tbuckley/cabot-search huggingface dataset:
Abstract 7235: New mouse strain NSG-SGM3xIL15xDKO is better for PBMC engraftment in Raji-bearing mice of minor immune subsets compared to NSG-MHC I/II DKO mouse
Authors: Nancy (Xiaoqing) Zheng, Guoxiang Yang, James Keck, Li-Chin Yao
Journal: Cancer Research (2025)

Abstract Introduction: PBMC-humanized MHC I/II double knock-out (#025216, DKO) strain has shown strong T cell engraftment with minimal acute GVHD. We recently have developed two new mouse strains, NSG-SGM3xIL15xDKO (SDKO) and NSG-FLT3LxDKO (FDKO), and their engraftment comparison data will be presented in the same meeting. Here we aimed to investigate the engraftment of various immune cell types in SDKO and FDKO mice in the presence of tumor stimulation. Methods: We assessed PBMC engraftment levels and immune subtypes in irradiated SDKO, FDKO, and DKO implanted with lymphoma (Raji-luc and Nalm6-luc) and breast cancer (MDA-MB-231-luc) xenografts. In addition, we investigated the differences between irradiated and non-irradiated mice of the above three strains implanted with Raji-Luc cells. Whole blood via retro-orbital bleeds and spleen were collected to analyze engraftment and immune cell populations by flow cytometry. Five different PBMC donors were used. Results: We found irradiated SDKO and FDKO achieved higher PBMC humanization levels compared to DKO. Interestingly, Raji-luc cells stimulated PBMCs to engraft at a significantly higher level compared to PBS, MDA-MB-231-luc and Nalm6-luc cells. hCD3+ T cells were activated (HLA-DR+) in Raji-luc groups. The stimulatory effect of Raji-luc cells was also validated in the three strains without irradiation. PBS treated irradiated mice without tumor stimulation, both SDKO and FDKO had approximately 9-15 folds engraftment of CD19+ B cells and CD56+ natural killer (NK) cells, and some donors showed 2-4 folds engraftment of CD11c+HLA-DR+ dendritic cells and CD64+ macrophages compared to what was seen in DKO mice in early engraftment. After Raji-luc cells stimulation, the engraftments of above cell types were enhanced 3-4 folds over the DKO. Non-irradiated SDKO and FDKO showed a 2-3 folds increase in B cells and NK cells compared to those in DKO mice in early engraftment in peripheral blood in the PBS group. With Raji-luc cells, the engraftments of B cell and NK cells were enhanced 2-4 folds in SDKO and FDKO over DKO mice. Other tumor data will also be presented. Conclusion: Both PBMC-humanized SDKO and FDKO show improved NK cells and myeloid cells engraftment compared to DKO after tumor antigen stimulation. The response may vary based on PBMC donors and cancer cell lines. Irradiation also helps certain cell types like myeloid cells to engraft compared to no irradiation in the cancer models. Citation Format: Nancy (Xiaoqing) Zheng, Guoxiang Yang, James Keck, Li-Chin Yao. New mouse strain NSG-SGM3xIL15xDKO is better for PBMC engraftment in Raji-bearing mice of minor immune subsets compared to NSG-MHC I/II DKO mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7235.
Abstract 6001: Unlocking therapeutic potential of rigosertib as a selective therapy for ovarian cancer
Authors: Shalini Nath, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E. Premkumar Reddy, Stephanie V. Blank, Olivier Elemento, Rachel Brody, Benjamin D. Hopkins
Journal: Cancer Research (2025)

Ovarian cancer has a devastating impact. In 2024 it is estimated that there will be 19,680 new ovarian cancer diagnoses and 12,740 fatalities in the United States. Despite advancements in treatment options, 80% of ovarian tumors recur or progress through treatments leading to a five year survival rate of just 50%. To address this unmet need, we employed a functional genomics approach to identify ovarian cancer specific drug sensitivities. Comparing the impact of each of the 117 drugs in our library across 32 cancer cell lines from 11 tumor lineages we identified Rigosertib, a small molecule RAS mimetic, as a selective agent for treatment of ovarian cancer. This ovarian cancer specific sensitivity to Rigosertib was validated in a panel of ovarian cancer cell lines and patient-derived organoids. This sensitivity fits with the observation that ovarian cancer exhibits a high frequency of alterations in both the PI3K and MAPK pathways, both of which can be negatively regulated through the disruption of RAS interactions. Concordantly, while the interplay between these pathways creates an inverse regulatory relationship by which inhibition of either pathway can lead to activation of the other, we observe that in all of the ovarian lines tested that treatment with Rigosertib leads to increases of MTOR signaling as indicated by phosphorylation of S6 both in vitro and in vivo. Subsequent combination drug screening revealed a cooperative effect between rigosertib and PI3K inhibitor (taselisib), suggesting that combining rigosertib with taselisib which restricts mTOR activation enhances therapeutic efficacy. This combination showed synergy across ovarian cancer cell lines, organoids, and xenograft models, with xenograft studies showing a significant reduction in tumor burden. These findings highlight the potential of rigosertib, especially when paired with PI3K inhibitors, to target the unique mutational landscape of ovarian cancer, offering a promising direction for more effective treatments. Citation Format: Shalini Nath, Sally Claridge, Genesis Lara Granados, Majd Al Assaad, Eric Park, Julie-Ann Cavallo, Maame Esi Ackon, Lamberto De Boni, Stacey Baker, E. Premkumar Reddy, Stephanie V. Blank, Olivier Elemento, Rachel Brody, Benjamin D. Hopkins. Unlocking therapeutic potential of rigosertib as a selective therapy for ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6001.
Abstract 6528: The role of health behaviors in microbial dysbiosis and lung cancer inequities
Authors: Murugesh Eswaran, Briana A. Brock, Hina Mir, Gabriela Oprea-Ilies, Eric Flenaugh, James W. Lillard, Brian M. Rivers, Rajesh Singh, Shailesh Singh
Journal: Cancer Research (2025)

Abstract Lung cancer remains the leading cause of cancer-related morbidity and mortality worldwide. African Americans (AA) are disproportionally affected by the disease, and mortality is higher in AA compared to European Americans (EA). The mortality rate among AA is higher than EA even when diagnosed at an early stage, implying biological differences associated with health behaviors such as smoking and its impact on microbial dysbiosis. A higher mortality rate in AA diagnosed at an early stage compared to EA highlights the biological differences in AA are primarily due to health behaviors such as smoking and its impact on microbial dysbiosis, making AA predisposed to higher risk and mortality. Microbial dysbiosis in lung cancer was analyzed using GEO and All of Us data repositories. Our analysis provides compelling evidence of the interplay between microbial dysbiosis, health behaviors, and racial disparities in lung cancer outcomes. Our study shows that smoking exacerbates microbial imbalances, particularly with the prevalence of Streptococcus and its differential impact on AA and EA. Dysbiosis correlates strongly with lung cancer pathogenesis, particularly the abundance of Streptococcus, Haemophilus, Neisseria, and Pseudomonas. AA participants show higher susceptibility to Streptococcus invasion, with detectable levels in the blood at just 7 cigars daily compared to 23 cigars in EAs. Urine samples of AAs smoking only 17 cigars per day are positive for streptococcus, while for EAs the bacteria is detected only when they smoke 20 cigars daily. These findings underscore a biological predisposition that amplifies cancer risk for AAs at lower smoking intensities. The lower thresholds for Streptococcus detection among AA populations suggest a heightened biological vulnerability, emphasizing the need for tailored public health interventions and early screening programs in these communities. These results underscore the importance of integrating microbial profiling in personalized medicine approaches and addressing underlying health inequities to improve lung cancer outcomes across diverse populations. Citation Format: Murugesh Eswaran, Briana A. Brock, Hina Mir, Gabriela Oprea-Ilies, Eric Flenaugh, James W. Lillard, Brian M. Rivers, Rajesh Singh, Shailesh Singh. The role of health behaviors in microbial dysbiosis and lung cancer inequities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6528.
Abstract 1460: Clinical relevance of a super-enhancer-associated actin polymerization promoting-factor in endometrial cancer
Authors: Kuniko Horie, Erina Iwabuchi, Kazuhiro Ikeda, Takashi Suzuki, Satoshi Inoue
Journal: Cancer Research (2025)

Abstract Super-enhancers (SEs) are defined as large clusters of enhancers regulating transcription of genes that exhibit cell-type specific functions. SEs in cancers are often different from those in healthy states and responsible for the development and progression of the disease. We here study the clinical role of a super-enhancer-associated actin polymerization promoting-factor, cordon-bleu WH2 repeat protein-like 1 (COBLL1), in endometrial cancer, since we previously demonstrated its tumor-promoting role in castration-resistant prostate cancer [Proc Natl Acad Sci USA 115:4975, 2018]. In the present study, using multiple patient-derived spheroid cultures established by our group [Endocrinology 160:1895, 2029], endometrial cancer-specific SEs were identified by chromatin immunoprecipitation (ChIP) sequencing for H3K27ac binding sites. Among top-ranked SE-associated genes, we focused on the relevance of COBLL1 in endometrial cancer. Then, we showed that COBLL1 silencing in endometrial cancer cells substantially repressed cell proliferation and reduced the populations of cells in S phase of the cell cycle. Of note, immunohistochemical study of clinical endometrial cancer tissues revealed that COBLL1 immunoreactivity was well correlated with poor prognosis of the patients. Our findings suggest that COBLL1 plays a relevant role in the pathophysiology of endometrial cancer and can be applied as a promising diagnostic and therapeutic target in endometrial cancer management. Citation Format: Kuniko Horie, Erina Iwabuchi, Kazuhiro Ikeda, Takashi Suzuki, Satoshi Inoue. Clinical relevance of a super-enhancer-associated actin polymerization promoting-factor in endometrial cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1460.
Abstract 5990: Pertuzumab enhances the antitumor activity of T-DXd in HER2-positive gastric cancer cells
Authors: Minsu Kang, Kui-Jin Kim, Ji Hea Sung, Milang Nam, Sung-Hyun Hwang, Eun Hee Jung, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Keun-Wook Lee
Journal: Cancer Research (2025)

Abstract Simultaneously targeting HER2 and HER3 pathways is a potentially effective strategy for treating patients with HER2-positive gastric cancer (GC). A recent significant advancement in targeted therapy for HER2-positive GC is the development of trastuzumab deruxtecan (T-DXd). However, the co-administration of HER3 blockade with T-DXd to HER2-positive GC has not yet been explored, making this a pioneering study. Our in vitro analysis showed that the cell growth inhibitory effect of T-DXd on HER2-positive GC cells resembled the antiproliferative effect pattern induced by trastuzumab, rather than that caused by DXd. T-DXd reduced the cell viability in a manner closely linked to HER2 expression on the cell membrane. We observed that T-DXd inhibited the phosphorylation of HER3 and, subsequently that of p-AKT S473. The addition of pertuzumab increased T-DXd-induced HER2 internalization and further enhanced its antitumor effect on HER2-positive GC cells, especially when the HER2-HER3 heterodimers are enriched in the cells. By translating our findings into a xenograft model, we showed that combining T-DXd and pertuzumab outperformed single-agent therapy, resulting in significant antitumor effects and apoptosis induction. Our study suggests additional clinical investigations of this new combination strategy using T-DXd and pertuzumab in patients with HER2 positive GC are warranted. Citation Format: Minsu Kang, Kui-Jin Kim, Ji Hea Sung, Milang Nam, Sung-Hyun Hwang, Eun Hee Jung, Koung Jin Suh, Ji-Won Kim, Se Hyun Kim, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Keun-Wook Lee. Pertuzumab enhances the antitumor activity of T-DXd in HER2-positive gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5990.
Abstract 1665: A comprehensive platform for the screening and assessment of IRAK4-targeting PROTACs
Authors: Zhaoxia Yin, Xiaojian Wang, Tj (Tiejun) Bing
Journal: Cancer Research (2025)

Abstract Interleukin-1 receptor-associated kinase 4 (IRAK4) serves as a pivotal mediator in the signaling cascades of both the interleukin 1 receptor (IL-1R) and toll-like receptor (TLR) pathways. It is crucial for myddosome signaling, as its kinase and scaffolding activities are indispensable for the proper formation and signaling of the myddosome complex. This complex, in turn, initiates the activation of key downstream pathways, including NFkB and interferon-responsive factors 5/7 (IRF 5/7), culminating in the release of inflammatory cytokines and chemokines such as TNF-α, IL-6, IL-1β, and IL-23. These molecules are associated with the development of various autoimmune diseases, such as pyogenic tonsillitis, psoriasis, and atopic dermatitis, positioning IRAK4 as a promising therapeutic target for dampening inflammation mediated by TLR/IL-1R. In this context, we have developed a comprehensive screening and evaluation platform for IRAK4 that spans from in vitro to in vivo studies. The platform encompasses an array of assays at both the biochemical and cellular levels. It features tests for binary and ternary complexes, intracellular detection of ternary complex formation, and a suite of methods for detecting target protein degradation, including flow cytometry, enzyme-linked immunosorbent assay (ELISA), and HiBiT. The platform also offers cellular function assays, such as cytokine release assays utilizing peripheral blood mononuclear cells (PBMCs) and whole blood, as well as assays focused on proteins associated with signal transduction pathways. It also includes off-target and selectivity testing, and extends to in vivo efficacy assessments within the IMQ-induced psoriasis model. Collectively, these assays are designed to facilitate a swift and thorough discovery and evaluation process for IRAK4-targeting PROTACs. Citation Format: Zhaoxia Yin, Xiaojian Wang, Tj (Tiejun) Bing. A comprehensive platform for the screening and assessment of IRAK4-targeting PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1665.
Abstract 6023: Intrabody-mediated TLR2 and TLR9 blockade as new strategy to inhibit inflammation-driven pancreatic cancer growth
Authors: Martin Gasser, Thomas Boeldicke, Ana Maria Waaga-Gasser
Journal: Cancer Research (2025)

Abstract Pancreatic cancer (pancreatic ductal adenocarcinoma, PDAC) remains a deadly cancer worldwide with a need for new therapeutic approaches. A dysregulation in the equilibrium between pro- and anti-inflammatory responses with a predominant immunosuppressive inflammatory reaction in advanced stage tumors seem to contribute to tumor growth and metastasis. The current therapies do not include strategies against pro-tumorigenic inflammation in cancer patients. We have shown that the upregulated cell surface expression of Toll-like Receptor (TLR) 2 and of TLR9 inside PDAC cells maintain chronic inflammatory responses, support chemotherapeutic resistance, and mediate tumor progression in human pancreatic cancer. We further demonstrated intracellular TLR2 and TLR9 targeting using specific intrabodies, which resulted in downregulated inflammatory signaling. In this study, we tested, for the first time, an intrabody-mediated TLR blockade in human TLR2- and TLR9-expressing pancreatic cancer cells for its effects on inflammatory signaling-mediated tumor growth. Newly designed anti-TLR2- and anti-TLR9-specific intrabodies inhibited PDAC growth. Co-expression analysis of the intrabodies and corresponding human TLRs showed efficient retention and accumulation of both intrabodies within the endoplasmic reticulum (ER), while co-immunoprecipitation studies indicated both intrabodies interacting with their cognate TLR antigen within the pancreatic cancer cells. Cancer cells with attenuated proliferation expressing accumulated TLR2 and TRL9 intrabodies demonstrated reduced STAT3 phosphorylation signaling, while apoptotic markers Caspases 3 and 8 were upregulated. To conclude, our results demonstrate the TLR2 and TLR9-specific intrabody-mediated signaling pathway inhibition of autoregulatory inflammation inside cancer cells and their proliferation, resulting in the suppression of pancreatic tumor cell growth. These findings underscore the potential of specific intrabody-mediated TLR inhibition in the ER relevant for tumor growth inhibition and open up a new therapeutic intervention strategy for the treatment of pancreatic cancer. Citation Format: Martin Gasser, Thomas Boeldicke, Ana Maria Waaga-Gasser. Intrabody-mediated TLR2 and TLR9 blockade as new strategy to inhibit inflammation-driven pancreatic cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6023.
Abstract 7014: Characterization and validation of PROTACs that recruit KLHL12
Authors: Zoe A. Petros, John Lee Sensintaffar, Anish Kizhakkekkara Vadukoot, Kwangho Kim, Manikandan Thangaraj, Alex G. Waterson, Stephen W. Fesik
Journal: Cancer Research (2025)

Abstract Proteolysis targeting chimeras (PROTACs) have emerged as a promising strategy for cancer therapy in the field of drug discovery. PROTACs are heterobifunctional small molecules that bind to both a target protein and an E3 ubiquitin ligase, thus facilitating degradation of the target protein of interest. Benefits of PROTACs as an alternative therapeutic strategy include the ability to target inaccessible proteins, the regulation of target protein signaling pathways, and overcoming drug resistance in certain types of cancer. There are more than 600 known E3 ligases in the human genome, but current PROTAC technology has been limited to the use of CRBN, VHL, XIAP, and MDM2. Therefore, the discovery of novel ligands for different E3 ligases could further improve current PROTAC technology. An application that our research group has focused on is exploring the possibility of tissue selective E3 ligases that are overexpressed in cancer cells compared to normal tissue to design tissue selective PROTACs for a target of interest. We have observed that protein levels of the E3 ligase KLHL12 are low in normal tissue and high in cancer cells. Using structure-activity relationship (SAR) by nuclear magnetic resonance (NMR), we identified hits that bound to the KLHL12 E3 ligase, which were then optimized to bind in the range of 10-100 nM Kd by SPR. We then generated KLHL12 based PROTACS that target BRD4 and Bcl-xL using thalidomide and A-115463 derivatives, respectively. PROTAC activity was optimized by measuring protein target degradation in HT29 cells by an in-cell western experiment where our most potent degrader had an average DC50 of 5.05 nM and achieved 89.65% degradation. Mechanism studies were carried out to verify that the PROTACs behaved in both a proteasome and target dependent manner. Future studies will support further characterization of KLHL12 by investigating its expression patterns across various cancer tissues, its functional essentiality in cells, and its involvement in protein-protein interactions. Citation Format: Zoe A. Petros, John Lee Sensintaffar, Anish Kizhakkekkara Vadukoot, Kwangho Kim, Manikandan Thangaraj, Alex G. Waterson, Stephen W. Fesik. Characterization and validation of PROTACs that recruit KLHL12 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7014.