tbuckley/cabot-search huggingface dataset:
Abstract LB017: Preclinical validation of HOXB13 as a therapeutic target in prostate cancer
Authors: Meera Shah, Tannu Suwal, Menaka Biala, Lisa Deaton, Cynthia Cienfuego, Art Nasamrans, Jose Juarez, Hedy Chan, Ryan Sullivan, Jisoo Park, Ansgar Brook, Andrew Schumacher, Jun Liu, Jake Haling
Journal: Cancer Research (2025)

Abstract HOXB13 is a lineage-dependent transcription factor involved in the growth of androgen-independent prostate cancer cells. It promotes cell proliferation in low-androgen environments by activating E2F signaling and inhibiting the expression of the p21 tumor suppressor. Its expression is restricted to prostate cancer and largely absent from normal tissue making it an intriguing oncology target. Furthermore, it is reported that HOXB13 is a regulator of the androgen receptor (AR), and the HOXB13 ChIP-seq signature overlaps with those of full-length AR and the AR splice variant lacking the AR ligand binding domain known as AR-V7. Thus, HOXB13 represents an alternative target in AR amplified and/or ARV7 prostate cancer and could combine well with existing or emerging therapies targeting AR. Here we describe both in vitro and in vivo experiments that further validate HOXB13 as a promising target in prostate cancer. Our work demonstrates that genetic knockdown of HOXB13 exhibits similar anti-proliferative activity to knockdown of AR across multiple prostate cancer cell lines. Furthermore, dox-induced knockdown of HOXB13 in the 22RV1 CDX model results in tumor stasis. These data suggest that HOXB13 can play a significant role in prostate cancer progression. Interestingly, HOXB13 is also expressed in AR negative (AR-) prostate tumors as well. Genetic knockdown of HOXB13 in the AR- PC3 cell line results in loss of cell viability, implying that HOXB13 also possesses an AR independent effect. To further elucidate the downstream targets affected by HOXB13, we utilized RNAseq following genetic knockdown of HOXB13 or AR in several prostate cancer cell lines. Our analysis reveals that loss of HOXB13 yields deeper downregulation of cell cycle pathway genes compared to AR. This suggests that cell cycle downregulation could be a key mechanism by which loss of HOXB13 exerts its antitumor effect in AR+ and AR- prostate cancer. Overall, this study is the first to our knowledge where a head-to-head comparison has been made between AR and HOXB13 across multiple cell line models. With limited treatment options available for prostate cancer patients, this finding opens the possibility of targeting HOXB13 as a new therapeutic option. Citation Format: Meera Shah, Tannu Suwal, Menaka Biala, Lisa Deaton, Cynthia Cienfuego, Art Nasamrans, Jose Juarez, Hedy Chan, Ryan Sullivan, Jisoo Park, Ansgar Brook, Andrew Schumacher, Jun Liu, Jake Haling. Preclinical validation of HOXB13 as a therapeutic target in prostate 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 LB017.
Abstract LB388: Innate immunity-independent roles of 2'3'-cGAMP in tumor metastasis control
Authors: Pengda Liu, Yu Deng
Journal: Cancer Research (2025)

Abstract c-di-GAMP was first identified in bacteria to promote colonization, while mammalian 2’3’-cGAMP is synthesized by cGAS to activate STING for innate immune stimulation. However, 2’3’-cGAMP function beyond innate immunity remains elusive. Here, we report 2’3’-cGAMP promotes cell migration independent of innate immunity. 2’3’-cGAMP interactome analysis identifies the small GTPase Rab18 as a 2’3’-cGAMP binding partner and effector in cell migration control. Mechanistically, 2’3’-cGAMP binds Rab18 to facilitate GTP loading and subsequent Rab18 activation, which further promotes FosB transcription in facilitating cell migration. Induced synthesis of endogenous 2’3’-cGAMP by intra-breast tumor bacterium S. aureus infection or low-dose doxorubicin treatment facilitates cell migration depending on the cGAS/cGAMP/Rab18/FosB signaling. Interestingly, we find lovastatin induces Rab18 deprenylation that abolishes 2’3’-cGAMP recognition therefore suppressing cell migration. Together, our study reveals a novel 2’3’-cGAMP function in cell migration control via the 2’3’-cGAMP/Rab18/FosB signaling that provides new insights into clinical applications of 2’3’-cGAMP. Citation Format: Pengda Liu, Yu Deng. Innate immunity-independent roles of 2'3'-cGAMP in tumor metastasis control [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 LB388.
Abstract LB447: Real-time visualization and quantitative analysis of mitochondrial fission and fusion using label-free 3D holotomography imaging
Authors: Sumin Lee, Hoyeon Lee, Jaehyeok Lee, Minju Kim, Hye-Jin Kim, YongKeun Park
Journal: Cancer Research (2025)

Abstract The balance between mitochondrial fission and fusion is essential for cellular homeostasis, with imbalances implicated in numerous diseases, making these dynamics essential biomarkers. However, morphological analysis of mitochondria using fluorescence and electron microscopy is limited by phototoxicity, photobleaching, and an inability to capture live cell dynamics. This study utilizes Holotomography (HT) imaging with the HT-X1 system for non-invasive, real-time, and 3D analysis of mitochondrial morphology without the need for fluorescent staining. We specifically investigated structural changes in mitochondria of fusion- and fission-induced Hep3B cells, capturing dose-dependent and temporal mitochondrial dynamics. Fusion and fission dynamics were induced by Mdivi-1 and MPP+, respectively. Through HT, we observed significant morphological changes, which were quantitatively assessed using the TomoAnalysis software enhanced with machine learning for accurate mitochondrial segmentation and length measurement. Additionally, we generated 8 distinct ilastik models optimized for each cell type: MCF-7, Hep3B, HeLa, Fibroblast, NIH-3T3, Huh-7, COS-7, and HepG2. By utilizing these distinct ilastik models, we achieved advanced segmentation and measurement of the morphological features of the mitochondria in each cell type. These sophisticated methodological approaches substantially advance mitochondrial research, providing reliable tools for biomarker identification and a more detailed understanding of the cellular processes involved in disease pathogenesis. Citation Format: Sumin Lee, Hoyeon Lee, Jaehyeok Lee, Minju Kim, Hye-Jin Kim, YongKeun Park. Real-time visualization and quantitative analysis of mitochondrial fission and fusion using label-free 3D holotomography imaging [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 LB447.
Abstract LB074: Targeting chromatin remodeling disrupts immune suppression by pathologically activated neutrophils in cancer
Authors: Fan Yang, Yi Bao, Lanbo Xiao, Yuanyuan Qiao, Yizhi Cao, Arul M. Chinnaiyan
Journal: Cancer Research (2025)

Abstract Chromatin remodelers play a critical role in regulating gene expression and chromatin organization, influencing tumor-intrinsic mechanisms linked to various immunological responses. Recent clinical evidence suggests that mutations in chromatin remodelers may enhance tumor sensitivity to immunotherapies, although the underlying mechanisms remain poorly understood. This study investigates the effects of chromatin remodeler antagonists in isogenic syngeneic tumor models with varying immunogenicity levels. Our findings demonstrate that these antagonists effectively modulate the immunosuppressive tumor microenvironment by reducing granulocytic myeloid-derived suppressor cells (G-MDSCs), also known as pathologically activated neutrophils, and enhancing the infiltration of functional CD8+ T cells. As a result, the antagonists significantly suppress tumor growth, exhibiting superior efficacy compared to anti-PD-1 monotherapy. Furthermore, they demonstrate synergistic antitumor effects when combined with anti-PD-1 treatment. This study identifies G-MDSCs as key mediators of chromatin remodeling activity and highlights the potential of specific chromatin remodeling antagonists as promising agents to improve immunotherapy responses in cancer patients. These findings contribute to our understanding of the complex interplay between chromatin remodeling, immune suppression, and cancer progression, paving the way for novel therapeutic strategies in cancer immunotherapy. Citation Format: Fan Yang, Yi Bao, Lanbo Xiao, Yuanyuan Qiao, Yizhi Cao, Arul M. Chinnaiyan. Targeting chromatin remodeling disrupts immune suppression by pathologically activated neutrophils in 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 LB074.
Abstract LB480: Cryogenic volume electron microscopy reveals restoration of organelle integrity by abemaciclib in hormone receptor-positive, HER2-negative metastatic breast cancer organoids
Authors: Gong-Her Wu, Mei-Kuang Chen, Kelly Hunt, Debu Tripathy, Khandan Keyomarsi, Wah Chiu
Journal: Cancer Research (2025)

Abstract Resistance to CDK4/6 inhibitors (CDK4/6i) remains a major clinical challenge in hormone receptor-positive, HER2-negative metastatic breast cancer (HR+/HER2- MBC). Despite advances in multi-omics and histopathology, these techniques often introduce artifacts and fail to capture the ultrastructural dynamics of tumor response. This study pioneers the application of cryogenic volume electron microscopy (cryo-vEM) with a focused ion beam/scanning electron microscopy (cryo-FIB/SEM) to patient-derived organoids (PDOs) as a means of investigating the subcellular impact of abemaciclib, a potent CDK4/6i.Using PDOs generated from a liver metastasis of a CDK4/6i-naïve patient who demonstrated durable clinical benefit from CDK4/6i therapy, we revealed significant abemaciclib-induced alterations in cellular architecture and organelle morphology. Initial room-temperature FIB/SEM imaging identified hallmark metastatic features, including hollow organoid structures, misshapen nuclei, enlarged mitochondria, and pseudopodia with invasive morphology. Following abemaciclib treatment, PDOs exhibited normalized nuclear shapes, prominent nucleoli, reduced pseudopodia, and a loss of hollow organoid architecture, indicating diminished metastatic potential.Cryo-FIB/SEM of vitrified organoid enabled artifact-free imaging of these structural changes in their native state. Mitochondria in treated PDOs showed fewer aberrant cristae folds, while untreated cells displayed nuclear-wrapped mitochondria, a feature absent post-treatment. This suggests a treatment-induced disruption of tumor-specific energy supply routes. Additionally, cytoskeletal remodeling was evident, reflecting a functional shift associated with reduced invasive capacity.These findings underscore the power of cryogenic imaging techniques in bridging the gap between cellular ultrastructure and therapeutic response. By integrating future molecular and multi-omics analyses, this approach has the potential to revolutionize drug evaluation, offering a pathway to personalized, artifact-free assessment of treatment efficacy in metastatic breast cancer. This work not only highlights abemaciclib’s mechanistic impact but also sets the stage for cryo-vEM as a transformative tool in cancer research. Citation Format: Gong-Her Wu, Mei-Kuang Chen, Kelly Hunt, Debu Tripathy, Khandan Keyomarsi, Wah Chiu. Cryogenic volume electron microscopy reveals restoration of organelle integrity by abemaciclib in hormone receptor-positive, HER2-negative metastatic breast cancer organoids [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 LB480.
Abstract SY41-01: Do individual cancer cells learn to become therapy resistant
Authors: Arjun Raj
Journal: Cancer Research (2025)

Abstract Do individual cancer cells learn to become therapy resistant? Do cells remember their past experiences? DNA is one way to encode these past experiences, but cannot generally be altered within a lifetime. How, then, can cells learn? We present data showing that cancer cells, in the context of therapy resistance, remember their past, and this past can influence their future. We find the molecular mechanism by which such regulatory flexibility is achieved. We think this mechanism may open new avenues for treating therapy-resistant tumors. Citation Format: Arjun Raj. Do individual cancer cells learn to become therapy resistant [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 SY41-01.
Abstract CT265: KRASG12Dtargeting using engineered exosomes in pancreatic cancer: Results from the iEXPLORE phase 1 trial
Authors: Valerie S. LeBleu, Brandon Smaglo, Krishnan Mahadevan, Michelle Kirtley, Kathleen M. McAndrews, Mayela Mendt, Sujuan Yang, Shubam Pant, Elizabeth Shpall, Anirban Maitra, Raghu Kalluri
Journal: Cancer Research (2025)

Abstract Despite its pivotal role in pancreatic ductal adenocarcinoma (PDAC), oncogenic Kras has eluded pharmacological targeting design, albeit with more recent and promising development. Given the preponderance of KrasG12D mutation in PDAC, we engineered exosomes from allogenic bone marrow derived mesenchymal cells with incorporation of KrasG12DsiRNA payload. We report on a comprehensive preclinical toxicology and biodistribution analysis of clinical grade iExosomes in mice and rhesus macaques, which informed on their safety as therapeutic agents in patients. We report on the clinical testing of iExosomes in a Phase 1 study that employed a classical 3+3 dose escalation design. Patients with metastatic disease were enrolled after multiple lines of therapy failure. No dose limiting toxicities (DLTs) were encountered for all 3 dose levels tested, and no DLT were noted for the 3 of the 9 patients who had stable disease after completing the first 3 cycles and allowed to undergo an additional 3 consecutive cycles. A follow up accelerated dose titration trial enrolled an additional 3 patients. The maximum tolerated dose was not reached, with no DLT encountered at the highest dosage used. Stable disease of target lesions was observed in 6 of the 12 patients treated with iExosomes, permitting their enrollment in additional iExosomes doses, with no DLT encountered. All patients eventually demonstrated PD. Target engagement was studied with down regulation of circulating KrasG12D DNA and pre- and post-biopsy tissue analysis for Kras signaling. Immune profiling revealed opportunistic synergy with immune checkpoint blockade (ICB). Murine studies confirmed synergy of iExosomes with anti-CTLA4 antibodies specifically, with iExosomes reprograming the tumor immune microenvironment and recruiting Tregs susceptible to anti-CTLA4 co-treatment. This trial is the first-in-human therapeutic trial utilizing engineered exosomes from bone marrow derived mesenchymal cells, and we report on the safety of exosomes as well as target engagement in pancreatic cancer with a payload suppressing oncogenic Kras. The trial informed on the opportunistic and future combination therapy with ICB. ClinicalTrials.gov identifier: NCT03608631. Citation Format: Valerie S. LeBleu, Brandon Smaglo, Krishnan Mahadevan, Michelle Kirtley, Kathleen M. McAndrews, Mayela Mendt, Sujuan Yang, Shubam Pant, Elizabeth Shpall, Anirban Maitra, Raghu Kalluri. KRASG12Dtargeting using engineered exosomes in pancreatic cancer: Results from the iEXPLORE phase 1 trial [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 CT265.
Abstract CT249: An open-label, multicenter, phase 2 study of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) Part 2
Authors: Funda Meric-Bernstam, Jung-Yun Lee, Vicky Makker, Ana Oaknin, Chiedozie Anoka, Lindsey Jung, Soham Puvvada, João Simões, Do Youn Oh
Journal: Cancer Research (2025)

Abstract Background: T-DXd is a HER2-directed antibody-drug conjugate that is approved in multiple countries for the treatment of HER2-positive and HER2-low breast cancer, HER2-positive gastric or gastroesophageal junction adenocarcinoma, and HER2-mutant non-small cell lung cancer (NSCLC). In April 2024, T-DXd received accelerated approval in the US for adult pts with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors that have progressed after prior systemic treatment and have no satisfactory alternative therapies. In Part 1 of the DP-02 study (N=267), T-DXd showed clinically meaningful investigator-assessed (INV) objective response rates (ORRs; 37.1% [95% CI 31.3, 43.2]) and INV median progression-free survival (PFS; 6.9 months [95% CI 5.6, 8.0]) in pretreated pts with HER2-expressing solid tumors, with the largest effect observed in pts with centrally confirmed HER2 IHC 3+ tumors (ORR 61.3% [95% CI 49.4, 72.4]; median PFS 11.9 months [95% CI 8.2, 13.0]); safety was consistent with the known profile. Here, we describe Part 2 of the DP-02 study. Methods: DP-02 (NCT04482309) is an open-label, multicenter, Phase 2 study evaluating T-DXd (5.4 mg/kg intravenously once every 3 weeks) in pts with HER2-expressing locally advanced or metastatic solid tumors that have progressed following prior systemic treatment or have no alternative treatment options. Part 2 will enroll ∼40 pts in each of the following cohorts: A, any HER2 IHC 3+ tumor; B, any HER2 IHC 2+ / in situ hybridization-positive tumor; C, HER2 IHC 2+/1+ endometrial cancer; D, HER2 IHC 2+/1+ ovarian cancer; or E, HER2 IHC 2+/1+ cervical cancer. Pts with breast, gastric, or colorectal cancer will not be enrolled; unlike in Part 1, pts with NSCLC will be eligible for cohorts A and B. HER2 expression will be determined by central testing and scored per ASCO/CAP gastric-specific criteria. The primary endpoint is INV confirmed ORR per RECIST 1.1. Secondary endpoints include duration of response, disease control rate, PFS, and overall survival. Safety, tolerability, pharmacokinetics, and immunogenicity will also be assessed. Previously presented at ESMO Asia 2024; Final Publication Number: 400 TiP; Jung-Yun Lee et al. Reused with permission Citation Format: Funda Meric-Bernstam, Jung-Yun Lee, Vicky Makker, Ana Oaknin, Chiedozie Anoka, Lindsey Jung, Soham Puvvada, João Simões, Do Youn Oh. An open-label, multicenter, phase 2 study of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) Part 2 [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 CT249.
Abstract LB007: Discovery of a novel molecular glue degrader of Nrf2
Authors: Timothy J. Read, Richard Steel, Leah Damon, Reo Yoo, Ardeshir Goliaei, Jenna Rimel, Jeff Hsu, David Simpson, Joseph Azofeifa
Journal: Cancer Research (2025)

Abstract Nrf2 is an oncogenic transcription factor that is frequently overactive in tumors bearing mutations in the NRF2/KEAP1 pathway, but to date, no direct Nrf2 inhibitors have been tested clinically. Using high-throughput transcriptomic screens in combination with biophysical assays, we discovered ARP-4922 as a potent molecular glue degrader of Nrf2. ARP-4922 degrades Nrf2 in a proteasome- and cullin- dependent manner with exceptional activity, especially in NRF2/KEAP1-mutant backgrounds. Genetic experiments identified the likely E3 ligase driving ARP-4922-mediated degradation of Nrf2, and biophysical approaches such as fluorescence polarization (FP) and size exclusion chromatography followed by affinity selection mass spectrometry (SEC-ASMS) confirmed the E3 ligase required for ARP-4922-mediated ternary complex formation and subsequent Nrf2 degradation. Importantly, FP experiments allowed definition of the E3 ligase-interacting degron within the Nrf2 protein and can distinguish between active and inactive ARP-4922 analogs. ARP-4922 has a favorable in vivo pharmacokinetic profile in mice and leads to 100% tumor growth inhibition in several cell-derived xenograft models, including models of lung adenocarcinoma (NCI-H2122) and lung squamous cell carcinoma (LK2), which possess mutations in KEAP1 and NRF2 respectively. ARP-4922 represents a promising novel approach to Nrf2 inhibition in NRF2/KEAP1 mutant cancers with high unmet medical need. Citation Format: Timothy J. Read, Richard Steel, Leah Damon, Reo Yoo, Ardeshir Goliaei, Jenna Rimel, Jeff Hsu, David Simpson, Joseph Azofeifa. Discovery of a novel molecular glue degrader of Nrf2 [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 LB007.