tbuckley/cabot-search huggingface dataset:
Abstract 1777: OST11098, an orally available and selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) with next-generation hormone agents (NHAs) resistance
Authors: Fangrui Wu, Lisheng Deng, None zhixiong Ma, Zhenyao Lu, Gabriel Deng
Journal: Cancer Research (2025)

Abstract Next-generation hormone agents (NHAs) such as abiraterone and enzalutamide have become standard treatments for castration-resistant prostate cancer (CRPC), significantly prolonging patient survival. However, resistance to NHAs inevitably develops, presenting a critical and unmet clinical challenge. Inhibition of CYP11A1 disrupts the entire biosynthesis pathway of androgens and other steroids by blocking the formation of pregnenolone. This mechanism halts the activation of the androgen receptor (AR) axis, thereby preventing further cancer progression and potentially overcoming NHAs resistance in heavily pretreated CRPC patients.In this study, we introduce OST11098, a newly identified, orally bioavailable, selective, and potent CYP11A1 inhibitor with demonstrated anti-tumor efficacy against NHA resistance. OST11098 displays favorable pharmacokinetic and safety profiles. In vitro, it effectively inhibited pregnenolone biosynthesis at low nanomolar concentrations in the H295R adrenocortical carcinoma cell line, leading to a rapid and complete blockade of all measured downstream steroid hormones. When administered orally, OST11098 showed consistent, dose-dependent pharmacokinetic/pharmacodynamic (PK/PD) correlations in adult non-castrated male mice, successfully inhibiting the biosynthesis of androgen receptor (AR) activators. In a VCaP CRPC xenograft mouse model, OST11098 demonstrated significant anti-tumor efficacy. Moreover, an engineered LNCaP CRPC xenograft mouse model with NHA resistance was successfully established and evaluated for its response to OST11098 treatment, providing compelling preclinical evidence supporting the use of CYP11A1 inhibitors as a promising strategy for managing NHA-resistance.Overall, our studies demonstrated OST11098 as a highly potent and selective CYP11A1 inhibitor with great PK properties, clean safety profiles, and significant anti-tumor activity for the treatment of CRPC. These promising preclinical results strongly support the potential of OST11098 to address unmet needs in CRPC treatment, justifying its further clinical development. Citation Format: Fangrui Wu, Lisheng Deng, zhixiong Ma, Zhenyao Lu, Gabriel Deng. OST11098, an orally available and selective Cyp11A1 inhibitor for the treatment of castration-resistant prostate cancer (CRPC) with next-generation hormone agents (NHAs) resistance [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 1777.
Abstract 5336: A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in preclinical models of PDAC
Authors: Caroline Broderick, Riccardo Mezzadra, Exequiel Sisso, Almudena Chaves-Perez, Ho Yu-Ji, Andrea Schietinger, Mallika Singh, Scott W. Lowe
Journal: Cancer Research (2025)

Abstract Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these ‘persister’ cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control. Citation Format: Caroline Broderick, Riccardo Mezzadra, Exequiel Sisso, Almudena Chaves-Perez, Ho Yu-Ji, Andrea Schietinger, Mallika Singh, Scott W. Lowe. A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in preclinical models of PDAC [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 5336.
Abstract 4875: B7-H3 (CD276) regulates the migration and infiltration of tumor-associated macrophages
Authors: A-Ram Kang, Da Hyun Yun, Eun Jung Lee, Jong Dae Ji, Serkin Park
Journal: Cancer Research (2025)

B7-H3 (CD276), a member of the B7 family of immune checkpoint proteins, is expressed on tumor cells as well as various immune cells within the tumor microenvironment (TME), including macrophages. While evidence from numerous in vitro, in vivo, and ongoing clinical studies highlights its potential as a promising therapeutic target, the function and molecular mechanisms of B7-H3 in distinct stromal cell populations within the TME remain unclear. In this study, we investigated the roles of B7-H3 in tumor-associated macrophages (TAMs) using B7-H3 knockout mice, macrophage-tumor co-culture spheroids, and in vitro experiments. B7-H3 expression was significantly upregulated during the progressive stages of bone marrow-derived macrophage (BMDM) differentiation in vitro, supporting its functional role in macrophages. For in vivo studies, we generated B7-H3 knockout mice. Immunohistochemical staining and flow cytometric analysis of B16F10 melanoma tumor tissues subcutaneously implanted in B7-H3 knockout mice revealed a significant reduction in F4/80+ TAMs compared to tumors in wild-type mice. Similarly, anti-B7-H3 antibody treatment in 4T1 breast cancer-bearing mice reduced F4/80+ TAMs compared to control IgG treatment. However, tumor growth and the number of PCNA+ proliferating tumor cells were unaffected by either knockout or antibody-dependent inhibition of B7-H3 in vivo. Subsequent in vitro studies demonstrated that migration of BMDMs from B7-H3 knockout mice was impaired in both two-dimensional scratch-wound migration assays and a three-dimensional macrophage-tumor co-culture spheroid model. Furthermore, interferon-gamma treatment significantly enhanced the migration of BMDMs from wild-type mice, an effect that was completely blocked by a pharmacologic STAT1 inhibitor (fludarabine). Interestingly, BMDMs from B7-H3 knockout mice exhibited a significantly attenuated response to both interferon-gamma and STAT1 inhibition, indicating that B7-H3-dependent macrophage migration is mediated through the interferon-gamma and STAT1 signaling pathway. Collectively, our data indicate that B7-H3 regulates the migration and infiltration of TAMs into tumor tissues via the interferon-gamma/STAT1 signaling pathway. These findings suggest that B7-H3 is a promising therapeutic target for solid tumors such as melanoma and breast cancer. Citation Format: A-Ram Kang, Da Hyun Yun, Eun Jung Lee, Jong Dae Ji, Serkin Park. B7-H3 (CD276) regulates the migration and infiltration of tumor-associated macrophages [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 4875.
Abstract 5335: A comparative study of CDK2 inhibitors
Authors: Lotte P. Watts, Lisa Nguyen, Marissa Baker, John Chionis, Ryan Vong, Advait Nagle, Stephen Dann, Sabrina L. Spencer
Journal: Cancer Research (2025)

Abstract CDK2 is a key Cyclin-Dependent Kinase that is responsible for driving cells through the cell cycle. CDK2 is both hyper-activated in a variety of cancers and is a mechanism of resistance to CDK4/6 inhibitors, making it an attractive therapeutic target. Using PF3600 and PF4091 (tagtociclib), we previously showed that upon CDK2 inhibition, cells exhibit a rapid drop in substrate phosphorylation that rebounds within several hours (‘drop-rebound’). We further showed that CDK4/6 activity compensates for inhibition of CDK2 and sustains the proliferative program by maintaining Rb hyper-phosphorylation and E2F transcription, allowing many cell types to continue cycling in drug. With the advent of numerous new CDK2 inhibitors in development and in clinical trials, we sought to compare five CDK2 inhibitors side-by-side. We first show that all five CDK2 inhibitors elicit the drop-rebound in CDK2 activity. Thus, the drop-rebound response to CDK2 inhibition is not drug-specific, but instead reflects how the cell cycle is wired for robustness. Second, we find that GTAI-664 is ten times more potent than other CDK2 inhibitors. This potency advantage paired with improved selectivity may result in greater target coverage at attainable plasma concentrations in preclinical models. In agreement, several xenograft tumor models appear to respond with better tumor growth inhibition when treated with GTAI-664 relative to PF4091. Finally, we test the combinability of CDK2 inhibitors with CDK4/6 inhibitors in vitro and in vivo. We hypothesize that durable cell-cycle arrest requires forcing Rb kinase activity below a specific threshold where the Rb-E2F positive feedback loop is broken. Our results are timely given the increasing interest in CDK2 inhibitors across a variety of cancer types. Citation Format: Lotte P. Watts, Lisa Nguyen, Marissa Baker, John Chionis, Ryan Vong, Advait Nagle, Stephen Dann, Sabrina L. Spencer. A comparative study of CDK2 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 5335.
Abstract 1956: Comparison of somatic variations between circulating tumor DNA and paired tissue in 1,111 pan-cancer patients
Authors: Meng Zhang, Yi Feng, Xue Du, Changda Qu, Meizhu Meng, Meiying Ye, Min Liang, Ziran Yang, Wenjuan Gong, Xingyu Ma, Jialiang Guo, Wenmei Li, Chenxuan Wang, Qiuxiang Ou, Sha Wang, Haimeng Tang, Shuqin Jia
Journal: Cancer Research (2025)

Abstract Circulating tumor DNA (ctDNA) offers a noninvasive method to assess tumor-specific mutations. This retrospective study investigated the concordance of genomic variations between ctDNA and tissue and its influence factors. Paired blood and tissue samples were collected from 1, 111 patients with ten tumor types and underwent sequencing of 425 genes. We evaluated the relationship between the concentration of cell-free DNA (cfDNA), sensitivity of ctDNA, mutation landscape, variant allele frequency, and various clinical parameters. The median concentration of cfDNA and overall sensitivity of ctDNA was 16.8 ng/ml and 61.5%, which correlated positively with clinical stage and tumor diameter and negatively with treatment response. The overall concordance rate of genomic alterations between ctDNA and tissue was 24.6%. The top five altered genes and pathway-based disruption signatures identified by ctDNA profiling were similar to tissue. For mutations with a normalized allele frequency less than 0.2, the proportion of ctDNA-specific mutations was higher than concordant mutations (61.5% and 9.7%). Advanced clinical stage, large tumor diameter, poor treatment response, the presence of liver metastasis, and impaired liver function lead to a high concordance rate. Patients with ctDNA-positive status, subclonal mutations, and more ctDNA-specific mutations had shorter overall survival than those with ctDNA-negative status, no subclonal mutations, and fewer ctDNA-specific mutations, respectively. In conclusion, a higher concordance rate of somatic variations between ctDNA and tissue indicated an advanced clinical stage, larger tumor size, worse treatment response, and presence of liver metastasis. Subclonal or more ctDNA-specific mutations detected were associated with poor prognosis. Citation Format: Meng Zhang, Yi Feng, Xue Du, Changda Qu, Meizhu Meng, Meiying Ye, Min Liang, Ziran Yang, Wenjuan Gong, Xingyu Ma, Jialiang Guo, Wenmei Li, Chenxuan Wang, Qiuxiang Ou, Sha Wang, Haimeng Tang, Shuqin Jia. Comparison of somatic variations between circulating tumor DNA and paired tissue in , pan-cancer patients [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 1956.
Abstract 5615: ALRN-0192519 is a potent and selective EGFR L858R mutation inhibitor that demonstrates anti-cancer activity in preclinical cancer models as monotherapy or in combination with osimertinib
Authors: Jiaqi Liang, Yezhen Zhang, Lisha Xie, Jihong Chen, Xipan Liu, Wenheng Liang, Tingru Zhou, Xiaobin Zhang, Tao Ji, David Pirovich, Xiang Zhai, Yipin Lu, Ming Yu, John Campbell, Fang Li, Yaoyu Chen, Lina Gu
Journal: Cancer Research (2025)

Epidermal growth factor receptor (EGFR) therapy with small-molecule tyrosine kinase inhibitors (TKIs) is initially effective in patients with EGFR-mutant lung cancer, but resistance to the treatment typically emerges over time. EGFR allosteric inhibitors bind to a distinct site on the EGFR protein, separate from the ATP-binding site targeted by existing EGFR TKIs, offering a potential strategy to overcome resistance associated with EGFR mutations. Here we report the development and preclinical characterization of ALRN-0192519, a novel, orally bioavailable small molecule mutant-selective allosteric EGFR inhibitor. In an enzymatic assay, ALRN-0192519 potently inhibits the activity of EGFR carrying L858R mutation with 50% inhibitory concentration (IC50) in the sub-nanomolar range. A very low hit rate is observed when ALRN-0192519 is assessed in kinome profiling, further revealing the selectivity of this compound. ALRN-0192519 exhibits single-digit nanomolar potency against the proliferation of BaF3 cells carrying different EGFR mutations and is more than 400× fold selective against BaF3 EGFR WT cells. In addition, X-ray crystal structure analysis revealed ALRN-0192519 as an EGFR allosteric binder. ALRN-0192519 led to tumor regression in multiple EGFR dependent CDX and PDX tumor models with daily oral dosing, while showing no effects on tumor growth in the EGFR WT xenograft tumor model at comparable dosing levels. When combined with osimertinib, ALRN-0192519 delayed the tumor regrowth much longer than osimertinib alone, demonstrating the potential advantage of combination therapy. Taken together, these results support that ALRN-0192519 is a promising EGFR allosteric inhibitor for treating lung cancer patients with the EGFR L858R mutation as either monotherapy or in combination with osimertinib. Citation Format: Jiaqi Liang, Yezhen Zhang, Lisha Xie, Jihong Chen, Xipan Liu, Wenheng Liang, Tingru Zhou, Xiaobin Zhang, Tao Ji, David Pirovich, Xiang Zhai, Yipin Lu, Ming Yu, John Campbell, Fang Li, Yaoyu Chen, Lina Gu. ALRN-0192519 is a potent and selective EGFR L858R mutation inhibitor that demonstrates anti-cancer activity in preclinical cancer models as monotherapy or in combination with osimertinib [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 5615.
Abstract 2071: Spatial tracking of the pre-metastatic niche in colorectal cancer
Authors: Chun Hua Hung, Chung-Ta Lee, Yu-Min Yeh, Chun-Hui Lee, Wen-Tai Liu, Meng-Ru Shen, Peng-Chan Lin
Journal: Cancer Research (2025)

Abstract Lymph node metastatic positively correlates with poor prognosis of colorectal cancer. Thus, it is urgent to uncover the molecular mechanisms and develop better prediction criteria of the metastasis. Tumor budding refers to the presence of a cluster of tumor cells at the leading edge of tumor invasion and metastasis. This cluster is composed of either a single tumor cell or multiple tumor cells. Tumor budding is commonly observed in various types of cancer, including colorectal cancer (CRC), on histopathological slides. It is recognized as an independent predictive factor for lymph node metastasis and prognosis. In this study, the NanoString GeoMx equipment was applied to establish the expression profile of cancer transcriptomic atlas (CTA) in CRC specimens. According to the morphology of CRC tissues determined by markers including pancytokaretin, CD45, and alpha-smooth muscle actin, the regions of interest (ROIs) were categorized into four groups, including normal, deep tumor, superficial tumor, and budding-enriched area. With digital spatial analysis, we compared the CTA expression among the four groups of regions of interests (ROIs). We characterized a marker panel for tumor budding and poorly-differentiated clusters in CRC, which tracks the progression of CRC from normal part to tumor invasive front. Our data show that the tumor budding-enriched gene panel is primarily composed of genes regulating cytoskeleton, extracellular matrix (ECM), and some secreted factors. Furthermore, our data also indicate that a morphology-based gene panel better delineates the invasion progression. Those results allow us tracking the evolution of signaling transduction for metastasis from the primary tumor to tumor budding and subsequent distant metastasis, facilitating the development of targeted drugs aimed at preventing metastasis in colorectal cancer. Citation Format: Chun Hua Hung, Chung-Ta Lee, Yu-Min Yeh, Chun-Hui Lee, Wen-Tai Liu, Meng-Ru Shen, Peng-Chan Lin. Spatial tracking of the pre-metastatic niche in colorectal 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 2071.
Abstract 2702: A novel inhibitor targeting DDR complex to suppress pancreatic cancer growth and progression
Authors: Chrid TP Do, Prabhakar P. Venkata, Jack Y. Prochnau, Deepika Singh, Santosh Timilsina, Panneerdoss Subbarayalu, Daisy Medina, Shahad Abdulsahib, Sajeed Khan, Manjeet K. Rao
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy, with a 5-year survival rate of 12%. The dense extracellular matrix (ECM) and cancer-associated fibroblast (CAF)-driven microenvironment contribute to tumor progression and resistance to current therapies, necessitating the development of novel treatments. This study introduces CIDD-8633, a selective small-molecule inhibitor targeting the Discoidin Domain Receptor (DDR) complex, which plays a crucial role in ECM-mediated signaling and PDAC progression. High-throughput screening identified CIDD-8633 as a potent inhibitor of DDR kinase activity. Functional assays demonstrated that CIDD-8633 significantly reduced PDAC cell proliferation, migration, and colony formation while inducing apoptosis and G1/S cell cycle arrest. RNA sequencing revealed that CIDD-8633 treatment downregulated pathways associated with DNA replication and repair, while upregulating apoptosis-related signaling pathways. In vivo, CIDD-8633 effectively suppressed tumor growth in PDAC xenograft models, reducing tumor volume and proliferation markers. Histopathological analysis showed decreased phosphorylated DDR and downstream RTKs expression, accompanied by enhanced apoptotic signaling. Furthermore, combination therapy with gemcitabine demonstrated synergistic effects, enhancing anti-tumor efficacy by reducing PDAC cell viability and metastatic potential more effectively than either agent alone. These findings position CIDD-8633 as a promising therapeutic candidate for PDAC, capable of targeting the DDR complex to disrupt tumor progression. This study highlights the potential of DDR inhibition as a novel therapeutic approach for overcoming the challenges of this aggressive cancer. Citation Format: Chrid TP Do, Prabhakar P. Venkata, Jack Y. Prochnau, Deepika Singh, Santosh Timilsina, Panneerdoss Subbarayalu, Daisy Medina, Shahad Abdulsahib, Sajeed Khan, Manjeet K. Rao. A novel inhibitor targeting DDR complex to suppress pancreatic cancer growth and progression [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 2702.
Abstract 4882: LCB39, a novel systemically deliverable STING agonist with strong preclinical activity and tolerability
Authors: Jihye Oh, Hyun Joo Bae, Ye Seul Jang, Sung Min Kim, Ho Young Song, Sook Kyung Chang, Chul-Woong Chung
Journal: Cancer Research (2025)

Abstract Direct STING activation with STING agonists is very effective in tumor control through Type I IFN responses in preclinical animal models. However, STING agonist therapeutics have faced major hurdles in clinical success due to limited bioavailability and suboptimal efficacy within tolerable doses. Here, we introduced LCB39, a novel non-CDN STING agonist small molecule currently at the preclinical development. LCB39 was intentionally generated toward the characteristics of lower cell permeability while maintaining its direct STING binding potency to improve systemic tolerability. Compared to diABZi compounds, such as GSK#3 or XMT-1616, LCB39 had about 100-fold lower THP-1 reporter activity with about 5-fold lower direct binding potency. As expected, LCB39 dramatically improved normal cell cytotoxicity to hPBMCs and HSCs. In addition, LCB39 did not induce stromal cell activation nor cell death. In contrast to the in vitro potency, LCB39 strongly promoted tumor growth suppression in a dose-dependent manner in several syngeneic mouse models. Mechanistically, LCB39 had a tumor-targeting and retention activity and promoted immune priming of tumor tissue including the activation of myeloid and lymphoid cells and induction of anti-tumor memory CD8 T cells in mice. In summary, systemically delivered LCB39 targeted tumor tissue and promoted robust anti-tumor activity with high tolerability in preclinical studies. LCB39 is a highly differentiated potent STING agonist with a safety profile, which suggested that LCB39 may have the potential to be the best-in-class STING agonist to treat solid cancers. LCB39 plans to enter first-in-human clinical study in early 2026. Citation Format: Jihye Oh, Hyun Joo Bae, Ye Seul Jang, Sung Min Kim, Ho Young Song, Sook Kyung Chang, Chul-Woong Chung. LCB39, a novel systemically deliverable STING agonist with strong preclinical activity and tolerability [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 4882.