tbuckley/cabot-search huggingface dataset:
Abstract 6112: Supercharging anti-tumor immunity in hepatocellular carcinoma with PH102: A CAR T-cell-based platform
Authors: Vincent Truong Pham, Shaozi Fu, Victoria Sanchez, Ya-Guang Liu, Kasie Liu, Araceli Bernal, LuZhe Sun, Gang Huang
Journal: Cancer Research (2025)

Abstract Hepatocellular carcinoma (HCC) is the 5th leading cause of cancer death in the US among males (7th among females) and remains a major cause of cancer-related death worldwide with especially high prevalence in South Texas (12 per 100,000). HCC is caused by HBV/HCV infections, metabolic dysfunction, and alcoholic steatohepatitis. The majority of HCC patients present clinically with advanced disease and are treated with ineffective systemic therapies including chemotherapy and/or immune checkpoint inhibitors. There’s a pressing need for an innovative, curative immunotherapy for advanced, unresectable HCC for whom liver transplantation is not possible. The tumor immune microenvironment (TiME) of HCC is a complex milieu of tumor, stromal, and immune cells that interact to modulate tumor growth. We designed a first-in-class precision immunotherapy approach based on established chimeric antigen receptor (CAR) T-cell technology that packages three different targeting approaches into a comprehensive cell-based platform to rebuild the anti-tumor TiME. PH102 is a CAR T-cell-based therapy targeting GPC3 (tumor antigen highly expressed in HCC but not healthy hepatocytes or normal tissues) while co-expressing factors A and B, immune signaling molecules that supercharge anti-tumor immune cells. We have shown exceptional preclinical safety and efficacy of PH102 in multiple solid tumor animal models including a tumor implantation model and a hydrodynamic tail vein injection (HTVI) murine model of in situ HCC. PH102 has been demonstrated to significantly improve probability of survival in mice carrying advanced HCC tumors, eliciting powerful elimination of advanced tumors via immune killing of cancer cells. Immunomodulatory factors A and B synergize to induce increased infiltration, expansion, and activation of cytotoxic T-cells, tissue resident memory T-cells, conventional NK cells, liver resident NK cells, and dendritic cells within the TiME. Altogether, PH102’s triple-hit approach induces a potent and durable anti-tumor, immune-triad-mediated killing program alongside creating long-term immune memory that persists long after CAR T-cell exhaustion. PH102 is warranted to be translated into a phase I/II HCC trial following final preclinical safety and efficacy validation. Citation Format: Vincent Truong Pham, Shaozi Fu, Victoria Sanchez, Ya-Guang Liu, Kasie Liu, Araceli Bernal, LuZhe Sun, Gang Huang. Supercharging anti-tumor immunity in hepatocellular carcinoma with PH102: A CAR T-cell-based platform [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 6112.
Abstract 4508: Quantitation of PD-1, PD-L1, and CTLA-4 in human melanoma using SMC® high sensitivity immunoassays
Authors: Anthony J. Saporita, Joseph Hwang, Matthew Lippold, Laila Faramarzi, Raad Gitan, Wen-Rong Lie, Brooke Gilliam, Rick Wiese
Journal: Cancer Research (2025)

Abstract Immune checkpoint proteins such as PD-1, PD-L1, and CTLA-4 play a central role in neoplastic cell immunosurveillance. Soluble forms of these cell surface proteins are currently being evaluated as potential biomarkers in the diagnosis, prognosis, and pathogenesis of several forms of cancer, such as melanoma. For this study, we first wanted to compare human plasma samples from 12 healthy donors and 12 individuals with melanoma using MILLIPLEX® Human Immuno-Oncology Checkpoint Protein Panel 1, a 17-plex immunoassay. Three immune checkpoint proteins (CD27, CD40, and TIM-3) exhibited statistically significant increases in melanoma samples versus healthy controls, despite the small sample size. While PD-1, PD-L1, and CTLA-4 trended toward increases in the disease state, differences were below the threshold of statistical significance when assessed by MILLIPLEX®. CTLA-4, in particular, was present in low abundance in circulation, with fifty percent of healthy plasma samples near the lower limit of quantification (LLoQ) for the MILLIPLEX® assay. To achieve greater sensitivity for this critical immune checkpoint protein, we developed a novel SMC® CTLA-4 high sensitivity immunoassay. SMC® technology delivers ultrasensitive biomarker measurements for low abundant proteins in comparison to the limits of traditional sandwich ELISA immunoassays. The SMC® assays for PD-1, PD-L1 and CTLA-4 consistently achieved LLoQs of 1.74 pg/mL, 0.78 pg/mL and 0.1 pg/mL, respectively. More importantly, these ultrasensitive SMC® kits allowed quantitation of these cell surface proteins in all plasma samples tested from both healthy donors and melanoma patients. Statistical differences in CTLA-4 (p-value &amp;lt;0.01) and PD-1 (p-value &amp;lt; 0.005) were observed with the SMC® kits in the melanoma cohort compared to the healthy samples. The integration of MILLIPLEX® multiplex assays and SMC® high sensitivity assays in a comprehensive workflow enables profiling of multiple analytes and a deeper understanding of immune response dynamics by accurately measuring low abundant proteins, thereby providing a powerful non-invasive tool for evaluating disease conditions. Citation Format: Anthony J. Saporita, Joseph Hwang, Matthew Lippold, Laila Faramarzi, Raad Gitan, Wen-Rong Lie, Brooke Gilliam, Rick Wiese. Quantitation of PD-1, PD-L1, and CTLA-4 in human melanoma using SMC® high sensitivity immunoassays [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 4508.
Abstract 6802: RLIP depletion promotes apoptosis in ovarian cancer
Authors: Sharad S. Singhal, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia
Journal: Cancer Research (2025)

Abstract Ral interacting protein (RLIP) is a multifunctional protein localized and distributed in the plasma membrane, cytosol, and nucleus of the cell. RLIP is ubiquitously expressed in various tissues, including the ovary. In tumorigenesis, RLIP emerges as a common feature for solid tumor growth. RLIP is an anti-apoptotic non-ABC glutathione (GSH)-conjugate transporter involved in receptor-ligand endocytosis, as well as in multispecific drug transport and resistance. The presence of RLIP appears to be indispensable for cancer cells as indicated by its overexpression in various malignant cell lines. Partial inhibition and or depletion of RLIP using antibodies or antisense in the absence of chemotherapy drug causes apoptosis in multiple ovarian cancer (OC) cell lines; in the presence of carboplatin, marked synergy is observed in vitro as well as in vivo. These findings indicate that RLIP is a good target for cancer cell killing, and that its down-regulation would promote apoptosis through both drug-dependent and drug-independent effects. To examine the effect of specific RLIP depletion on apoptosis, we tested the effect of RLIP antisense in a number of OC cell lines. Growth inhibition and apoptosis were observed in all cases upon RLIP depletion. Cytotoxic synergy between RLIP antisense, RLIP antibodies, and carboplatin was examined in cell culture and xenografts of OVCAR8 OC cells. RLIP inhibition by antibodies was equally as effective as antisense and enhanced carboplatin efficacy in OC xenografts. Taken together, these results show that RLIP is a rational and promising new target for OC therapy. (This work was supported in part by the Department of Defense grant W81XWH-22-1-0331. Funding from the Beckman Research Institute of City of Hope is also acknowledged). Citation Format: Sharad S. Singhal, Madhu Krishna, Prakash Kulkarni, David Horne, Ravi Salgia. RLIP depletion promotes apoptosis in 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 6802.
Abstract 5745: Selective anticancer activity and mechanistic insights of novel compounds identified through NCI-60 cancer cell line screening
Authors: Rakaia S. Abdullah, Md Emran Hossain, Eneye David Ajayi, Mostafa M. Aref, Hamed I. Ali
Journal: Cancer Research (2025)

Targeted cancer therapies aim to maximize efficacy while minimizing side effects. The NCI 60 Human Tumor Cell Line Screen provides a comprehensive platform for identifying compounds with selective anticancer potential across various subtypes. To identify and validate potent anticancer compounds from a 150 compound library, focusing on molecular selectivity, mechanistic insights, and preclinical efficacy. High-throughput screening was performed using the NCI60 platform, followed by cytotoxicity assays (IC50), kinase selectivity profiling, and molecular modeling. Further evaluation utilized 3D spheroid and organoid models, in vivo testing in xenograft models, and mechanistic studies via Western blot to assess apoptosis and pathway modulation. Seventeen compounds (HA45, HA46, HA7, HA12, HA14, HA15, HA16, HA19, HA21, HA23, HA25, HA26, HA64, HA88, HA94, HA96) exhibited significant selectivity, with GI50 values in the nanomolar and micro range. Lead compounds HA45 and HA46 against CNS SNB 74 cell line demonstrated potent kinase inhibition profiles and induced apoptosis through disruption of critical signaling pathways. Molecular docking and dynamics simulations revealed stable interactions with target kinases, corroborating structure-activity relationships. Testing in 3D models confirmed their physiological relevance, and in vivo studies showed tumor growth inhibition with minimal toxicity. This study highlights the utility of integrated methodologies for advancing selective anticancer agents toward clinical application. The findings underscore the importance of combining computational, in vitro, and in vivo approaches in the development of novel cancer therapeutics. Citation Format: Rakaia S. Abdullah, Md Emran Hossain, Eneye David Ajayi, Mostafa M. Aref, Hamed I. Ali. Selective anticancer activity and mechanistic insights of novel compounds identified through NCI-60 cancer cell line screening [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 5745.
Abstract 6534: Bacterial infection as a modulator of tumor growth in ovarian cancer
Authors: Shinya Nakano, Ryosuke Sonobe, Miho Suzuki, Keiko Shinjo, Yutaka Kondo
Journal: Cancer Research (2025)

Abstract Ovarian cancer exhibits the lowest survival rate among gynecologic malignancies, emphasizing the critical need for more effective treatment strategies and a comprehensive understanding of its progression mechanisms. Recent studies have suggested that certain microorganisms may contribute to the development and progression of various cancers. Our previous research identified specific microbiota in the uterus and ovaries, which were considered to be sterile. This finding raises the possibility that microbiota within the female reproductive organs may influence the progression of gynecologic cancers. In this study, we investigated whether bacterial communities contribute to the proliferation of ovarian cancer. To confirm the presence of bacteria in ovarian cancer tissues, we performed DNA fluorescence in situ hybridization (DNA FISH) using 16S rRNA probes specific to bacteria on ovarian cancer specimens. Approximately 60% of the tissue samples were found to harbor specific bacteria, predominantly located in the stroma. To evaluate the impact of these bacteria on tumor growth, we developed an in vivo mouse model by introducing bacteria found in ovarian cancer tissues via intraperitoneal injection, followed by intraperitoneal transplantation of mouse ovarian cancer cells. Tumor growth was significantly enhanced in the bacteria-exposed group compared to the control group, indicating that bacterial infection promotes tumor progression. Bacterial infection in the stromal area may induce chronic inflammation conducive to tumor growth, modulate the immune microenvironment, reprogram fibroblasts, and promote angiogenesis. We aim to further discuss these multifaceted roles and their implications in tumor biology and potential therapeutic strategies. Citation Format: Shinya Nakano, Ryosuke Sonobe, Miho Suzuki, Keiko Shinjo, Yutaka Kondo. Bacterial infection as a modulator of tumor growth in 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 6534.
Abstract 7499: Driver mutations propel subclonal evolution and spatial patterns of tumor growth in intrahepatic cholangiocarcinoma
Authors: Evit John, Pooja Shukla, Anish Jain, Alexandria Lau, Tom Lesluyes, Huw Ogilvie, Maxime Tarabichi, Jason Roszik, Yinyin Yuan, Peter Van Loo, Lawrence Kwong, Yun Shin Chun
Journal: Cancer Research (2025)

Abstract Intrahepatic cholangiocarcinoma (ICC) is a highly lethal cancer of the bile ducts that exhibits a diversity of driver oncogenic mutations, several of which have been shown to be frequently subclonal. However, existing tumor evolution studies in ICC have been limited by either the number of sub-regions assessed or a paucity of driver mutation heterogeneity. Here, we conducted a multi-omic analysis of 90 tumor regions from 11 discrete tumors in 10 patients, identifying subclonal driver mutations in 5 of the patients, in the genes PBRM1, PIK3CA, TP53, ARID1A, BRAF, MLH1, and CDKN2A. This high-number multi-region approach also allowed us to unambiguously identify distinct subclonal evolutionary branches and map them to the spatial location of the samples. Importantly, each subclonal driver mutation was tightly associated with these defined branches, implicating them as a frequent mechanism of driving subclonal evolution. Additionally, subclonal branching showed a spatial correlation on surgical resection depicting the strength of multi-region sequencing in treatment. In total, we conclude that while subclonal branching can be driven by a number of factors, the acquisition of bona fide driver mutations strongly propels subclonal evolution and spatial patterns of tumor growth. Citation Format: Evit John, Pooja Shukla, Anish Jain, Alexandria Lau, Tom Lesluyes, Huw Ogilvie, Maxime Tarabichi, Jason Roszik, Yinyin Yuan, Peter Van Loo, Lawrence Kwong, Yun Shin Chun. Driver mutations propel subclonal evolution and spatial patterns of tumor growth in intrahepatic cholangiocarcinoma [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 7499.
Abstract 4330: Employing synthetic mRNA therapeutic platform to restore p53 function to suppress growth of p53 mutant cancer
Authors: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Sol-Bi Shin, Soye Jeon, Aran Park, Jooyun Byun, Daejin Kim, In Young Choi
Journal: Cancer Research (2025)

Abstract TP53, a gene encoding p53, is a critical tumor suppressor gene, and its mutation serves as a major driver in various cancer types, deeply influencing tumor progression and patient prognosis. Efforts to restore wild-type p53 function have included targeting specific p53 mutants with small molecules, preventing p53 degradation through inhibition of its negative regulators, and employing adenoviral vectors to deliver wild-type p53. However, these strategies face challenges, including limited efficacy and the heterogeneity of p53 mutations. In this study, we present an optimized mRNA-based approach to restore p53 functionality, utilizing both in vitro and in vivo models of cancers with high p53 mutation frequencies. To enhance therapeutic efficacy, we optimized key elements of p53 mRNA, including the 5' and 3' untranslated regions (UTRs), the open reading frame (ORF), and Hanmi’s 5' capping reagent. Using cancer cell lines derived from lung, ovarian, pancreatic, and head and neck cancers harboring p53 mutations, we evaluated the therapeutic potential of our p53 mRNA therapy. Selectivity was assessed by examining its effects on both normal and p53 wild-type cancer cells. Our findings demonstrate that Hanmi’s p53 mRNA therapy selectively inhibits the proliferation of p53-mutant cancer cells by inducing apoptosis and cell cycle regulators such as PUMA, BTG2, and p21. Importantly, in vivo studies revealed significant tumor growth inhibition in xenograft models of lung, ovarian, and pancreatic cancers, with no notable impact on mouse body weight. Additionally, we tested the efficacy of our p53 mRNA therapy in a cancer orthotopic model, confirming its potent antitumor activity in a clinically relevant setting and demonstrating the selective efficacy against tumor. These results underscore the promise of p53 mRNA as a novel and efficient therapeutic strategy for selectively targeting p53 mutant cancers, paving the way for improved outcomes in precision oncology. Citation Format: Yong Ho Heo, Seung-Hyun Shin, Youngjin Han, Chang Gyu Lim, Innah Kim, Ji Hee Lee, Sol-Bi Shin, Soye Jeon, Aran Park, Jooyun Byun, Daejin Kim, In Young Choi. Employing synthetic mRNA therapeutic platform to restore p53 function to suppress growth of p53 mutant 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 4330.
Abstract 7507: Towards transparent and context-specific annotation of driver and passenger mutations in cancer
Authors: Madhumita Madhumita, Jon Teague, Philip A Beer, Zbyslaw Sondka
Journal: Cancer Research (2025)

Abstract Cancer arises from the accumulation of somatic genetic alterations, with only a subset acting as "drivers" that promote malignant transformation. Distinguishing between driver and passenger mutations is fundamental for both clinical and research applications, yet current in-silico variant annotation tools often fall short. Our previous evaluation of multiple algorithms revealed a concerning reliance on pre-computed, black-box models that are rarely updated and typically limited to missense mutations. These tools also lack transparency and biological context, leading to inconsistent predictions that hinder effective cancer driver identification. Building on these findings, our current study emphasizes the need for a new framework in cancer genomics. This framework should be characterized by explainable, unbiased approaches, long-term support, and the integration of recurrence data as a marker of positive selection. To address the above limitations, we leverage 20 years of manually curated COSMIC data. By systematically analysing mutation peaks or hotspots within cancer-associated genes, we uncover patterns indicative of positive selection, a hallmark of driver mutations. Our approach is enriched by integrating additional biological metrics, including dN/dS ratios, which measure selection pressure on genes, and allele frequency data from diverse human populations to account for background genetic variation. Furthermore, we incorporate gene-specific functional insights to enhance the contextual relevance of our predictions. Our integrative methodology aims to establish a robust, reproducible set of rules for annotating driver mutations, leveraging multiple layers of evidence to reduce biases and increase predictive accuracy. By prioritizing algorithmic transparency and the inclusion of biologically informed data, we lay the foundation for a more reliable classification system that adapts to emerging discoveries in cancer genomics. Ultimately, our work seeks to transform cancer mutation annotation into a reproducible and clinically actionable process, paving the way for better-targeted therapies and more precise diagnostic tools. Through this, we aspire to bridge the existing gaps in driver mutation identification and to propel cancer genomics towards its full potential in precision medicine. Citation Format: Madhumita Madhumita, Jon Teague, Philip A Beer, Zbyslaw Sondka. Towards transparent and context-specific annotation of driver and passenger mutations in 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 7507.
Abstract 6166: Identification of immunogenic cell death inducers from Komaroviquinone (KQN)-derived compounds
Authors: Maiko Matsushita, Koki Kurita, Taisei Fujinami, Himari Yamada, Yusuke Yamamoto, Yutaka Suto
Journal: Cancer Research (2025)

Abstract Background: Immunogenic Cell Death (ICD) is a type of cell death accompanied by expression of calreticulin (CRT) and release of ATP and HMGB1, which is induced by photodynamic therapies (PDT), oncolytic viruses and several chemotherapeutic drugs. ICD could enhance the therapeutic effect of other immunotherapies through maturation of dendritic cells and activation of T cells. Multiple myeloma (MM) remains incurable despite of the development of novel therapies including several immunotherapies, such as CAR-T therapy. Therefore, we tried to detect novel drugs which can induce immunogenic cell death in MM cells using a library of Komaroviquinone(KQN) - derived compounds (GTN compounds). We also investigated the mechanism of the ICD induced in MM cells. Methods: We screened 38 kinds of GTN compounds. MUM24 cell line was treated with each of GTN compounds and the cell surface expression of calreticulin (CRT) and release of ATP and HMGB1 were evaluated by FACS, ENLITEN ATP Assay System® and Western Blotting respectively. We also examined the effect of candidate drugs on differentiation of dendritic cells (DCs) by coculture of human monocyte-derived DCs with drug-treated MUM24 and detection of the expression of CD80, CD83 and HLA-DR by FACS. Production of ROS was also measured by CM-H2DCFDA assay. Finally, RNA sequence analysis was conducted using total RNA extracted from 4 MM cell lines treated with GTN057. Results: Five out of 38 GTN derivatives could induce ICD in MM cells. When DCs were co-cultured with drug-treated MUM24, increased expression of HLA-DR, CD80 and CD83 were observed with GTN025, 040, 057. Cell surface expression of CRT was not abrogated by antioxidants, despite that those compounds facilitated ROS production. Furthermore, analysis of RNA sequences revealed that ER-stress-related genes were up-regulated by GTN057. Conclusions: Our results suggest that some of GTN compounds effectively induce ICD in MM cells. Although further investigation using in vivo model is needed, those compounds might have synergistic effects when used in combination with other immunotherapies. Citation Format: Maiko Matsushita, Koki Kurita, Taisei Fujinami, Himari Yamada, Yusuke Yamamoto, Yutaka Suto. Identification of immunogenic cell death inducers from Komaroviquinone (KQN)-derived compounds [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 6166.