tbuckley/cabot-search huggingface dataset:
Abstract 2306: Estrogen metabolism-related lifestyle scores and breast cancer risk among 62,000 Chinese and American postmenopausal women: Findings from two large prospective cohort studies
Authors: Fangcheng Yuan, Wanqing Wen, Steven C. Moore, Wei Zheng
Journal: Cancer Research (2025)

Background: An increased 2-hydroxylation (2-OH) of estrogen has been linked to reduced risk of breast cancer (BC). We hypothesized that lifestyle patterns related to an elevated estrogen 2-OH metabolism were associated with lower BC risk and tested this hypothesis among post-menopausal women in two prospective cohorts. Methods: Estrogens and estrogen metabolites (EMs) were profiled by liquid chromatography-mass spectrometry in a subset of post-menopausal women in the Shanghai Women’s Health Study (SWHS, n=804) and Prostate, Lung, Colorectal and Ovarian Screening Trial (PLCO, n=842), respectively. Blood (PLCO) or urine (SWHS) samples used in these assays were collected at baseline prior to any cancer diagnosis. We applied elastic net regularized regression to derive two lifestyle scores that characterize relative abundance of 2-OH pathway EMs, estimated separately by the ratio of 2-OH EMs to parent estrogens and the ratio of 2-OH EMs to parent estrogens and all EMs combined. Intakes of foods and nutrients assessed by baseline food frequency questionnaires, and measures of body fat, alcohol intake, cigarette smoking, and leisure-time physical activity were included as predictors. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations of derived lifestyle scores with post-menopausal BC risk in the larger SWHS (N=35,453) and PLCO (N=26,758) cohorts, after adjusting for potential confounders. Results: The lifestyle scores explained 10-12% of the total variance in the 2-OH EM ratios. A high lifestyle score for the ratio of 2-OH EMs to parent estrogens was associated with decreased BC risk in the SWHS (HR=0.73, 95% CI=0.59-0.90 for the highest versus lowest quartile, Ptrend=0.001). This inverse association was seen only among estrogen receptor (ER)-positive BC cases (Pheterogeneity=0.03). A similar association was observed for the lifestyle score for the ratio of 2-OH EMs to the combined parent estrogens and EMs. In the PLCO, the score for the ratio of 2-OH EMs to parent estrogens was inversely related to BC risk (HR=0.83, 95% CI=0.70-0.99, Ptrend=0.06), whereas no significant association was found for the other lifestyle score. Conclusion: A lifestyle pattern reflecting elevated estrogen 2-OH metabolism may lower post-menopausal BC risk. Women with a low 2-OH of estrogen may benefit from diet and lifestyle modifications. Citation Format: Fangcheng Yuan, Wanqing Wen, Steven C. Moore, Wei Zheng. Estrogen metabolism-related lifestyle scores and breast cancer risk among 62,000 Chinese and American postmenopausal women: Findings from two large prospective cohort studies [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 2306.
Abstract 2781: Enabling low cell input and high throughput processing of cell fixation for single cell RNA profiling using combinatorial barcoding
Authors: Olivia Kaplan, Sarah Schroder, Vuong Tran, Simone Marrujo, Alec Salvino, Ajay Sapre, Ian Dowsett, Zeynep Sayar, Alex Koriath, Alex Sova, Gary Geiss, Charles Roco, Alex Rosenberg
Journal: Cancer Research (2025)

Abstract Single cell analysis is a critical approach to tease out nuanced information in any biological system. Combinatorial barcoding is an extremely efficient method for scRNA-seq at scale, achieving both sensitivity in gene detection and flexibility in sample input. This approach, however, is challenging when starting with sample inputs of less than 100,000 cells. To address this, we have developed a modified fixation and cell capture method for low sample inputs that is compatible with the combinatorial barcoding approach. This allows researchers working with low sample inputs to fix, store and barcode their cells efficiently without the need for costly or specialized instruments. Low Input Fixation can be used to fix and profile up to 384 samples in parallel, results in a shorter workflow, and enables consistent handling (which minimizes both experimental error and burden on scaling). This method maintains the stability of fixed samples at -80°C and capture efficiency remains consistently high for inputs as low as 10,000 cells. The workflow maximizes sample recovery while providing accurate and comprehensive results of transcriptional changes from experimental perturbations. As proof-of-concept we screened a cancer drug panel with cell input amounts between 10,000 - 20,000 cells per treatment. Robust cell capture minimizes loss during drug perturbations resulting in consistent gene detection. Whole transcriptome analysis using Evercode WTK identifies changes in gene expression associated with each drug class and cell type. Results of the screen validate putative drug targets in the panel. Additionally, panel-based perturbation allows for detection of off-target impacts at scale. This work demonstrates the combination of low input fixation with combinatorial barcoding to enable high throughput cancer drug and compound screening. Citation Format: Olivia Kaplan, Sarah Schroder, Vuong Tran, Simone Marrujo, Alec Salvino, Ajay Sapre, Ian Dowsett, Zeynep Sayar, Alex Koriath, Alex Sova, Gary Geiss, Charles Roco, Alex Rosenberg. Enabling low cell input and high throughput processing of cell fixation for single cell RNA profiling using combinatorial barcoding [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 2781.
Abstract 2038: Antibody Drug Conjugates Treatment Response Score (ADC TRS) for predicting ADC treatment response
Authors: Sachdev P. Thomas, Laurel A. Habel, Jennifer M. Suga, Ninah Achacoso, Joshua R. Nugent, Chen Jiang, Elaine Chung, Stephanie Bush, Michael D. Nitchie, Katarina M. Robinson, Jasie Inman, Ryan White, Komal Plouffe, Daniel R. Rhodes, Scott A. Tomlins, Bryan Johnson
Journal: Cancer Research (2025)

Abstract Background: Predictive biomarkers for multiple ADCs/tumor types (beyond 3+ HER2 IHC) are lacking. We previously reported the discovery of ADC TRS—an algorithm combining individual ADC target expression, proliferation, and adhesion by RNAseq to predict ADC clinical benefit across tumor types/targets—and association with OS after ADC treatment (Abstract 3140, ASCO 2024). Here we evaluated the final ADC TRS biomarker (ADC-specific; tuned on &amp;gt;100 tumor type/ADC RRs) by a qRT-PCR based clinical trial assay (CTA) for predicting ADC clinical benefit. Methods: Adults in the Kaiser Permanente Northern California (KPNC) system with advanced bladder or breast cancer in an observational trial (NCT03061305) who were treated with an approved ADC (enfortumab vedotin [EV], sacituzumab govitecan [SG] or trastuzumab deruxtecan [T-DXd]; first dose by Apr. 21, 2023) with valid CTA TRS results from FFPE tissue (collected prior to 1st ADC treatment) were eligible; patients with prior trastuzumab or hormonal (between tissue collection/ ADC start) treatment were excluded. KPNC oncologists (blinded to ADC TRS status) determined best response to therapy from chart review. ADC TRS status (+ vs. -) / response data were merged by the KPNC statistician and analyzed per a prespecified plan. Results: A total of 117 KPNC patients with advanced bladder (n=58 [50%]) or breast (n=59 [50%]) cancer treated with an approved ADC (n= 56 [48%], 47 [40%], and 14 [12%] EV, SG, and T-DXd, respectively) were evaluable for TRS and RR. As shown in the Table, TRS+ status was associated with significantly higher RR and longer PFS and OS for approved ADC treatment; results were generally similar across ADCs and tumor type. Conclusions: By a qRT-PCR based CTA, TRS+ status was associated with improved RR, PFS and OS for approved ADCs in an observational cohort of patients with advanced bladder or breast cancer. Prospective validation for approved and/or investigational ADCs is warranted. Citation Format: Sachdev P. Thomas, Laurel A. Habel, Jennifer M. Suga, Ninah Achacoso, Joshua R. Nugent, Chen Jiang, Elaine Chung, Stephanie Bush, Michael D. Nitchie, Katarina M. Robinson, Jasie Inman, Ryan White, Komal Plouffe, Daniel R. Rhodes, Scott A. Tomlins, Bryan Johnson. Antibody Drug Conjugates Treatment Response Score (ADC TRS) for predicting ADC treatment response [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 2038.
Abstract 3565: Personalized Drug Discovery Process (PDDP): An AI-driven, sustainable, and equitable solution for cancer drug discovery
Authors: Pietro Veronesi, Adekunle Odunsi, Marciano Siniscalchi, Marina Chiara Garassino
Journal: Cancer Research (2025)

Abstract Background: Personalized medicine has improved survival rates for lung cancer patients with common targetable alterations. However, developing drugs for rare or ultra-rare molecular alterations is likely to become economically unsustainable, potentially creating unequal access to personalized therapies for patients with these mutations. Methods: We formulate a new mathematical model and use Monte Carlo simulations to calculate pharma companies’ projected profits from targets that affect an increasingly smaller fraction of the world population, considering the costs of R&amp;D and Randomized Clinical Trials (RCTs) and the probability of drug approval. We then use similar methods to calculate projected profits for an alternative, feasible, AI-driven approach called the Personalized Drug Discovery Process (PDDP), which has four steps: target identification, protein synthesis, drug matching or repurposing, and bioassay synthesis. Findings: At the current annual price for targeted therapies of around $200, 000/patient and RCT costs of $100, 000 per subject, the financial incentives for further drug discovery under the current approval paradigm evaporate for targets affecting less than 0.5% of the lung cancer population, even if Phase 0 and I R&amp;D costs are as low as $100 million/target. To ensure proper incentives for Pharma companies to innovate even for targets affecting less than 0.5% of lung cancer patients, targeted therapies would require margins of over $828, 000/year per patient over manufacturing costs, implying global societal costs of over $1.45 trillion/year. PDDP is instead projected to be sustainable, even accounting for the required investments in infrastructure. At peak, we calculate PDDP will cost $1, 250 per lung cancer patient, net of drug manufacturing costs. Pharma companies will invest in PDDP and hence foster further research if successful personalized drugs yield margins between $25, 000 - $90, 000/year per patient. Conclusions: PDDP is already a feasible and sustainable drug discovery process. This can create a paradigm shift in drug discovery by testing the process instead of specific drugs. By contrast, under current regulatory agency requirements, the drug discovery and development process is unsustainable for targets with a frequency of less than 0.5%. This approach promotes innovation and equity in access for all patients with any identifiable target mutation Citation Format: Pietro Veronesi, Adekunle Odunsi, Marciano Siniscalchi, Marina Chiara Garassino. Personalized Drug Discovery Process (PDDP): An AI-driven, sustainable, and equitable solution for cancer drug discovery [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 3565.
Abstract 416: Spatial transcriptomic analysis of breast cancer patients with early and late progression of disease after endocrine and CDK4/6 treatments: deconvoluting the tumor microenvironment
Authors: Sunil S. Badve, Shihan Liu, Madhubanti Basu, Chiao-Wang Sun, Shanrun Liu, Jian Hu, Yesim Gokmen-Polar
Journal: Cancer Research (2025)

Abstract Background: Cyclin-dependent kinase inhibitors, CDK4/6i, have been one of the most significant practice-changing advancements for the estrogen receptor positive (ER+) breast cancer therapy in the recent decade. However, no molecular biomarkers are successful in predicting sensitivity/resistance to CDK4/6 inhibitors in clinical trials. It is believed that the heterogeneity of the tumor microenvironment (TME) plays a key role in resistance and metastasis. Deconvolution of TME in CDK4/6 treated samples may provide novel tumor-specific strategies to overcome resistance and reduce mortality in ER+ breast cancer. Methods: Samples of primary tumors from patients treated for metastatic ER+ breast cancer with CDK4/6 inhibitors were identified from the database of Emory University hospital. Archival FFPE sections were analyzed using 10X CytAssist-enabled Visium Spatial transcriptomics using the UAB Flow Cytometry and Single Cell Core Facility. IRIS and cell type deconvolution analyses were performed to identify TME parameters (immune markers and cell types) associated with time to progression on CDK4/6i. Results: The analysis was performed on 10 patients who were all treated with Palbociclib and endocrine therapy. The early time to progression (&amp;lt;6 months; n=6) exhibited differential cellular phenotypes (Tumor, Stroma, and Immune Cells) in comparison to late time of progression (&amp;gt;30 months; n=4). The study revealed that both B cells, and CD4+ and CD8+ T cells, are present in significantly higher proportions in the progression of the &amp;lt;6 months group, suggesting a role for immune-related mechanisms in the development of resistance. In addition to lymphocytes, cancer-associated fibroblasts (CAFs) were more prominent in early progression cases suggesting the involvement of tumor microenvironment. Additional confirmatory analyses are on-going. Conclusion: Deconvolution of the TME using spatial transcriptomics will be a powerful tool for understanding the tumor heterogeneity. Better understanding of the cellular interactions could provide novel strategies to prevent CDK4/6 inhibitor resistance. Citation Format: Sunil S. Badve,Shihan Liu,Madhubanti Basu,Chiao-Wang Sun,Shanrun Liu,Jian Hu,Yesim Gokmen-Polar. Spatial transcriptomic analysis of breast cancer patients with early and late progression of disease after endocrine and CDK4/6 treatments: deconvoluting the 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 416.
Abstract 410: The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models
Authors: Alberto J. Arribas, Elisa Civanelli, Camilla Scalise, Luciano Cascione, Andrea Rinaldi, Davide Rossi, Emanuele Zucca, Francesco Bertoni
Journal: Cancer Research (2025)

Abstract Introduction: Targeting the B cell receptor (BCR) signaling with BTK and PI3K inhibitors is efficacious in treating patients with lymphoid tumors, including marginal zone lymphoma (MZL). Unfortunately, resistance occurs, indicating the need for combinations and novel approaches. BGB-16673 is a first-in-class cereblon-mediated BTK degrader currently in phase 1 for refractory/relapsed B cell lymphoma patients, including MZL. Here, we assessed BGB-16673 in MZL models as a single agent to provide the rationale for future trials in MZL patients. Methods: Effect on cell viability was assessed by MTT assay after 5 days of exposure to increasing concentrations of compounds or DMSO (control) in MZL cell lines and in cell lines with secondary resistance to idelalisib (n.=2), copanlisib (n.=1), ibrutinib (n.=2), and copanlisib/venetoclax. Analyses included apoptosis and cell cycle analysis by flow cytometry, immunoblotting, and RNA-Seq. Results: Six MZL cell lines (SSK41, Karpas1718, VL51, HC1, HAIRM, and ESKOL) were treated with the BTK degrader BGB-16673 at a concentration of up to 10μM. The BTK degrader was very active in 2 models (SSK41, IC50=0.1 nM; Karpas1718, 1.7 nM). VL51 achieved a maximal reduction in proliferation of 25% at 10 nM. Less than 20% of the reduction was observed in HC1, HAIRM and ESKOL. The activity of BGB-16673 did not differ from the BTK inhibitor zanubrutinib and, accordingly, was limited in cells resistant to ibrutinib (n.=2), idelalisib (n.=2), copanlisib (n.=1), and copanlisib/venetoclax (n.=2). BGB-16673 induced apoptosis and cell cycle arrest in sensitive Karpas1718 and SSK41. It importantly inhibited p-BTK(Tyr223) and decreased total BTK protein levels in all six cell lines. RNA-Seq was performed on Karpas1718 exposed to BGB-16673, zanubrutinib or DMSO. Both molecules down-regulated the BCR-TLR-NF-κB signaling pathway, MYC target genes, and upregulated genes involved in DNA damage. Oxidative phosphorylation, commonly associated with resistance to multiple therapies, was repressed by BGB-16673 but upregulated by zanubrutinib. Conclusions: Its ability to degrade BTK protein and its antitumor activity position the BTK degrader BGB-16673 as a promising candidate for further development in MZL patients. Citation Format: Alberto J. Arribas, Elisa Civanelli, Camilla Scalise, Luciano Cascione, Andrea Rinaldi, Davide Rossi, Emanuele Zucca, Francesco Bertoni. The BTK degrader BGB-16673 shows anti-tumor activity in marginal zone lymphoma models [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 410.
Abstract 2962: Enhanced HER2 internalization by clathrin-dependent endocytosis in non-small cell lung cancer positive for <i>HER2</i> mutations
Authors: Atsushi Shimauchi, Eiji Iwama, Ritsu Ibusuki, Hirono Tsutsumi, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Kentaro Tanaka, Hiroyuki Inoue, Isamu Okamoto
Journal: Cancer Research (2025)

Abstract Introduction: Mutations in the gene for human epidermal growth factor 2 (HER2) result in constitutive phosphorylation of the protein and are driver alterations in cancer. HER2 mutations are present at a frequency of 1% to 4% in non-small cell lung cancer (NSCLC), with exon-20 insertion mutations such as A775_G776insYVMA and G776delinsVC being among the most common of these latter mutations. Although HER2-targeted ADCs have shown marked efficacy for HER2 mutation-positive NSCLC, the detailed molecular mechanisms underlying such efficacy are not well understood. Methods: The intracellular trafficking and dimerization patterns of HER2 were examined in cells expressing wild-type (WT) or mutant forms of the protein with the use of live cell imaging and an in situ proximity ligation assay, respectively. Proteins that preferentially associate with mutant HER2 were identified by liquid chromatography and tandem mass spectrometry to shed light on the pathway of HER2 trafficking in HER2-mutated cells. Results: HER2 internalization was enhanced in NSCLC cells expressing mutant forms of HER2 compared with those expressing HER2(WT). Homodimers of HER2(WT) were localized mainly at the cell surface, whereas those of mutant HER2 were present mostly in the cytoplasm. Although siRNA interference of EGFR or HER3 effectively suppressed the HER2 internalization in cells stably expressing WT forms of HER2, such internalization was not affected in the cell lines expressing mutant forms of HER2. The enhanced internalization of mutant HER2 was mediated by clathrin-dependent endocytosis, as was reflected by increased binding of the ubiquitin ligase c-Cbl to mutant HER2 and its consequent ubiquitination. Zongertinib, a HER2-specific tyrosine kinase inhibitor, attenuated HER2 phosphorylation, the binding of c-Cbl to HER2, and HER2 internalization in HER2-mutated cells. Conclusions: Upregulation of HER2 phosphorylation promotes internalization of mutant forms of HER2 mediated by clathrin-dependent endocytosis, which may contribute to the efficacy of HER2-targeted ADCs in NSCLC positive for HER2 mutations. Citation Format: Atsushi Shimauchi, Eiji Iwama, Ritsu Ibusuki, Hirono Tsutsumi, Daisuke Shibahara, Kohei Otsubo, Yasuto Yoneshima, Kentaro Tanaka, Hiroyuki Inoue, Isamu Okamoto. Enhanced HER2 internalization by clathrin-dependent endocytosis in non-small cell lung cancer positive for HER2 mutations [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 2962.
Abstract 344: IBI3014, a TROP2xPD-L1 bi-specific ADC integrating ADC killing with checkpoint blockade within one molecule, exhibits promising efficacy and safety in preclinical models
Authors: Xiguang Zhang, Yanping Jin, Jinchang Lu, Ninghuan Li, Zhihai Wu, Min Wu, Yan Bian, Fenggen Fu, Weiwei Wu, Shuaixiang Zhou, Huizhong Xiong
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) have emerged as a distinguished class of anticancer therapeutics. ADCs targeting Trophoblast Cell Surface Antigen 2 (TROP2) have shown efficacy in treating various epithelial tumors, such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). Programmed Death Ligand 1 (PD-L1) serves as both an immune checkpoint and a tumor-associated antigen (TAA), commonly overexpressed in diverse tumor types. Growing evidence showed that ADCs can increase the efficacy of immunotherapeutic agents by multiple mechanisms, such as induction of immunogenic cell death, dendritic cell maturation, increase of T cell infiltration and expression of immune-regulatory proteins including PD-L1 and MHC. Both preclinical and early clinical studies suggest that ADCs and immunotherapy are promising combination options for tumor treatment. IBI3014 is an innovative TROP2 and PD-L1 dual-targeting ADC, comprising a humanized bispecific antibody linked to a novel DNA topoisomerase I inhibitor, NT1, via a cleavable linker. In vitro studies demonstrated the unconjugated bispecific antibody of IBI3014 has potent internalization activity potent immune checkpoint blocking activity. IBI3014 demonstrated superior cytotoxicity to benchmark and parental ADCs across several cell line-derived xenograft (CDX) models with different TROP2 and PD-L1 expression pattern, offering broader tumor type coverage. IBI3014 showed acceptable stability profile in mice and monkeys and can be well tolerated in monkeys with a highest non-severely toxic dose (HNSTD) of 50 mg/kg. Conclusion: IBI3014 represents a first-in-class bispecific ADC that integrates targeted cytotoxicity with checkpoint blockade within a single molecule. This dual mechanism of action not only enhances therapeutic efficacy but also maintains a favorable safety profile, which provides a promising approach for cancer therapy. Citation Format: Xiguang Zhang, Yanping Jin, Jinchang Lu, Ninghuan Li, Zhihai Wu, Min Wu, Yan Bian, Fenggen Fu, Weiwei Wu, Shuaixiang Zhou, Huizhong Xiong. IBI3014, a TROP2xPD-L1 bi-specific ADC integrating ADC killing with checkpoint blockade within one molecule, exhibits promising efficacy and safety in preclinical models [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 344.