tbuckley/cabot-search huggingface dataset:
Abstract 3213: IA-05592: A breakthrough oral PD-L1 inhibitor with exceptional anti-tumor efficacy and immune activation potential
Authors: Yeo Wool Kang, Ye Eun Kim, Garam Choi, Sol Lee, Deokmo Yang, Jongmin Sung, Kye Jung Shin, Tae-Hwe Heo, Taegwon Oh, Myung Jin Kim
Journal: Cancer Research (2025)

Abstract Programmed death-ligand 1 (PD-L1) is a key immune checkpoint protein that interacts with PD-1 on T cells to suppress anti-tumor immunity. While PD-1/PD-L1 antibodies have become a cornerstone of cancer therapy, their limitations, including poor tumor penetration, immunogenicity, immune-related risks due to long half-life, and high production costs, have driven interest in small-molecule alternatives. IA-05592, a novel orally bioavailable small-molecule PD-L1 inhibitor, was developed using structure-based drug design to disrupt PD-1/PD-L1 interactions. This compound offers advantages such as oral bioavailability, reduced costs, and a novel mechanism of action involving PD-L1 internalization and degradation. Biochemical assays using fluorescence resonance energy transfer (FRET) demonstrated IA-05592’s potency in disrupting PD-1/PD-L1 interactions, while cellular activity assays confirmed its ability to activate T cells, with an EC50 of 14 nM in NFAT reporter assays. IA-05592 reduced PD-L1 expression on tumor cells by inducing internalization and degradation, a mechanism confirmed in MC38 cells engineered to express human PD-L1 (MC38-hPD-L1). In vivo, daily oral administration of IA-05592 in a human PD-L1 knock-in MC38 syngeneic mouse model at doses of 10, 30, and 90 mg/kg resulted in dose-dependent tumor reduction. Combination studies with Fingolimod confirmed that IA-05592’s anti-tumor effects are immune-mediated. Pharmacokinetic and ADME studies in rodents revealed high oral bioavailability and systemic exposure, further supporting its therapeutic potential. These findings position IA-05592 as a promising candidate for next-generation cancer immunotherapy, offering a unique mechanism of action and robust preclinical anti-tumor efficacy comparable to anti-PD-L1 antibodies. Ongoing studies aim to advance IA-05592 as a key component of all-oral cancer immunotherapy regimens. Citation Format: Yeo Wool Kang, Ye Eun Kim, Garam Choi, Sol Lee, Deokmo Yang, Jongmin Sung, Kye Jung Shin, Tae-Hwe Heo, Taegwon Oh, Myung Jin Kim. IA-05592: A breakthrough oral PD-L1 inhibitor with exceptional anti-tumor efficacy and immune activation potential [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 3213.
Abstract 6945: Targeting Chek2-YBX1&amp;3 axis to enhance response to immune checkpoint blockade therapy in gliomas
Authors: Heba Ali, Ningjia Zhou, Li Chen, Vivekanudeep Karri, Mahalakshmi Harish, Yalu Zhou, Vasilios Kalas, Karl Habashy, Victor A. Arrieta, Kwang-Soo Kim, Si Wang, Joseph Duffy, Ragini Yeeravalli, Deanna M. Tiek, Xiao Song, Snehasis Mishra, Catalina Leechang, Atique Ahmed, Prasanna Venkatraman, Gabriel J. Rocklin, Adam M. Sonabend, Crismita Dmello
Journal: Cancer Research (2025)

Abstract Although the immunosuppressive microenvironment of glioblastoma (GBM) is well-established, the tumor-intrinsic mechanisms underlying resistance to CD8+ T cell-mediated killing remain incompletely understood. Our previous study identified Checkpoint Kinase 2 (Chek2) as the top contributor to CD8+ T cell resistance in GBM through an in vivo CRISPR screen. Therapeutic evaluation demonstrated that Chek2 inhibition, combined with PD-1/PD-L1 immune checkpoint blockade, significantly enhanced CD8+ T cell-mediated tumor killing and improved survival in preclinical glioma models. Here, we aimed to elucidate the immunosuppressive function of Chek2. Immunoprecipitation-mass spectrometry (IP-MS) and phosphoproteomics identified the transcriptional repressors and RNA-stabilizing proteins YBX1 and YBX3 as critical interactors of Chek2. Single-gene knockout and overexpression studies of Chek2, YBX1, and YBX3 in multiple glioma cell lines revealed that these proteins positively regulate each other’s expression at the protein level. RNA sequencing coupled with ChIP-seq analysis demonstrated that the Chek2-YBX1-YBX3 interaction represses the expression of inflammatory cytokines. Targeting Chek2, YBX1, and YBX3 with the small-molecule inhibitor SU056 enhanced antigen presentation and promoted CD8+ T cell proliferation. Moreover, combining SU056 with PD-1 blockade significantly improved survival in multiple glioma models. Collectively, these findings reveal an immunosuppressive mechanism mediated by the Chek2-YBX1-YBX3 axis and propose its inhibition as a promising therapeutic strategy to enhance responses to immune checkpoint blockade therapies in gliomas. Citation Format: Heba Ali, Ningjia Zhou, Li Chen, Vivekanudeep Karri, Mahalakshmi Harish, Yalu Zhou, Vasilios Kalas, Karl Habashy, Victor A. Arrieta, Kwang-Soo Kim, Si Wang, Joseph Duffy, Ragini Yeeravalli, Deanna M. Tiek, Xiao Song, Snehasis Mishra, Catalina Leechang, Atique Ahmed, Prasanna Venkatraman, Gabriel J. Rocklin, Adam M. Sonabend, Crismita Dmello. Targeting Chek2-YBX1&amp;3 axis to enhance response to immune checkpoint blockade therapy in gliomas [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 6945.
Abstract 6932: Phloroglucinol suppresses metastasis in CAV1 overexpressing cancer cells
Authors: Layla Simon, Keila Torres, Andrew F. Quest
Journal: Cancer Research (2025)

Abstract Metastasis is the process by which malignant cells dissociate from a primary tumor and disseminate to distant organs or tissues. This phenomenon presents one of the most significant challenges in oncology, as it is strongly associated with poor clinical outcomes and increased mortality rates. Caveolin-1 (CAV1) plays a crucial role in the metabolic reprogramming of cancer cells, particularly by promoting glycolysis, which enhances tumor cell migration and metastasis. This study aimed to evaluate the anti-metastatic potential of phloroglucinol, a monomer of phlorotannins from brown algae with anti-tumorigenic effects. The effects of phloroglucinol were assessed in metastatic breast (MDA-MB-231) and melanoma (B16-F10) cells expressing or not CAV1. Cell viability, migration, hexokinase activity and L-lactate levels were analyzed. C57BL/6 mice (N=5) were injected with B16-F10 cells pre-treated with phloroglucinol, and after 21 days, lung metastasis was assessed. In vitro, phloroglucinol significantly inhibited the migration of CAV1-expressing cancer cells and reduced lactate levels in the supernatants of the treated cells. Additionally, phloroglucinol suppressed CAV1-enhanced glycolysis by inhibiting hexokinase activity. In vivo, pre-treatment with phloroglucinol reduced the metastatic potential of CAV1-overexpressing cells. These findings suggest that phloroglucinol holds promise as a novel therapeutic agent for preventing cancer metastasis by targeting cancer cell metabolism. Funding: ANID FONDECYT Iniciación [11230112] (L.S.), ANID-FONDECYT-Regular [1210644] (A.F.G.Q.), Fondo de Investigación Avanzada en Áreas Prioritarias (FONDAP) Grant 15130011 and 1523A0008 (A.F.G.Q.). Citation Format: Layla Simon, Keila Torres, Andrew F. Quest. Phloroglucinol suppresses metastasis in CAV1 overexpressing 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 6932.
Abstract 6574: Plant-derived vesicles as potential therapy for neuroendocrine prostate cancer
Authors: Sharanjot Saini, Amritha Sreekumar
Journal: Cancer Research (2025)

Abstract Background: Neuroendocrine prostate cancer (NEPC) is a highly aggressive lethal variant of prostate cancer (PCa) with extremely poor survival times (&amp;lt;1 year). Clinical management of NEPC is currently challenging as there are limited treatment options for these patients. These patients are treated with platinum-based chemotherapy that is associated with toxicity and relapses. This emphasizes the need for newer, more effective therapeutic interventions against this challenging disease. The overall objective of this study was to develop an effective, non-toxic, cheap yet scalable extracellular vesicle (EV)/nanovesicle-based therapeutic intervention against NEPC. Methods: We isolated intact nanovesicles from pomegranate juice, referred to as POM-EVs, using a combination of ultracentrifugation and filtration. Vesicles were characterized by Nanosight Tracking Analyses and Electron Microscopy. Further, we examined the therapeutic potential of POM-EVs in a panel of prostate cell lines in vitro. Prostate cancer cell lines were treated with POM-EVs for 7 days followed by assessment of cellular proliferation, apoptosis, RNA analyses and Western blot analyses. To understand the mechanistic basis of POM-EV induced alterations in NCI-H660 cells, we performed next generation RNA sequencing in control vs POM-EV treated NCI-H660 cells on Illumina HiSeq platform. To examine the effect of POM-EVs in NEPC, we established LuCaP 145.1 tumors in FOX-Chase SCID mice. Once established, animals were divided into two groups: Control and Test (n=5/group). Test mice were administered POM-EVs via tail vein twice a week. Controls included xenografts treated with PBS. Tumor volumes were measured regularly. Further, studies were conducted to assess active moieties of POM-EVs with therapeutic activity in NEPC. Results: POM-EVs led to a significant reduction in viability of neuroendocrine cell lines, NCI-H660 and LASCPC-01 as assessed by MTT assay. We further performed apoptosis assay that showed that POM EV treatment led to a significant increase in apoptotic populations. POM-EV treated mice showed significant regression of LuCaP145.1 tumors. Sequencing studies identified that genes involved in ECM-receptor interaction, focal adhesion, proteoglycans in cancer and small cell lung cancer genes were significantly impacted by treatment with POM-EVs. Remarkably, POM-EVs led to significantly attenuated levels of key proneural/neuronal transcription factors. Conclusions: Systemic administration of POM-EVs can be employed as a novel treatment modality in neuroendocrine prostate cancer. Citation Format: Sharanjot Saini, Amritha Sreekumar. Plant-derived vesicles as potential therapy for neuroendocrine prostate 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 6574.
Abstract 6952: PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability
Authors: Kimberly S. Meza, Wafik S. El-Deiry, Sheldon L. Holder
Journal: Cancer Research (2025)

Abstract Renal cell carcinoma (RCC) cases are on the rise globally. RCC tumors’ acquired resistance to current RCC therapies necessitates the identification of novel biomarkers and therapeutic strategies. Oncogenic PIM1 kinase is overexpressed in human RCC tissue and cell lines and is associated with worse clinical outcomes in RCC. PIM1 is an emerging clinically relevant biomarker and target in the treatment of RCC. The overexpression of PIM kinases has been previously reported in a glioblastoma model and knockdown or pharmacological inhibition of PIM kinases promoted the increased membrane expression of TNFRSF10B/DR5. Death Receptor 5 (DR5) is the specific receptor to TRAIL, a cancer-selective apoptosis-inducing ligand. A relationship between PIM kinases and regulation of DR5 expression for TRAIL-induced apoptosis is not yet described for RCC. Here we identify a potential link between PIM kinases' involvement in DR5 regulation and TRAIL apoptosis in RCC. RCC and nonmalignant renal epithelial cells were treated with PIM inhibitors (SGI-1776, TP-3654) or vehicle control for 24 hours and then evaluated for membrane DR5 levels via flow cytometry. Low doses (5µM) of PIM inhibitors were sufficient to induce the increased mean membrane expression of DR5 in 786-O cells by more than eleven fold (3.03% control vs 36.07% treated). To investigate synergism between PIM inhibitors and recombinant human TRAIL (rhTRAIL), RCC cell lines were treated with increasing concentrations of SGI-1776 or TP-3654 and rhTRAIL (TLY012) for 24 hours and assessed for viability via Cell Titer Glo assay. Combinations of PIM inhibitors and rhTRAIL reveal that PIM inhibition sensitized RCC cells to TRAIL induced apoptosis. These results reveal novel therapeutic strategies for the treatment of RCC, highlighting PIM kinases as targets to potentiate TRAIL induced apoptosis. Current studies are ongoing to understand the mechanism of PIM kinase involvement in DR5 regulation and sensitivity to TRAIL in RCC. Citation Format: Kimberly S. Meza, Wafik S. El-Deiry, Sheldon L. Holder. PIM inhibition increases membrane expression of TNFRSF10B(DR5) and combination with recombinant human TRAIL synergizes to reduce renal cell carcinoma cell viability [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 6952.
Abstract 2164: BAL0891 as a dual kinase inhibitor inducing anti-tumor immunity: A promising partner for immune checkpoint inhibitors
Authors: MinKyung Kang, Sanghee Yoo, Seunghyun Ma
Journal: Cancer Research (2025)

Abstract BAL0891 is a first-in-class dual inhibitor targeting threonine tyrosine kinase (TTK) and polo-like kinase 1 (PLK1). These kinases collaborate to activate the mitotic spindle assembly checkpoint (SAC) at the kinetochore, ensuring proper chromosome alignment and segregation prior to mitotic exit. Dual inhibition of TTK and PLK1 by BAL0891 rapidly disrupts the SAC, leaving tumor cells insufficient time for proper chromosome segregation, thereby exerting potent anti-cancer effects. Recent studies have underscored the potential of cell cycle inhibitors, including TTK and PLK1 inhibitors, as therapeutic partners for immune checkpoint inhibitors in various cancers. Given these findings, we investigated whether BAL0891 induces anti-cancer immune responses and evaluated its potential for combination therapy with immune checkpoint inhibitors.Our results demonstrate that BAL0891 induces aberrant cell cycle progression in cancer cells, leading to elevated levels of cytosolic DNA, a well-known activator of the cGAS/STING signaling pathway. Activation of this pathway by BAL0891 promotes cellular senescence and enhances anti-tumor immunity through the secretion of pro-inflammatory cytokines and chemokines. Notably, BAL0891 treatment increases pro-inflammatory factors such as IFNβ1, CXCL10, and CXCL11. Among these, IFNβ1 plays a pivotal role in upregulating PD-L1 expression on cancer cells, potentially enhancing the efficacy of immune checkpoint inhibitors like anti-PD-1/PD-L1 agents. Furthermore, CXCL10 and CXCL11 contribute to recruiting immune cells to the tumor microenvironment, further amplifying immune responses. In an in vivo syngeneic mouse model, BAL0891 treatment increased the presence of CD4+ T cells, CD11c+ dendritic cells (DCs), and NK1.1+ NK/NKT cells, while reducing immunosuppressive populations such as regulatory T cells (CD25+ FoxP3+ CD4+) and myeloid-derived suppressor cells (Gr-1+ CD11b+) in tumors and tumor-draining lymph nodes. These results demonstrate BAL0891’s potential to reshape the tumor microenvironment in favor of anti-tumor immunity.This study highlights the potential of BAL0891 as a combination partner for immune checkpoint inhibitors in cancer therapy. By dual inhibition of TTK and PLK1, BAL0891 not only exerts potent anti-cancer activity but also enhances anti-tumor immunity through activation of the cGAS/STING pathway and modulation of the tumor microenvironment. These results support further investigation of BAL0891 in preclinical and clinical studies, particularly in combination immunotherapy strategies. Citation Format: MinKyung Kang, Sanghee Yoo, Seunghyun Ma. BAL0891 as a dual kinase inhibitor inducing anti-tumor immunity: A promising partner for immune checkpoint inhibitors [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 2164.
Abstract 5455: TAVO605, a novel CD318 (CDCP1) ADC, for the treatment of solid cancers that are non-responding or resistant to Enhertu treatment
Authors: Guangmao Mu, Fulai Zhou, Honglei Bi, Zhengxia Zha, Sheng Huang, Ying Jin, Mingcan Yu, Chao Han, Mark Chiu, Di Zhang
Journal: Cancer Research (2025)

Background: CD318, also known as Cub Domain Containing Protein 1 (CDCP1), is a single span transmembrane receptor containing three Cub domains with low level expression in healthy epithelial tissues. The CD318 expression is significantly upregulated in response to RAS transformation in several major types of solid tumors, including breast, lung, pancreatic, colorectal, bladder and prostate cancers. CD318 is an important mediator of aberrant cancer-associated cascades critical for survival, growth, metastasis, and treatment resistance of tumor. The elevated expression of CD318 is associated with poor prognosis and overall survival of cancer patients. Methods and Results: We discovered several anti-CD318 antibodies with high binding affinities and prepared ADC conjugates with MMAE/MMAF. The CD318-ADC showed potent cytotoxicity to multiple cancer cell lines in in vitro cytotoxicity assays. The cytotoxicity activities correlated with the cell surface receptor densities and the binding affinities of CD318 antibodies. In multiple CDX and PDX solid tumor xenograft models involving pancreatic, colon, triple negative breast and non-small cell lung cancer, CD318-MMAE (DAR=4) showed potent tumor growth inhibition activities with efficacies comparable to or better than Enhertu (DS-8201). By employing an anti-CD318 antibody with cross-reactivity to murine CD318, we confirmed that the CD318-ADC with high drug dosing level was tolerable in a mouse toxicity study. Conclusions: By targeting a novel tumor associated antigen CD318 (CDCP1) with high expression in multiple major solid tumors, our lead CD318-ADC molecule (TAVO605) showed potent cytotoxicity to multiple tumor cell lines as well as in CDX and PDX solid tumor xenograft models. CD318-ADC was tolerable and will be further evaluated in preclinical monkey toxicity studies. Our data supported the further development of TAVO605 as a potent therapy for solid tumors non-responding or resistant to current available treatments, e.g., by Enhertu, especially in tumors with low or no HER2 expression such as triple negative breast cancers. This antibody can also be used in other modalities to control solid tumors. Citation Format: Guangmao Mu, Fulai Zhou, Honglei Bi, Zhengxia Zha, Sheng Huang, Ying Jin, Mingcan Yu, Chao Han, Mark Chiu, Di Zhang. TAVO605, a novel CD318 (CDCP1) ADC, for the treatment of solid cancers that are non-responding or resistant to Enhertu treatment [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 5455.
Abstract 2148: HDAC6 inhibitors modulate macrophage functional activity in the post-radiotherapy tumor microenvironment
Authors: Xintang Li, Satish Noonepalle, Karen Tan, Sonia Sebaoui, Manasa Suresh, Nithya Gajendran, Marie Durr, David Quiceno-Torres, Bryan Weselman, Vidhi Sharma, Abishek Sehgal, Scott Grindrod, Anatoly Dritschilo, Alejandro Villagra
Journal: Cancer Research (2025)

Abstract Introduction: In recent decades, radiation therapy (RT) has been a significant therapeutic tool for treating multiple cancer types. Primarily, radiation-induced immunogenic tumor cell death re-modulates the tumor microenvironment (TME) with the potential to enhance the efficacy of immunotherapies. Tumor-associated macrophages (TAMs) play a critical role in the anti-tumor innate immune response. However, post-RT, the phenotype of TAMs can easily convert from the pro-inflammatory M1-like to the immunosuppressive and tumor-promoting M2-like due to their plasticity. M2-like macrophages cause relapse and metastasis of the tumor. Therefore, reprogramming TAMs is critical. Our lab has reported that targeting Histone Deacetylase 6 (HDAC6) in macrophages can disrupt their phenotype shifting from M1-like to M2-like in TME. Methods: We demonstrated the suppressive effect of HDAC6 inhibitors (HDAC6i) on M2-like macrophage phenotype markers by flow cytometry and qRT-PCR. Furthermore, in-vitro assays were performed, including trans-well migration assays, phagocytosis assays, and in-vivo syngeneic tumor models against different tumor cell types, including SM1 murine melanoma, 4T1 breast cancer, and TRAMP-C2 prostate cancer. Results: The trans-well-based migration assay indicated an increment in M2-like macrophage migration to irradiated cancer cells compared to M1-like macrophages. This increment was suppressed when culturing M2 macrophages with HDAC6i. Furthermore, the co-culture assay between macrophages and cancer cells indicated that M1 macrophages showed a higher phagocytosis rate when co-culture with irradiated cells and HDAC6i treatment increased tumor cell phagocytosis. Meanwhile, an in-vivo study based on the 4T1 and SM1 tumor models model suggested that RT combined with HDAC6i treatment has better efficacy than the monotherapy treatment arms due to increased M1/M2 macrophage ratio. These results demonstrate that targeting macrophages with HDAC6is could enhance the overall therapeutic outcome of radiation therapy. Citation Format: Xintang Li, Satish Noonepalle, Karen Tan, Sonia Sebaoui, Manasa Suresh, Nithya Gajendran, Marie Durr, David Quiceno-Torres, Bryan Weselman, Vidhi Sharma, Abishek Sehgal, Scott Grindrod, Anatoly Dritschilo, Alejandro Villagra. HDAC6 inhibitors modulate macrophage functional activity in the post-radiotherapy tumor microenvironment [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 2148.