tbuckley/cabot-search huggingface dataset:
Abstract 2187: Functional classification of tumor-associated macrophages and changes in TAM subpopulations in response to various immunotherapies
Authors: Bryan T. Weselman, Satish K. Noonepalle, Manasa Suresh, Marie Durr, Nithya Gajendran, Alejandro Villagra, Xintang Li
Journal: Cancer Research (2025)

Despite single-cell omics ushering in many attempts at reclassifying tumor-associated macrophages (TAMs), there remains a lack of a consensus for a widely applicable model that accurately describes their biological functions. Based on single-cell RNA seq data from both mouse and human melanoma tumors, we propose a new model for categorizing TAMs by their function in the tumor microenvironment (TME). We identified eight clusters with various functions including a distinct population of proliferating macrophages with tissue-resident characteristics. Samples from mice with SM1 melanoma tumors that have been treated with ɑ-PD-1 immune checkpoint blockade, the novel HDAC6 inhibitor SS208, combination SS208 + ɑ-PD-1, and adoptive cell therapy (ACT) using HDAC6 inhibition show changes in the proportions of putative subpopulations, most notably a significant decrease in “Pro-Angiogenic/Arginine Metabolism” macrophages within tumors after all treatments, an increase in “Antigen Presenting/Phagocytosis” macrophages in mice treated with ɑ-PD-1 therapy, and an increase in proliferating macrophages in mice treated with ACT. We also identified heterogeneity in the expression of certain markers historically categorized as “M1” or “M2,” indicating that using specific markers interchangeably may be inaccurate in measuring different subpopulations within the tumor. In an attempt to move away from artificial polarization of macrophages in vitro via cytokines, TAMs were cultured in tumor-conditioned media and M-CSF to more accurately retain TME phenotype. The proposed functions of these subpopulations have been further confirmed by in vitro and ex vivo functional assays from isolated TAMs. Additionally, we outline an efficient method for applying the proposed subpopulation gene signature to bulk RNA seq data of macrophages, which allows for more accurate analysis of changes in TAM subpopulation in response to therapy. Citation Format: Bryan T. Weselman, Satish K. Noonepalle, Manasa Suresh, Marie Durr, Nithya Gajendran, Alejandro Villagra, Xintang Li. Functional classification of tumor-associated macrophages and changes in TAM subpopulations in response to various immunotherapies [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 2187.
Abstract 1277: <i>Ex ovo</i> system for rapid and quantitative modelling of immunotherapy responses in pre-clinical and patient-derived xenografts: PDX<i>ovo</i>
Authors: Olivia R. Grafinger, Kabir A. Khan, Esther I. Matus, Sara Mar, Yan Li, David Goertz, Jean Gariépy, Katarzyna J. Jerzak, Robert Kerbel, Hon S. Leong
Journal: Cancer Research (2025)

Abstract Precision oncology for triple-negative breast cancer (TNBC) is urgently needed because not all patients will benefit from PDL1-based immunotherapy. Unfortunately, the expression of PDL1 or abundance of tumor infiltrated lymphocytes (TILs) does not correlate with objective response rates and/or overall survival. We have developed a novel patient-derived xenograft (PDX) model system that offers phenotype-based metrics to predict immunotherapy response prior to receiving treatment. In our PDX model (PDXovo), the patient’s tumour is engrafted onto the chorioallantoic membrane (CAM) of chick embryos. Our PDX model offers significant advantages over mouse PDXs which are expensive, time-consuming, and cannot evaluate immunotherapies. To test the efficacy of this model, we implanted immunocompetent mice with a murine mammary cancer cell line (serving as a surrogate for patients), and implanted tumours into the PDXovo system. We found our model to reliably recapitulate immunotherapy responses observed in mice, with anti-PDL1-treated tumours being significantly smaller in volume as compared to IgG-treated tumours. We also found our model to reliably predict patient response to adoptive cell therapy, wherein TILs were FACS-sorted from murine tumour digests, activated and expanded in vitro, and then engrafted together with cultured murine mammary carcinoma cells. We are now testing this model with patient-derived tumours of a variety of origins, in partnership with the Ontario Institute of Cancer Research. To date we have tested tumour responses to Pembrolizumab in five patient-derived samples from various sites, with an 80% success rate in xenograft formation. We have observed varied responses to immunotherapy, which did not correlate with PDL1 expression on TILs in these samples, highlighting the importance of such a qualitative model for precision oncology. This technology has the potential to make a positive impact in the clinic and improve objective response rates, increase progression-free survival intervals, and increase overall survival. Citation Format: Olivia R. Grafinger, Kabir A. Khan, Esther I. Matus, Sara Mar, Yan Li, David Goertz, Jean Gariépy, Katarzyna J. Jerzak, Robert Kerbel, Hon S. Leong. Ex ovo system for rapid and quantitative modelling of immunotherapy responses in pre-clinical and patient-derived xenografts: PDXovo [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 1277.
Abstract 2579: Integrated sequencing analysis reveals prognostic thyroid cancer-associated fibroblast subpopulations
Authors: Matthew A. Loberg, George J. Xu, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Sheau-Chiann Chen, Hua-Chang Chen, Quanhu Sheng, Eric C. Huang, Fei Ye, Ryan H. Belcher, Ethan Lee, Vivian L. Weiss
Journal: Cancer Research (2025)

Abstract Thyroid cancers exist on a continuum of differentiation. Our group recently defined dynamic changes in the tumor microenvironment co-occurring with tumor histotypes and de-differentiation. Here, we integrate 423, 733 cells from seven distinct single-cell RNA-sequencing cohorts to define unique thyroid cancer- specific fibroblast subtypes occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory, perivascular-like, and myofibroblastic cancer-associated (myCAF) populations. The myCAF population, specifically, is only found in malignant samples, and mapping myCAFs to three thyroid cancer bulk RNA-sequencing cohorts reveals an association with disease progression, with hazard ratio of 3.0 (95% CI, 1.7-5.3). Within this myCAF population, we identify subpopulations with immune-regulating phenotypes that are specifically associated with de-differentiated tumors. Additionally, we identify an invasive tumor cell phenotype in both differentiated and de-differentiated tumors marked by TNC and LAMB3. Ligand-receptor interaction analysis indicates robust interaction of myCAFs and invasive tumor cells through TGF-beta, tenascin, and collagen signaling pathways. Multiplex immunofluorescence, immunohistochemistry, and spatial transcriptomics analysis of 28 tumors (13 differentiated, 8 de-differentiated, 7 with areas of differentiated and de-differentiated histopathology) confirms robust upregulation of myCAFs in de-differentiated tumors. Further, myCAFs spatially localize next to the leading edge of de-differentiated tumors and near invasive cells from differentiated tumors, supporting a tumor-promoting role for myCAFs in aggressive thyroid carcinomas. In summary, our study provides an integrated atlas of thyroid cancer fibroblast subtypes, spatial analysis on patient samples, and an association of fibroblasts with disease progression. Citation Format: Matthew A. Loberg, George J. Xu, Claudia C. Wahoski, Kailey P. Caroland, Megan L. Tigue, Sheau-Chiann Chen, Hua-Chang Chen, Quanhu Sheng, Eric C. Huang, Fei Ye, Ryan H. Belcher, Ethan Lee, Vivian L. Weiss. Integrated sequencing analysis reveals prognostic thyroid cancer-associated fibroblast subpopulations [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 2579.
Abstract 841: The preclinical pharmacokinetics and pharmacodynamics of AZD0022: A potent, oral KRASG12D-selective agent exhibiting oral bioavailability and KRAS pathway suppression in the GP2D xenograft model
Authors: Kevin Beaumont, Sofia Guzzetti, Pablo Morentin-Gutierrez, Rhys D. Jones, Ken Grime, Carla Martins, Alex Koers, Alison Peter, Simon T. Barry, Susan Critchlow, Michele Moschetta, Michael Niedbala
Journal: Cancer Research (2025)

Abstract Objectives: AZD0022 is a small molecule selective inhibitor of KRASG12D. These studies investigate the preclinical PKPD relationships of AZD0022 to inform clinical development. Methods: Measurement of plasma and tumor concentrations were completed using standard extraction techniques with quantitation by LC-MS/MS methods. Target modulation (pRSK inhibition) was assessed in Nude mice implanted with GP2D human tumors by Western blot. Results: The preclinical PK properties of AZD0022 are defined by its physicochemistry (MW 614, extensive lipophilicity with log D(7.4) 2.5, dibasic with pKa values of 8.4 and 7.4). Oral administration studies suggest that AZD0022 is 30 to 70% absorbed from the gastrointestinal tract. AZD0022 exhibits extensive distribution into tissues. It also undergoes time-dependent partitioning into the red blood cell fraction of whole blood, suggesting that whole blood is the matrix that best represents the PK of the molecule. Blood clearance of AZD0022 was 8.2 and 8.6 mL/min/kg in mice and dogs, respectively. The measured Vss values based on blood were 10.8 and 20.4 L/kg, respectively. These characteristics suggest that in human, AZD0022 should be orally absorbed and exhibit a half-life consistent with once daily administration. In the GP2D model, single oral 150 mg/kg doses displayed prolonged plasma and tumour exposure. AZD0022 was estimated to be 18x more bound in tumour tissue than in plasma. Seven days of continuous 150mg/kg BID dosing resulted in up to approx. 75% pRSK inhibition. A dose range of 10, 50 and 150 mg/kg BID over 7 days displayed exposure-dependent pRSK modulation, with maximal of 75% pRSK inhibition. PKPD modelling suggested an unbound IC50 of 1.4 nM for pRSK inhibition. Conclusions: The results presented here support the clinical development of AZD0022 which is currently being tested in a first in human Phase I/IIa study (ALAFOSS-01, NCT06599502) Citation Format: Kevin Beaumont, Sofia Guzzetti, Pablo Morentin-Gutierrez, Rhys D. Jones, Ken Grime, Carla Martins, Alex Koers, Alison Peter, Simon T. Barry, Susan Critchlow, Michele Moschetta, Michael Niedbala. The preclinical pharmacokinetics and pharmacodynamics of AZD0A potent, oral KRASG12D-selective agent exhibiting oral bioavailability and KRAS pathway suppression in the GP2D xenograft model [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 841.
Abstract 776: Identifying gene expression patterns in intraductal carcinoma of the prostate using spatial gene expression analysis: Potential for new biomarkers and treatments
Authors: Ryuta Watanabe, Haruna Arai, Mie Kurata, Noriyoshi Miura, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika
Journal: Cancer Research (2025)

Abstract Introduction and Objective: Intraductal carcinoma of the prostate (IDC-P) is a form of prostate cancer where abnormal cells grow inside the ducts and glands, while the outer basal cell layer stays intact. IDC-P is often linked to certain genetic changes, including TMPRSS2-ERG fusions, as well as mutations or deletions in key genes like TP53, RB1, and PTEN. Given these findings, NCCN guidelines advise early genetic testing for IDC-P patients. Correctly diagnosing IDC-P and applying this knowledge to tailor treatments is essential for improving patient outcomes. Methods: We performed spatial gene expression analysis (using CytAssist Visium) on prostate cancer tissue samples with IDC-P. The goal was to identify gene abnormalities that could help in diagnosing IDC-P or serve as targets for future treatments. We analyzed how gene expression was distributed in IDC-P regions compared to other parts of prostate cancer tissue. Results: Our analysis showed that IDC-P regions had a unique gene expression profile, distinct from other prostate cancer areas. Specific genes such as MUC6, MYO16, NPY, and KLK12 were highly expressed in IDC-P, and these genes are associated with more aggressive cancer behavior. Additionally, genes related to hypoxia like HIF1A, BNIP3L, PDK1, and POGLUT1 were highly upregulated in IDC-P areas. At the same time, markers for immune cells (CCR5, FCGR3A) and fibroblasts (CCL5, TRAC) were downregulated. This suggests that IDC-P may be more aggressive due to hypoxia and fewer immune and fibroblast cells in the tumor environment. Conclusions: This study used spatial gene expression analysis to characterize IDC-P (Watanabe et al., IJMS 2024), providing valuable insights. However, this method also has some challenges, such as capturing signals from different cell types in the same spots, which makes it harder to distinguish between them. In future studies, combining spatial gene analysis with single-cell RNA sequencing or using more advanced techniques like Xenium could address these challenges. We are currently working on those studies and will be able to present the latest data on the day of the presentation. These approaches may help identify new diagnostic markers and lead to more personalized treatment options for patients with IDC-P. Citation Format: Ryuta Watanabe, Haruna Arai, Mie Kurata, Noriyoshi Miura, Riko Kitazawa, Tadahiko Kikugawa, Takashi Saika. Identifying gene expression patterns in intraductal carcinoma of the prostate using spatial gene expression analysis: Potential for new biomarkers and treatments [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 776.
Abstract 3464: Advancing antibody therapeutics: a 3D <i>in vitro</i> model for penetration assessment of immunoglobulins in human tumor spheroids
Authors: Sue Fontaine Grepper, Maja Nedic, Charlotte Veser, Michal Rudnik, Matthias Zbinden, Irina Agarkova, Madhu Nag, Laure-Anne Ligeon
Journal: Cancer Research (2025)

Abstract The advancements in biotechnology and the successful application of monoclonal antibody therapeutics have incited the development of innovative therapeutic antibody modalities, including bi-or tri-specific antibodies, antibody fragments (e.g. Fab), and other formats (e.g. DARPin). These have transformed cancer treatments; however, monoclonal antibodies often demonstrate limited efficacy in cancer therapy due to poor tumor penetration, leaving regions of untargeted and untreated tumor areas that can escape therapy. Addressing this limitation requires the development of advanced in vitro culture models that accurately replicate tumor-tumor microenvironment (TME) interactions. To bridge the gap between traditional 2D in vitro cultures and animal models, 3D human tumor spheroids offer a promising solution. In this context, InSphero has developed an in vitro 3D Antibody Penetration Assay. We demonstrate that 3D InSight™ Human Tumor Microtissues closely mimic the complexity and heterogeneity of the TME, while maintaining uniform composition and size across spheroids, providing reliable and reproducible models to enhance drug discovery. Using 3D InSight™ human tumor spheroids, we evaluated the efficacy, distribution, and penetration depth of a therapeutic antibody and an antibody-drug conjugate (ADC). Results showed that both modalities successfully penetrated the 3D InSight™ lung cancer tumor (A549) model. After 30 minutes of treatment, antibodies were detected at the periphery of the spheroids, while longer treatment windows resulted in progressively deeper penetration. This assay offers a robust and reliable platform for assessing the distribution and penetration of antibody therapeutics, biologics, ADCs, and other agents in solid tumor models, leveraging advanced in vitro 3D human tumor models to improve drug discovery and therapeutic development. Citation Format: Sue Fontaine Grepper, Maja Nedic, Charlotte Veser, Michal Rudnik, Matthias Zbinden, Irina Agarkova, Madhu Nag, Laure-Anne Ligeon. Advancing antibody therapeutics: a 3D in vitro model for penetration assessment of immunoglobulins in human tumor spheroids [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 3464.
Abstract 6237: Eco-evolutionary guided pathomics analysis to predict DCIS upstaging
Authors: Mehdi Damaghi, Yujie Xiao
Journal: Cancer Research (2025)

Abstract Cancers evolve in a dynamic ecosystem. Thus, characterizing cancer’s ecological dynamics is crucial to understanding cancer evolution and can lead to discovering novel biomarkers to predict disease progression. Ductal carcinoma in situ (DCIS) is an early-stage breast cancer characterized by abnormal epithelial cell growth confined within the milk ducts. In this study, we show that ecological habitat analysis of hypoxia and acidosis biomarkers can significantly improve prediction of DCIS upstaging. First, we developed a novel eco-evolutionary designed approach to define habitats in the tumor intra-ductal microenvironment based on oxygen diffusion distance. Then, we identify cancer cells with metabolic phenotypes attributed to their habitat conditions, such as the expression of CA9 indicating hypoxia responding phenotype, and LAMP2b indicating the acid adaptation. Traditionally these markers have shown limited predictive capabilities for DCIS upstaging, if any. However, when analyzed from an ecological perspective, their power to differentiate between pure DCIS and upstaged DCIS increased significantly. Second, using eco-evolutionary guided computational and digital pathology techniques, we discovered distinct niches with spatial patterns of these biomarkers and used the distribution of such niches to predict patient upstaging. With a 5-fold validation on the biopsy cohort, we trained a random forest classifier to achieve the area under curve (AUC) of 0.74. Our results affirm the importance of using eco-evolutionary-designed approaches in biomarkers discovery. Citation Format: Mehdi Damaghi, Yujie Xiao. Eco-evolutionary guided pathomics analysis to predict DCIS upstaging [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 6237.
Abstract 1646: Elucidating the molecular mechanism of action of the first in human SMARCA2 selective degrader PRT3789
Authors: Min Wang, Miles Cowart, Joy Cote, Justin Kurian, Stephanie Rodgers, Chaoyi Xu, Corey Basch, Philip Pitis, Klare Bersch, Raul Leal, Liang Lu, Michael Hulse, Andrew Moore, Alexander Grego, Joseph Rager, Tom Emm, Koichi Ito, Neha Bhagwat, Andrew Combs, Sandy Geeganage, Peggy Scherle
Journal: Cancer Research (2025)

Abstract Mammalian SWI/SNF (BAF) complexes play an important role in controlling gene expression by remodeling chromatin. SMARCA2 (BRM) and SMARCA4 (BRG1) are the core catalytic subunits of the SWI/SNF complexes and regulate the composition of nucleosomes via their ATPase activity. Approximately 10-12% of non-small cell lung cancer (NSCLC) patients harbor SMARCA4 mutations, resulting in loss of SMARCA4 protein or loss of its function (LOF). These SMARCA4-deficient cancer cells are highly dependent on the paralog gene SMARCA2 for their growth and survival. We have identified PRT3789, a first-in-class SMARCA2 selective targeted protein degrader currently in clinical trials (NCT05639751). PRT3789 promoted the formation of ternary complexes between the bromodomain of SMARCA2 or SMARCA4 with the VHL E3 ligase. Although SMARCA2 and SMARCA4 share 87% identity in their bromodomain, the structural differences between PRT3789 induced SMARCA2-VHL and SMARCA4 -VHL ternary complexes lead to more productive ubiquitination on SMARCA2 compared to SMARCA4. Proteomics and mutagenesis studies identified specific lysine residues that were ubiquitinated on the bromodomain of SMARCA2 and SMARCA4, and a unique loop on SMARCA2 that contributed to ternary complex stabilization and ubiquitination. In summary, we describe the systematic characterization of PRT3789 mediated SMARCA2 degradation and illustrate the molecular mechanism of action for how PRT3789 achieves degradation selectivity against SMARCA4. Citation Format: Min Wang, Miles Cowart, Joy Cote, Justin Kurian, Stephanie Rodgers, Chaoyi Xu, Corey Basch, Philip Pitis, Klare Bersch, Raul Leal, Liang Lu, Michael Hulse, Andrew Moore, Alexander Grego, Joseph Rager, Tom Emm, Koichi Ito, Neha Bhagwat, Andrew Combs, Sandy Geeganage, Peggy Scherle. Elucidating the molecular mechanism of action of the first in human SMARCA2 selective degrader PRT3789 [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 1646.