohesin-dependent loops and strengthened topologically associating domains (TADs). This phenomenon was specific to the G1 phase and was not observed in the S phase, indicating that this novel RB function is regulated by the cell cycle. Mechanistically, RB showed extensive colocalization with cohesin in the human genome, and it impacted cohesin’s distribution on the chromatin. Active RB reduced cohesin from RB-bound TAD boundaries and decreased cohesin activity therein, as assessed by the increased K105/106 acetylation of the cohesin subunit SMC3. This led to reduced insulation in chromosome conformation capture assays. Importantly, by weakening the insulation activity of the adjacent insulators, RB non-canonically enhanced the expression of non-E2F target genes salient for cell adhesion and extracellular matrix organization. When RB was lost, cells showed a more rapid cellular detachment rate and an elevated migration rate, indicating that this novel RB function controls specific transcriptional programs rather than arbitrary genes to regulate the process of cell adhesion and migration. Overall, we conclude that RB has a central role in the interplay between cell cycle and chromatin organization, by repressing the cohesin-dependent loop formation at TAD boundaries. This RB function safeguards E2F-independent transcriptional programs driven by active enhancers and helps maintain cellular adhesion to the extracellular matrix. Citation Format: Hanjun Lee, Ioanna-Maria Gkotinakou, Badri Krishnan, Nicholas J. Dyson, Michael S. Lawrence, Ioannis Sanidas. RB represses cohesin-dependent loop formation and activates E2F-independent transcription [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 1648.
Abstract 5444: EGFR missense mutation(s) induce OLIG2 expression to regulate glioma stem cells maintenance and therapeutic resistance
Authors: Sidney Weaver, Aunay Miller, Mylan Blomquist, James McNamara, Keely Orndorff, Chris Sereduk, Jean Kloss, Joseph Loftus, Shwetal Mehta, Nhan L. Tran
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) tumors contain a subpopulation of glioma stem cells (GSC) which can escape therapeutic effects through self-renewal and invasion. Epidermal growth factor receptor (EGFR) mutations are the most common alteration in GBM (50%). One example includes extracellular domain missense mutations like G598V, A289V, and R108K (10-15%). These extracellular domain missense mutations increase ligand binding affinity, inducing a highly active receptor. Earlier reports have shown these EGFR missense mutations exhibit therapeutic resistance; however, the molecular mechanism of these missense mutations in GBM remains unknown. In this study, we show high oligodendrocyte transcription factor 2 (OLIG2) expression in GSCs with EGFR-G598V and EGFR-A289V missense mutations. OLIG2 is universally expressed in glioma and essential for reprogramming GBM cells into stem-like tumor cells. Here, we report GSCs with these point mutations display increased self-renewal, growth, invasion, and therapeutic resistance. In addition, EGFR-G598V and EGFR-A289V trigger distinct downstream signaling pathways in GSCs to regulate OLIG2 function. These missense mutation(s) also represent different pathway-based GBM subclassifications, where A289V induces a Neuronal subtype and G598V induces a Glycolytic/Plurimetabolic subtype. We hypothesize that GBM tumors harboring EGFR missense mutations (G598V, A289V) influence stem cell properties via multiple pathways to evade therapeutic effects and inhibiting these different signaling pathways will decrease therapeutic resistance in GBM. Understanding the mechanism of these EGFR mutations may lead to improved therapeutic strategies for GBM patients. Citation Format: Sidney Weaver, Aunay Miller, Mylan Blomquist, James McNamara, Keely Orndorff, Chris Sereduk, Jean Kloss, Joseph Loftus, Shwetal Mehta, Nhan L. Tran. EGFR missense mutation(s) induce OLIG2 expression to regulate glioma stem cells maintenance and therapeutic resistance [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 5444.
Abstract 6061: Development of target cell-penetrating scFv conjugate degrader for the selective inhibition of mutant, resistant KRAS cancer
Authors: Gookjin Yoon, Beom Soo Jo, Dong Woo Lee, Jinwook Yang, Min-Ho Park, Sanghui Seok, Jue Yeon Lee, Chong Pyoung Chung, Yoon Jeong Park
Journal: Cancer Research (2024)

Abstract The activation of mutations in the RAS gene, which is frequently observed in human cancers, induces downstream critical effectors, contributing to tumorigenesis. While attempts to directly target the GTP-bound, activated RAS have shown some success in certain cancer treatments, resistance remains a challenge. Our objective is to develop a cell-penetrating single-chain fragment variable (scFv) degrader that targets mutant KRAS for degradation. The scFv, binding specifically to antigens, can mitigate the side effects of non-specific binding seen with chemical drugs. However, due to the limited cell-penetrating capability of scFv, a delivery carrier is often necessary. In this study, a cancer targeting, and cell-penetrating synthetic peptide (CPP) was developed as a drug delivery carrier and added to the sequence of scFv. To this conjugate, a von Hippel-Lindau (VHL) expressing sequence was added to enable the scFv binding to mutant KRAS, enabling its proteasomal degradation. These conjugates were engineered as a plasmid DNA to be expressed as a protein conjugate in CHO cells. The purity of the scFv-VHL-CPP degrader was confirmed by SDS PAGE. In SPR results, the degrader not only exhibited high binding ability to mutant KRAS but also influenced the proliferation of KRAS mutant cells in cell viability tests. Mutant GTP-bound KRAS was reduced by the KRAS degrader in KRAS mutant cancer cells. The in vivo study further confirmed the degradation of the KRAS, as reflected by the significantly reduced tumor growth. In conclusion, a degrader protein binding to mutant KRAS that consists of cell penetrating peptide, scFv, and VHL is expected to become a new protein anticancer drug especially effective against mutant, resistant KRAS-mediated cancer cells. Especially, the design of the target cell penetrating peptide-scFv-VHL would be served as a platform for the target protein degrader development. Citation Format: Gookjin Yoon, Beom Soo Jo, Dong Woo Lee, Jinwook Yang, Min-Ho Park, Sanghui Seok, Jue Yeon Lee, Chong Pyoung Chung, Yoon Jeong Park. Development of target cell-penetrating scFv conjugate degrader for the selective inhibition of mutant, resistant KRAS 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 6061.
Abstract 6801: Cellular senescence involves spatial evolution in colorectal cancer
Authors: Tae Jun Park, Seok Yun Kang, Jang Hee Kim, Hyun Woo Lee, Yong Won Choi, Soon Sang Park, Young-Kyoung Lee
Journal: Cancer Research (2024)

Abstract Cancer evolution is a continuous process involving cellular changes that promote progression and metastasis. Recent studies demonstrate that cancer evolution is spatially associated: a phenomenon called “the spatial evolution of cancer.” In our data, colorectal cancer cells gradually evolve from an adenoid to a collective invasion morphology, ultimately developing a partial epithelial-mesenchymal transition phenotype as they form an invasive front. Trajectory analysis showed that cancer cells at the invasive front of a tumor exhibit a totally different gene expression pattern from those at the center, and that cellular senescence plays a crucial role in this transition. Epigenetic changes in the promoter/exon1 region of the CDKN2A gene caused by increased reactive oxygen species level are crucial for expression of p16INK4A and induction of senescence in the cancer cells. Two types of senescent tumor cells (type I and type II) were observed, and they played different roles in cancer progression due to different gene expression. Type II senescent tumor cells (p16INK4A+/LAMC2+/MMP7+), a final evolved form of cancer cells, are strongly associated with local invasion and lymph node metastasis of colorectal cancer and worsen the prognosis for patients. Citation Format: Tae Jun Park, Seok Yun Kang, Jang Hee Kim, Hyun Woo Lee, Yong Won Choi, Soon Sang Park, Young-Kyoung Lee. Cellular senescence involves spatial evolution 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 6801.
Abstract 1747: The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma
Authors: Hanno Witte, Axel Künstner, Thomas Hahn, Veronica Bernard, Stephanie Stoelting, Kathrin Kusch, Kumar Nagarathinam, Nikolas von Bubnoff, Cyrus Khandanpour, Arthur Bauer, Michael Grunert, Annette Arndt, Konrad Steinestel, Hartmut Merz, Hauke Busch, Alfred Feller, Niklas Gebauer
Journal: Cancer Research (2024)

Abstract Introduction: In classical Hodgkin-lymphoma (cHL), only a few cases recur, and only a limited fraction of patients is primary-refractory to standard-polychemotherapy. Underlying genomic features of unfavorable clinical courses remain sparsely characterized. Here, we investigated the genomic characteristics of primary-refractory/relapsed cHL in contrast with long-term-responders (LTR). Methods: Therefore, ultra-deep next-generation panel-sequencing was performed on a total of 59 samples (20 LTR, 26 relapsed (rHL: 11 initial-diagnosis, 15 relapse) and 13 primary-refractory (prHL: 8 initial-diagnosis, 5 progression) from 44 cHL-patients applying a hybrid-capture approach. We compared samples associated with distinct disease courses concerning their oncogenic drivers, mutational signatures, and perturbed pathways. Results: Compared to LTRs, mutations in genes such as PMS2, PDGFRB, KAT6A, EPHB1, and HGF were detected more frequently in prHL/rHL. Additionally, we observed that in rHL or prHL, BARD1-mutations occur, whereas ETV1, NF1, and MET-mutations were eliminated through clonal selection. A significant enrichment of non-synonymous variants was detected in prHL compared to LTRs and a significant selection process in favor of NOTCH-pathway mutations driving rHL or prHL was observed. Conclusion: This study delineates distinct mutational signatures between LTR and rHL/prHL, whilst illustrating longitudinal dynamics in mutational profiles using paired samples. Further, several exploitable therapeutic vulnerabilities for rHL and prHL were identified. Citation Format: Hanno Witte, Axel Künstner, Thomas Hahn, Veronica Bernard, Stephanie Stoelting, Kathrin Kusch, Kumar Nagarathinam, Nikolas von Bubnoff, Cyrus Khandanpour, Arthur Bauer, Michael Grunert, Annette Arndt, Konrad Steinestel, Hartmut Merz, Hauke Busch, Alfred Feller, Niklas Gebauer. The mutational landscape and its longitudinal dynamics in relapsed and refractory Hodgkin lymphoma [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 1747.
Abstract 1247: PPARsing epigenetic memory in intestinal stem cells: High-fat diet and oncogenic susceptibility
Authors: Dominic R. Saiz, Thomas Hartley-McDerrmott, Yesenia Barrera-Millan, Karla Fabiola Castro-Ochoa, Abhigyan Shukla, Matthew Torel, Miyeko D. Mana
Journal: Cancer Research (2024)

Abstract Diet has a profound impact on health and susceptibility to cancer. Adaptation to a Western diet is strongly associated with increased colorectal cancer (CRC) and obesity prevalence. This study demonstrates the epigenetic changes in intestinal stem cells (ISCs) induced by a pro-obesity high-fat Western diet (HFD) and the heightened risk of oncogenic transformation. A HFD induces a phenotype characterized by increased ISC frequency, proliferation, regenerative capacity, and ability to initiate adenomas. We hypothesized that a HFD generates lasting epigenetic alterations in ISCs thereby enhancing oncogenic susceptibility. We evaluated the chromatin landscape of intestinal stem cells (ISCs) and the reversibility of the epigenetic changes. Mice carrying a fluorescent reporter of the ISC marker Lgr5, were subjected to a control diet, HFD, or HFD with a return to control. We isolated ISCs by flow cytometry and used an assay for transposase-accessible chromatin sequencing (ATAC-seq) to identify differentially accessible genomic regions correlated with the ISC phenotype. We found that a HFD induces distinct changes in the chromatin landscape that persist after removal from the HFD. These accessible regions are associated with genes involved in lipid metabolism and are enriched with PPAR (Peroxisome Proliferator-Activated Receptor) binding motifs. We demonstrate that these lipid metabolism regulators, PPAR-delta and PPAR-alpha, are necessary for the majority of significant accessible regions. We further show that HFD-induced accessibility significantly correlates with early chromatin alterations seen by loss of tumor suppressor APC. Our data supports a mechanistic pathway for diet-induced epigenetic reprogramming due to PPAR activity and suggests that the HFD imposes a preneoplastic stem cell chromatin state that stokes the risk of oncogenic change. Citation Format: Dominic R. Saiz, Thomas Hartley-McDerrmott, Yesenia Barrera-Millan, Karla Fabiola Castro-Ochoa, Abhigyan Shukla, Matthew Torel, Miyeko D. Mana. PPARsing epigenetic memory in intestinal stem cells: High-fat diet and oncogenic susceptibility [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 1247.
Abstract 2071: Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal cancers
Authors: Sanjoy Das, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Zgheib, Amit Nayyar, Anh Minh Thao Nguyen, Bogdan Alexandru Danalache, Richard Beliveau, Christian Marsolais, Borhane Annabi
Journal: Cancer Research (2024)

Abstract Limitations in current colorectal cancer (CRC) camptothecin (CPT)-based chemotherapy have mostly been attributed to low specificity and high systemic cytotoxic side effects. More effective therapies are therefore required to improve the clinical outcomes of patients with CRC. Here, we developed a selective and better anticancer drug delivery of CPT through conjugation to a peptide (TH19P01) that targets Sortilin (SORT1), a scavenging receptor expressed in various tumor tissues including CRC. In the current study, significant SORT1 expression was detected in various CRC cell lines as well as that of irinotecan analogs efflux pump (ABCG2) in LoVo and HT-29 cells. Considering this result, we used our proprietary peptide conjugation SORT1 technology to increase cell targeting selectivity and cell delivery efficacy of CPT analogs. Different peptide drug conjugates (PDCs) were generated linking the TH19P01 peptide to SN-38 (an irinotecan metabolite) or exatecan, which are two main CPT derivatives used in recent antibody drug conjugates (ADC) as payloads. In vitro, immunonofluorescent microscopy revealed that TH19P01 was rapidly internalized (&amp;lt;15 min) in a SORT1-positive human HT-29 CRC cell model. These PDCs also inhibited CRC cell proliferation at low nM concentrations (3-90 nM). In vivo, weekly administration of TH2101 (SN-38) and of TH2303 (exatecan) conjugates were well tolerated as they had little impact on mouse body weight but caused a more potent growth inhibition of the HT-29 CRC tumor xenograft model than did either unconjugated irinotecan or exatecan molecules. In fact, at their maximum tolerable dose, irinotecan and exatecan caused a tumor growth inhibition of only 48% and 45% whereas TH2101 and TH2303 inhibited the growth of HT-29 tumors by 83% and 91%, respectively. These results provide strong pre-clinical evidence for the future development of novel CPT PDCs therapeutics with targeting of SORT1-positive CRC cells. Citation Format: Sanjoy Das, Jean-Christophe Currie, Michel Demeule, Cyndia Charfi, Alain Zgheib, Amit Nayyar, Anh Minh Thao Nguyen, Bogdan Alexandru Danalache, Richard Beliveau, Christian Marsolais, Borhane Annabi. Pre-clinical evidence for new camptothecin-peptide conjugates in the treatment of sortilin-positive colorectal 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 2071.