tbuckley/cabot-search huggingface dataset:
Abstract LB437: LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants
Authors: Ming Li, Ruipeng Zhang, Meijuan Hu, Junyan Chen, Xiaofen Lin, Justin Gu
Journal: Cancer Research (2025)

Abstract PIK3CA is one of the most frequently mutated oncogenes - found in 15-30% of all cancers, particularly prevalent in patients with breast, colorectal, endometrial, and various other cancers. Three hotspot mutations on the p110α subunit of PI3Ka (H1047R in the kinase domain and E545K, E542K in the helical domain) are recognized activating mutations accounting for more than 1/3 of all PI3Ka mutations. In response to this, pan-mutant selective PI3Ka inhibitors including RLY-2608 and STX-478 are being developed in clinical trials for cancer patients with PIK3CA mutations. By sparing wild type PI3Ka, these inhibitors demonstrated improved therapeutic window compared with orthosteric PI3Ka inhibitors and maintained good clinical responses for the kinase domain mutants. However, due to relatively weak potency against PIK3CA helical domain mutants, these two inhibitors have less favorable clinical responses in patients harboring this type of mutations. Therefore, there is a pressing need to develop novel pan-mutant selective PI3Ka inhibitors with improved activity against helical domain mutants to expand treatment options for a broader patient population.LAE118 is a promising novel allosteric pan-mutant selective PI3Ka inhibitor demonstrating excellent in vitro anti-proliferation activities against both kinase and helical domain mutant cells. Preclinical studies revealed that LAE118 effectively inhibits tumor growth in Xenograft models, including GP2D (H1047L), HCC1954 (H1047R), MCF7 (E545K) and MDA-MB-361 (E545K) at doses that are much lower than other pan-mutant selective PI3Ka inhibitors. Additionally, LAE118 exhibits strong efficacy in patient-derived xenograft (PDX) models. Importantly, LAE118 has clean profiles in the kinase panel and in the secondary pharmacology panel, and balanced PK profiles with low clearance and good oral bioavailability across animal species. Human PK projection indicates LAE118 has the potential to achieve continuous inhibition of pAKT in clinic without causing hyperglycemia. LAE118 is currently in IND enabling stage, positioning it as a promising candidate for the treatment of cancers with PIK3CA mutations. Citation Format: Ming Li, Ruipeng Zhang, Meijuan Hu, Junyan Chen, Xiaofen Lin, Justin Gu. LAE118, a pan mutant-selective PI3Ka inhibitor with superb activity against both the kinase domain and helical domain mutants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB437.
Abstract LB372: Real-world evidence from AACR Project Genie: Overall survival with combination chemotherapy plus endocrine and targeted therapy in HER2-negative, ER-positive metastatic breast cancer
Authors: Alexandrina Balanean, Samuel Baird, Brooke Leon, Parisa Asgarisabet, Camryn Craig, Yolaine Smith, Harlen Hays, Bruce Feinberg, Shahnjayla Connors
Journal: Cancer Research (2025)

Abstract Introduction: In HER2-negative (HER2-), estrogen receptor-positive (ER+), stage III/IV metastatic breast cancer (mBC), overall survival (OS) and time to progression depend on treatment response as well as patient factors, molecular profiles, and prior therapy. We questioned whether combination chemotherapy + fulvestrant + aromatase inhibitor (AI) + targeted therapy improves OS and delays progression versus chemotherapy + endocrine therapy excluding fulvestrant and AI ± targeted therapy. Methods: Using AACR Project Genie, we compared OS (median, 12-, 24-, 36-, 48-, 60-, 72-month landmark) between women treated with chemotherapy + fulvestrant + AI + combination cyclin-dependent kinase 4/6 (CDK 4/6), mammalian target of rapamycin (mTOR), or AKT inhibitor (Group A) versus chemotherapy + combination endocrine therapy excluding fulvestrant + AI with or without targeted therapy with AKT, CDK 4/6, or mTOR inhibitor (Group B). Adjusting for confounding, we used inverse propensity score weighting and Cox proportional hazards to estimate hazard ratios (HRs) with Kaplan-Meier (KM) methods in R v4.4.1. We also compared between-group ages at initial and metastatic diagnosis as time-to-event (TTE) end points. Results: Among 111 patients, adjusted weighted median OS was 89.87 (67.43-not estimable [NE]) months for Group A versus 52.53 (43.06-NE) months for Group B (HR 0.42, 95% CI 0.24-0.75; P&amp;lt;.001). A numeric OS advantage emerged at 24 months in Group A, reached significance at 48 months, and remained at 72 months. Mean TTE was 3 years in Group A versus 1.6 years in Group B (HR 0.60, 95% CI 0.42-0.87; P=.005). Discussion: In HER2-, ER+, late-stage mBC, we found statistically significantly delayed TTE and a mean 58% OS advantage with chemotherapy plus fulvestrant + AI + targeted therapy over chemotherapy plus endocrine-based regimens excluding fulvestrant and AI. As neither OS nor progression can be attributed to treatment alone, future studies should evaluate these regimens long-term in the context of contributing factors and explore the potential for more personalized care. Citation Format: Alexandrina Balanean, Samuel Baird, Brooke Leon, Parisa Asgarisabet, Camryn Craig, Yolaine Smith, Harlen Hays, Bruce Feinberg, Shahnjayla Connors. Real-world evidence from AACR Project Genie: Overall survival with combination chemotherapy plus endocrine and targeted therapy in HER2-negative, ER-positive metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB372.
Abstract SY26-02: Keeping Mitochondria Happy: How peroxisomes regulate mitochondria oxidative stress
Authors: Peter Kijun Kim
Journal: Cancer Research (2025)

Abstract Cancer cells undergo complex metabolic reprogramming, allowing them to survive and proliferate in their specific niche. Mitochondria play a key role in metabolism remodeling, and these changes can often lead to mitochondrial stress. However, the cancer cells must keep mitochondria “happy” due to their role in cellular death pathways. Mitochondria are the major producer of reactive oxygen species (ROS). Although mitochondrial ROS is required for cell signaling, excessive ROS production can activate various cell death pathways. Thus, understanding how cancer cells regulate mitochondrial ROS may provide insights into new therapeutic targets for cancer treatments. Yet, our understanding of how cells regulate mitochondria redox homeostasis is limited. Peroxisomes possess one of the most potent antioxidants, Catalase, and it has long been believed to regulate cellular redox homeostasis by scavenging cellular ROS. Interestingly, genetic mutations in peroxisomal genes called Zellweger Spectrum Disorders (ZSD) result in the loss of peroxisomal structures but not Catalase. However, in both patient tissues and animal models of ZSD, an accumulation of oxidatively damaged mitochondria was observed in almost all cell types. This talk will present published and unpublished work addressing how peroxisomes regulate mitochondria redox homeostasis. Our work suggests that peroxisomes directly interact with respiring mitochondria to regulate mitochondrial redox homeostasis. In the end, we will present a model by which peroxisomes regulate mitochondria health during conditions of cellular stress and its potential as a therapeutic target to induce cell death. Citation Format: Peter Kijun Kim. Keeping Mitochondria Happy: How peroxisomes regulate mitochondria oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY26-02.
Abstract LB261: GPR171, a prognostic marker of improved survival in cervix cancer: A Deep South Consortium in Oncology (DSCO) Project
Authors: Tanvi Joshi, Elisabeth Murphy, Sagar Chokshi, Kevin J. Lee, Sharon Wu, Joanne Xiu, Matthew J. Oberley, Britt K. Erickson, Charles A. Leath, Symmes Johnson, Bunja Rungruang, Rodney P. Rocconi, Nathaniel Jones, Jennifer Scalici
Journal: Cancer Research (2025)

Abstract Background: Recent evidence shows that G-protein-coupled receptor-171 (GPR171) may be an important T-cell checkpoint in tumor immunity. The role of GPR171 in cervical cancer has not been studied. Here, we sought to investigate the association of GPR171 with other tumor immune markers and DNA damage in cervical cancer and its impact on patient survival. Methods: 3,371 samples were sequenced for RNA (NovaSeq, WTS) (Caris Life Sciences, Phoenix, AZ). GPR171, CD274, CD96 and TIGIT were stratified by top 25% (-H) and bottom 75% (-L). T-cell inflamed gene expression profile (GEP) signature was calculated by Ayers 2017. Real-world overall survival (rwOS) information was obtained from insurance claims and calculated from tissue collection or first cycle of pembrolizumab to last contact for molecularly defined cohorts. DNA damage was evaluated by repair-assisted damage-detection assay (RADD). Hazard ratio (HR) was calculated by Cox proportional hazards model and p-values were calculated by log-rank test. Results: GPR171-H was associated with longer rwOS compared to GPR171-L (+9.3 mo, HR=0.73, CI 0.652 - 0.819; p&amp;lt;0.001). This was independent of histological subtype as well as HPV status. GPR171 expression was positively correlated with markers of tumor immunity PD-L1, CD96, TIGIT expression and T-cell inflamed GEP. High expression of GPR171, TIGIT and CD96 showed improved rwOS and post-pembrolizumab survival (+18.9-mo, HR: 0.56, CI 0.478 - 0.651; p&amp;lt;0.001; +7.2-mo, HR: 0.683, CI 0.518 - 0.901; p=0.007). High expression of all targets also correlated with the presence of high DNA damage. Conclusions: GPR171-H was associated with improved survival, increased expression of markers of tumor immunity and DNA damage. Our data elucidates its potential role in immune cell infiltration and inflammation within the tumor microenvironment. This study shows the potential of GPR171 as a novel prognostic marker for survival in cervical cancer. Citation Format: Tanvi Joshi, Elisabeth Murphy, Sagar Chokshi, Kevin J. Lee, Sharon Wu, Joanne Xiu, Matthew J. Oberley, Britt K. Erickson, Charles A. Leath, Symmes Johnson, Bunja Rungruang, Rodney P. Rocconi, Nathaniel Jones, Jennifer Scalici. GPR171, a prognostic marker of improved survival in cervix cancer: A Deep South Consortium in Oncology (DSCO) Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB261.
Abstract LB445: Extrinsic induction of apoptosis and tumor suppression via the p53- Reprimo-Hippo-YAP/TAZ-p73 pathway
Authors: Rieko Ohki
Journal: Cancer Research (2025)

Abstract The most commonly mutated gene in human cancer is the p53 tumor suppressor gene, which plays a pivotal role in tumor suppression. We have characterized and reported the molecular function of several novel p53 target genes, including Noxa, Reprimo, AEN, FUCA1, IER5 and PHLDA3 (Science, 2000, Cell, 2009, PNAS, 2014, etc). Reprimo is a p53 target gene known to be involved in tumor suppression, but its molecular function has remained elusive. Here we report the Reprimo protein is secreted and extrinsically induces apoptosis in recipient cells. We further identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo induces apoptosis through the Hippo-YAP/TAZ-p73 axis by transactivating pro-apoptotic p73 target genes. In vivo analyses further support the tumor suppressive effects of secreted Reprimo. These findings identify p53-Reprimo-Hippo-YAP/TAZ-p73 as a novel, extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Citation Format: Rieko Ohki. Extrinsic induction of apoptosis and tumor suppression via the p53- Reprimo-Hippo-YAP/TAZ-p73 pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB445.
Abstract SY47-02: Metabolic interactions driving metastasis growth
Authors: Sarah-Maria Fendt
Journal: Cancer Research (2025)

Abstract Metastasis formation is the leading cause of death in cancer patients. We find that metabolic rewiring is a liability of metastasizing cancer cells. For example, we discovered that extracellular remodeling of the metastatic niche, a process essential to metastasis formation, requires a transcriptional-independent regulation via the metabolites. Moreover, we provide knowledge on intratumor heterogeneity of metabolism and its role in pre-metastatic niche and metastasis formation. Thus, we study the metabolism of metastasizing cancer cells with the goal to define novel therapeutic strategies. Citation Format: Sarah-Maria Fendt. Metabolic interactions driving metastasis growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY47-02.
Abstract LB427: The MTA-cooperative PRMT5 inhibitor ABSK131 exhibits potent activity and broad synergistic potential in MTAP-deleted cancer models
Authors: Bin Shen, Qianqian Chen, Cong Li, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen, Nannan Zhang
Journal: Cancer Research (2025)

Abstract Background: Approximately 15% of all cancers harbor homozygous MTAP deletions, which are associated with poor prognoses. MTAP loss leads to the accumulation of 5′-methylthioadenosine (MTA), a competitive inhibitor of S-adenosylmethionine (SAM) binding to PRMT5. This has established MTA-cooperative PRMT5 as a synthetic lethal target in MTAP-deleted cancers. Despite advancements in selective PRMT5*MTA inhibitors, there remains a need for improvements in potency, selectivity, and brain penetration. ABSK131, developed by Abbisko, demonstrates a potential best-in-class profile in these aspects. Here, we evaluate the preclinical efficacy of ABSK131 in cancer cell lines of interest and its synergistic effects in combination with other therapeutic agents. Method: The anti-proliferative activity of ABSK131 was assessed using the CellTiter-Glo® assay in a panel of lung, pancreatic, and breast cancer cell lines. Combination studies were conducted to evaluate the synergy of ABSK131 with various therapeutic agents, including inhibitors targeting KRAS, MAT2A, PARP, and others, in both in vitro and in vivo settings. Results: Lung and pancreatic cancer cell lines with homozygous MTAP deletions exhibited high sensitivity to ABSK131, whereas breast cancer cell lines showed lower dependency. ABSK131 demonstrated broad synergistic activity when combined with the indicated agents in cellular proliferation assays. In mouse models, ABSK131 significantly enhanced anti-tumor efficacy when combined with other therapeutic agents, such as the MAT2A inhibitor IDE397. Conclusion: ABSK131 exhibits strong anti-tumor activity in MTAP-deleted lung and pancreatic cancer models and synergizes effectively with multiple therapeutic agents. These findings support the continued clinical development of ABSK131 as both a monotherapy and in combination regimens for MTAP-deleted cancers. Citation Format: Bin Shen, Qianqian Chen, Cong Li, Jie Wang, Jie Zhang, Manqi Liu, Zhui Chen, Nannan Zhang. The MTA-cooperative PRMT5 inhibitor ABSK131 exhibits potent activity and broad synergistic potential in MTAP-deleted cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB427.
Abstract LB439: HP568, a highly potent and orally bioavailable ER PROTAC for breast cancer treatment, currently undergoing phase 1/2 clinical studies
Authors: Jing Li, Zhilin Tu, Luchan Deng, Zhipeng Quan, Wu Du, Xinghai Li
Journal: Cancer Research (2025)

Abstract HP568, an estrogen receptor (ER)-targeting proteolysis-targeting chimera (PROTAC) degraders that enhances the interaction between ER and an E3 ligase complex, resulting in ubiquitylation and subsequent proteasome mediated degradation. This compound exhibits high potency against both wild-type (half-maximal degradation concentration (DC50) &amp;lt; 1 nM) and ER mutants (DC50s &amp;lt; 5 nM), selectively inhibiting the proliferation of ER-dependent breast cancer cell lines in vitro. With an excellent ADME profile, it outperforms current ER-targeting PROTACs. In direct efficacy comparisons with ARV-471, HP568 shows superior, dose-dependent tumor growth inhibition (TGI) of 90%-123%, well correlated with drug exposure and pharmacodynamic biomarkers. Importantly, in models resistant to fulvestrant, including MCF-7 ERα D538G and Y537S cell-derived CDX mice, it demonstrates significant dose-dependent TGI (29%-115%) while maintaining favorable safety profiles. Moreover, HP568 demonstrates synergistic effects when combined with a CDK4/6 inhibitor. Secondary pharmacology and animal toxicity studies support its excellent safety and tolerability, together with the pharmacodynamic data, positioning it as a potential best-in-class ER-targeting degrader. The IND applications for HP568 have been approved by the China National Medical Products Administration and the U.S. FDA. An ongoing Phase 1/2 study (CTR20244203, NCT06757335) is currently being conducted in China for patients with ER+/HER2- advanced breast cancer. The Phase 1 dose escalation part of the study is assessing safety, pharmacokinetics, pharmacodynamics, preliminary antitumor activity, and potential efficacy biomarkers. The Phase 2 expansion will evaluate HP568 both as a monotherapy and in combination with a CDK4/6 inhibitor.HP568 structure will not be disclosed. Citation Format: Jing Li, Zhilin Tu, Luchan Deng, Zhipeng Quan, Wu Du, Xinghai Li. HP568, a highly potent and orally bioavailable ER PROTAC for breast cancer treatment, currently undergoing phase 1/2 clinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB439.
Abstract LB449: InTraSeq unveils transcriptomic and proteomic landscapes of Th17 differentiation
Authors: Majd Ariss
Journal: Cancer Research (2025)

Abstract Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cellular heterogeneity. However, scRNA-seq primarily focuses on gene expression, limiting our ability to fully characterize cellular states and their underlying regulatory mechanisms. Here, we present InTraSeq, a novel multimodal assay that enables simultaneous measurement of mRNA, surface markers, cytoplasmic proteins, and nuclear proteins within individual cells. InTraSeq utilizes oligo-barcoded antibodies to profile protein expression in conjunction with scRNA-seq. We demonstrate the application of InTraSeq to study Th17 cell differentiation, revealing novel insights into the dynamics of this complex process. InTraSeq provides a powerful tool for investigating cellular heterogeneity and regulatory mechanisms, enabling a more comprehensive understanding of cellular function in health and disease. Citation Format: Majd Ariss. InTraSeq unveils transcriptomic and proteomic landscapes of Th17 differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB449.
Abstract LB362: Optimizing non-viral genome editing workflow for primary activated T cells with advanced electroporation technology
Authors: Shahan Molla, Lauren Gentles, Bindhu Hosuru, Namritha Ravinder, Arseny Smirnov
Journal: Cancer Research (2025)

Abstract CAR-T therapy has shown remarkable success in treating hematologic cancers such as leukemia and lymphoma. The Neon™ NxT Electroporation System with 8-Channel Pipette is a powerful tool for streamlined optimization of electroporation programs and other electroporation conditions for primary cells and cell lines. Here, we showcase the system's performance in efficiently optimizing CRISPR/Cas9 based non-viral genome editing of primary activated T cells.Using the Neon™ NxT Electroporation System with 8-Channel Pipette, we generate CAR-T cells by delivering CD19 donor DNA, a TRAC gRNA, and CTS™ HiFi™ Cas9 to activated T cells. We measure editing efficiency as well as T cell viability and phenotype using flow cytometry through 10 days post-T cell isolation.First, we demonstrate the capacity to simultaneously test multiple electroporation conditions, significantly reducing the time required for optimization experiments. Through systematic screening of voltage, pulse duration, and pulse number, we optimize the delivery of CRISPR/Cas9 RNP based gene editing while maintaining high cell viability. We show that this system is easily adapted to DoE analysis.Furthermore, we present data on the evaluation of electroporation buffers. By comparing the performance of Genome Editing, T, and R buffers, we demonstrate that Genome Editing Buffer is the most effective buffer for CAR-T cell editing across multiple donors, resulting in up to 99% TCR knockout with 84% of those CAR positive 10 days post-isolation. Our results highlight the impact of buffer components on transfection efficiency and cell viability.Importantly, we demonstrate the clinical relevance of our findings by culturing the edited T cells in a 96-well plate format out to 10 days post-isolation and show that these results are scalable to the larger Xenon™ Electroporation System. Throughout the culture process, we measured CD4 and CD8 markers as well as markers of T cell central memory. This not only enabled determination of how the electroporation parameters impact T cell editing, but also the effect on the cellular phenotypes. This analysis provides valuable insights for developing customer-relevant protocols that result in defined cell populations.The Neon™ NxT Electroporation System enables rapid optimization of electroporation parameters for editing of activated T cell cultures and is scalable to larger manufacturing systems. Citation Format: Shahan Molla, Lauren Gentles, Bindhu Hosuru, Namritha Ravinder, Arseny Smirnov. Optimizing non-viral genome editing workflow for primary activated T cells with advanced electroporation technology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB362.