tbuckley/cabot-search huggingface dataset:
Abstract 586: Combining advanced peptide screening methods to identify candidates for PDC/RDC/POC development
Authors: Weiliang Xu, Jin Zhang
Journal: Cancer Research (2025)

Abstract Peptide-based therapeutics, including peptide-drug conjugates (PDCs), peptide-radionuclide conjugates (RDCs), and peptide oligonucleotides (POCs), are gaining recognition as highly promising targeted treatment options due to their exceptional specificity, low toxicity, and flexible pharmacokinetic profiles. To expedite the identification of effective peptide candidates, we have developed an advanced peptide discovery platform that combines Peptide Information Compression Technology (PICT), Disulfide-Rich Peptides (DRPs) phage display, animal toxin libraries, nano macrocyclic peptides, and virtual peptide libraries. This cutting-edge platform efficiently discovers multicyclic peptide hits with antibody-like binding affinity (sub-nM to pM), enhanced serum stability (lasting from hours to days), and bi-functional properties optimized to engage multiple receptor targets within a six-month timeframe. Our integrated screening approach employs high-throughput techniques to swiftly identify peptide leads that meet the stringent criteria required for PDC, RDC, and POC development. We have successfully discovered peptide leads with high binding affinity and endocytosis on over 40 targets, including tumor biomarkers such as FAP, Nectin-4, Trop2, GRPR, FGFR2, GPC3 and DLL3. The platform’s combination of diverse peptide libraries and sophisticated computational modeling enhances the selection of candidates with superior binding affinities, structural stability, and functional adaptability. By leveraging these advanced screening technologies, we address the limitations of traditional peptide discovery methods, shortening development timelines and reducing the reliance on extensive medicinal chemistry optimization. Our findings illustrate that this platform significantly streamlines the discovery process for peptide-based therapeutics, establishing a powerful pipeline for the development of next-generation bi-functional peptides with broad applications in oncology, inflammation, and other therapeutic areas. Citation Format: Weiliang Xu, Jin Zhang. Combining advanced peptide screening methods to identify candidates for PDC/RDC/POC development. [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 586.
Abstract 1053: Cellular heterogeneity and stress response in lung tumors: understanding cancer disparities through spatial transcriptomics
Authors: Sabrina Akter, Aiman Soliman, Zeynep Madak-Erdogan, Sage J. Kim
Journal: Cancer Research (2025)

Abstract Background: Despite having lower smoking rates, Black men have a higher incidence of lung cancer. Previously, we showed that social stressors, such as neighborhood violent crime, may influence tumor biology through stress response pathways. In this study, we investigated the relationship between neighborhood violent crime rates and glucocorticoid biosynthesis in lung tumors. Specifically, we examined how cell populations change in tumor regions with high glucocorticoid metabolism and receptor activity. Methods: We analyzed spatial transcriptomic data from 15 lung tumor samples. Pathway activity and cell type associations were examined using gene set co-regulation analysis (GESECA). We computed univariate and bivariate local Moran's I to assess spatial co-localization at p &amp;lt; 0.05. To validate these spatial associations, we performed unsupervised cell-type deconvolution using STdeconvolve and applied spatial interpolation to enhance the resolution of cell-type distributions. Results: We identified a positive correlation between neighborhood violent crime rates and glucocorticoid biosynthesis pathway activity (p &amp;lt; 0.05). Several epithelial cell types, including adventitial fibroblasts, basal cells, club cells, and mesothelial cells, were significantly associated with glucocorticoid biosynthesis-enriched regions in lung tumor samples from high-crime neighborhoods. Cell type deconvolution and spatial interpolation confirmed localized clustering of these epithelial cells within glucocorticoid biosynthesis-active regions at high resolution. Conclusions: Our findings suggest that social stressors, such as neighborhood violent crime, may contribute to lung cancer disparities by influencing tumor development through stress-induced pathways. This study highlights the importance of understanding cellular heterogeneity within the tumor microenvironment, which could inform targeted cancer prevention and control interventions. Citation Format: Sabrina Akter, Aiman Soliman, Zeynep Madak-Erdogan, Sage J. Kim. Cellular heterogeneity and stress response in lung tumors: understanding cancer disparities through spatial transcriptomics [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 1053.
Abstract 938: HHV-7-mediated downregulation of HLA-F: a mechanism for immune evasion in angiosarcoma
Authors: Bavani Kannan, Janos Luka, Tun Kiat Ko, Jason Chan
Journal: Cancer Research (2025)

Abstract Background: Human herpesvirus-7 (HHV-7) is a ubiquitous, CD4+ T cell lymphotropic virus. It establishes lifelong latency and may reactivate, particularly in immunocompromised individuals. We had previously detected the presence of HHV-7 in two-thirds of angiosarcoma clinical samples. HHV-7-positive (HHV-7+) tumors were shown to be relatively enriched for B- and mast cells and had high tumor inflammation signature scores compared to HHV-7-negative tumors. Objective: To investigate HHV-7 pathogenesis in host cells and its role in angiosarcoma. Methods: A SupT1 infection model was established. Images and cell pellets were collected at Days 0 and 4 (early infection phase) and Days 8 and 14 (late infection phase) for bulk RNA-seq analysis. Gene expression data was validated with quantitative PCR (qPCR). RNA-seq and Nanostring gene expression profiling with the Pancancer IO360 panel were previously performed on HHV7+ fresh frozen and FFPE angiosarcoma samples respectively. Results: Infected SupT1 cells exhibited cytopathic effects (CPEs) such as membrane blebbing, syncytia formation and growth arrest during early infection phase. Cell lysis, followed by recovery of cell growth, were observed during late infection phase. RNA-seq revealed significant pathway alterations across the infection course, supporting these observations. Early infection showed notable upregulation in arachidonic acid metabolism and antigen processing and presentation pathways, indicating an anti-viral response in host cells. The downregulation in actin cytoskeleton and cell cycle pathways were seen, corresponding to the observed CPEs. During late infection, there was a significant downregulation in antigen processing and presentation pathways (padj. &amp;lt;0.05), suggesting immune evasion the virus, along with a significant downregulation of tumor suppressor genes such as RNF43 and CBFA2T3. Through the course of infection, a general upward trend of oncogenic and inflammatory pathways was seen, with the latter being observed in HHV-7+ angiosarcomas as well. Narrowing down on specific genes, we observed the significant downregulation of HLA-F and upregulation of HK2 in both late-stage SupT1 infection and HHV-7+ angiosarcomas, implicating these genes in immune evasion and tumor progression. Conclusions: Our study provides the first RNA-seq profiling of HHV-7 infection in host cells. The study reveals alterations in key cellular pathways that promote an immunosuppressive and pro-inflammatory environment. These changes likely facilitate tumor progression and immune evasion in angiosarcoma. Citation Format: Kuo-Chu Lai. Metabolic alterations in skeletal muscle and serum of tumor-bearing cachectic mice [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 286.
Abstract 1161: A systematic evaluation of off-target binding in antibody-based biologics during clinical and preclinical development
Authors: Diana Norden, Carmen Navia, Tabb Sullivan, Alexander Hobby, Benjamin Doranz
Journal: Cancer Research (2025)

Abstract Background: Specificity profiling is a requirement for monoclonal antibodies (MAbs) and antibody-based biotherapeutics such as CAR-T prior to initiating human trials. Traditional approaches to assess MAb specificity, primarily tissue cross-reactivity (TCR) studies, have been unreliable and have resulted in undetected off-target binding. Cell-based protein arrays represent an alternative and improved assessment tool for MAb specificity that have been recommended in recent FDA guidance. Methods: We developed a cell-based protein array, the Membrane Proteome Array (MPA), to assess binding across the full human membrane proteome. The MPA encompasses ∼6, 000 membrane proteins, each individually expressed in their native structural configuration within unfixed cells. The MPA enables quantitative and high sensitivity detection using flow cytometry. Here, we used the MPA to estimate the frequency of off-target binding by candidate antibody therapeutics. We conducted a retrospective analysis of 250 customer preclinical antibodies screened on the MPA and produced and screened 83 biosimilars of FDA-approved and clinical-stage therapeutic antibodies. Results: Retrospective analysis of customer antibodies that were screened using the MPA indicates a surprisingly high off-target rate, with 33% of lead candidates displaying off-target binding. Moreover, about 20% of therapeutic MAbs in clinical development and currently on the market displayed off-target binding. To directly compare cell-based protein arrays to TCR studies, we compared our own MPA data for therapeutic MAbs to publicly available TCR data and in several cases identified discrepancies in off-target binding results. Conclusion: Overall, the presented case studies and off-target rates at the different phases of drug approval suggest that off-target binding is a major cause of adverse events and drug attrition that could be ameliorated with better specificity screening. Citation Format: Diana Norden, Carmen Navia, Tabb Sullivan, Alexander Hobby, Benjamin Doranz. A systematic evaluation of off-target binding in antibody-based biologics during clinical and preclinical development [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 1161.
Abstract 95: MTAP deficiency closely correlates with p16 status in non-small cell lung cancer but is unrelated to tumor aggressiveness or patient prognosis
Authors: Natalia Gorbokon, Nina Schraps, Katharina Möller, Seyma Büyücek, Maximilian Lennartz, Florian Viehweger, Christoph Fraune, Christian Bernreuther, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Martin Reck, Till Olchers, Florian Lutz, Till S Clauditz, Martina Kluth, Stefan Steurer
Journal: Cancer Research (2025)

Abstract Loss of S-methyl-5′-thioadenosine phosphorylase (MTAP) expression is often caused by genomic deletions of chromosome 9p21 in non-small cell lung cancer (NSCLC). Complete MTAP loss results in a critical vulnerability of cancer cells towards drugs targeting adenine synthesis and the methionine cycle. To study the clinical impact and heterogeneity of MTAP expression in lung cancer, a tissue microarray containing 470 adenocarcinomas and 235 squamous cell carcinomas, and conventional whole sections from all (5-15, average 7.4) tumor-containing tissue blocks of 5 lung cancers were analyzed by for immunohistochemical (IHC) expression of MTAP. MTAP expression was lost (0+) in 13.2%, weak (1+) in 45.4% and strong (2+/3+) in 41.4% of 423 interpretable adenocarcinomas (ADC), and 0+ in 25.8%, 1+ in 46.4% and 2+/3+ in 27.8% of 209 interpretable squamous cell carcinomas (SQCC) of the lung. MTAP deficiency was unrelated to parameters of tumor aggressiveness, including pT status, pN status, histological grade, and patient survival, in ADC and in SQCC. In 40 analyzed mesotheliomas, a MTAP loss was seen in 45% (p&amp;lt;0.0001 for adenocarcinoma vs. mesothelioma). Among the 5 consecutive lung cancers from which a total of 37 whole sections were analyzed, MTAP was homogeneously deficient in 1 case, heterogeneously deficient in another case, and homogeneously retained in the remaining 3 cases. In conclusion, loss of MTAP expression occurs in 13% (ADC) to 25% (SQCC) of NSCLC irrespective of tumor extent or metastasis stage. These findings identify a potential application of MTAP IHC in NSCLC for diagnosis of malignancy and the identification of patients who might benefit from MTAP-based therapies. However, the possible therapeutic efficacy could be impaired in patients with heterogeneous MTAP loss. Citation Format: Natalia Gorbokon, Nina Schraps, Katharina Möller, Seyma Büyücek, Maximilian Lennartz, Florian Viehweger, Christoph Fraune, Christian Bernreuther, Elena Bady, Lisa Hornsteiner, Ronald Simon, Guido Sauter, Martin Reck, Till Olchers, Florian Lutz, Till S Clauditz, Martina Kluth, Stefan Steurer. MTAP deficiency closely correlates with p16 status in non-small cell lung cancer but is unrelated to tumor aggressiveness or patient prognosis [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 95.
Abstract 959: Engineering tumor-avid bacteria as anticancer immunotherapy
Authors: Noah Chen, Mathieu Rouanne, Zaofeng Yang, Tal Danino, Nicholas Arpaia
Journal: Cancer Research (2025)

Abstract The observation that bacteria colonize tumors, but not normal organs, after intravenous administration has spurred new interest in bacteria as tumor-targeted delivery systems. Since bacteria replicate within the tumor site, intravenous administration of bacteria leads to specific expression of peptide-based therapeutics at the tumor site. However, most prior bacterial cancer therapies have relied on this natural tumor tropism since the mechanisms behind this tumor-specificity are poorly understood. Additionally, clinical trials with bacterial therapeutics have shown lower tumor colonization rates in humans, which limits their translatability. This study used a pooled barcode library approach to screen the E. coli genome for pathways which may influence tumor colonization. We found specific pathways, include glucose catabolism, which promote E. coli tumor colonization, and non-glucose catabolic pathways which inhibit E. coli tumor colonization. KO of these inhibitory metabolic pathways increase E. coli glucose uptake and utilization. This was associated with increased tumor colonization as validated by competitive infection experiments, which was further enhanced when glucose was introduced into the tumor microenvironment. Together, these results support a major role for E. coli glucose catabolism in defining bacterial tumor tropism and suggest a promising method by which bacterial tumor tropism can be fine-tuned. Citation Format: Noah Chen, Mathieu Rouanne, Zaofeng Yang, Tal Danino, Nicholas Arpaia. Engineering tumor-avid bacteria as anticancer immunotherapy [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 959.
Abstract 950: Engineered oncolytic vesiculovirus downsizes pancreatic tumor and boosts immune response
Authors: Khandoker Usran Ferdous, Mulu Z. Tesfay, Aleksandra Cios, Isabelle R. Miousse, Bolni Marius Nagalo
Journal: Cancer Research (2025)

Abstract Vesicular stomatitis virus (VSV) is one of the leading oncolytic virus prototypes used in both preclinical and clinical cancer research. A newly engineered chimeric vesiculovirus, VMG, has been tested against various cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, the effectiveness of virotherapies for PDAC is often limited by the immunosuppressive factors present in the tumor microenvironment. Moreover, the presence of hyaluronic acid (HA) and collagen (CN) in the microenvironment contributes to increased tumor stiffness and interstitial fluid pressure, which impede the delivery of drugs, oncolytic viruses, and immune cells into the tumor. To address these challenges, we developed VMG expressing bacterial collagenase (CNase), mouse hyaluronidase (mPH20), or a special enzyme (Enz) having both CNase and PH20-like effects; and evaluated their efficacy in a preclinical Pan02 PDAC model. Genetic modifications to VMG did not compromise its oncolytic activity or replicability in vitro, as shown by MTS assays and kinetic studies. In vivo studies revealed that VMG-Enz significantly reduced tumor volume compared to other synthetic viruses. Immunohistochemistry (IHC) and quantitative polarized light imaging (QPLI) confirms that the hybrid VMG viruses effectively dismantled stromal components, facilitating enhanced viral infection and propagation into the tumor. Flow cytometry analysis indicated a substantial increase in CD8+ T cells, granzyme B+ T cells, dendritic cells, and natural killer cells, alongside a decrease in M-MDSCs, which are indicators of successful onco-immunotherapy. However, we also noticed an elevation of immune checkpoint markers, including PD-1, PDL-1, PDL-2, and anti-viral resistance genes for IFN-α, IFN-β and Mx-1 after viral treatment which may have limited complete tumor remission by the VMG vectors. We conclude that VMG-Enz successfully enhanced immune response and significantly reduced tumor volume by altering stromal HA and collagen levels. Further studies are needed to explore VMG-Enz's potential as combination therapy with immune checkpoint inhibitors or type I interferon antagonists to achieve complete tumor eradication and enhance survival benefits in experimental animals. Citation Format: Khandoker Usran Ferdous, Mulu Z. Tesfay, Aleksandra Cios, Isabelle R. Miousse, Bolni Marius Nagalo. Engineered oncolytic vesiculovirus downsizes pancreatic tumor and boosts immune 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 950.
Abstract 430: Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer
Authors: Jessica Armand, Sungsoo Kim, Kibum Kim, Eugene Son, Minah Kim, Hee Won Yang
Journal: Cancer Research (2025)

Abstract The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy has revolutionized treatment for hormone receptor-positive (HR+) metastatic breast cancer. However, the emergence of resistance in most patients often leads to treatment discontinuation with no consensus on effective second-line therapies. The therapeutic benefits of maintaining CDK4/6i or incorporating CDK2 inhibitors (CDK2i) after disease progression remain unclear. Here, we demonstrate that sustained CDK4/6i therapy, either alone or combined with CDK2i, significantly suppresses the growth of drug-resistant HR+ breast cancer. Continued CDK4/6i treatment induces a noncanonical pathway for retinoblastoma protein (Rb) inactivation via post-translational degradation, resulting in diminished E2F activity and delayed G1 progression. Importantly, our data highlight that CDK2i should be combined with CDK4/6i to effectively suppress CDK2 activity and overcome resistance. We also identify cyclin E overexpression as a key driver of resistance to CDK4/6 and CDK2 inhibition. These findings provide crucial insights into overcoming resistance in HR+ breast cancer, supporting the continued use of CDK4/6i and the strategic incorporation of CDK2i to improve therapeutic outcomes. Citation Format: Jessica Armand, Sungsoo Kim, Kibum Kim, Eugene Son, Minah Kim, Hee Won Yang. Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast 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 430.
Abstract 315: Dose-response and tumor size at time of treatment with TD001, a novel ADC against PSMA, drive potent tumor growth inhibition in a CRPC CDX castrated mouse model
Authors: Roberta Frapolli, Ezia Bello, Marina Meroni, Daniela Impellizzieri, Elisa Storelli, Carlo V. Catapano, Lavinia Morosi, Maurizio D'Incalci, Jemila Houacine, Esteban Cvitkovic
Journal: Cancer Research (2025)

Abstract Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein belonging to the folate receptor family, is highly expressed in metastatic castrate-resistant prostate cancer (CRPC), and increases following androgen deprivation therapy. TD001 is a novel antibody-drug conjugate (ADC) composed of a deimmunized anti-PSMA IgG1 monoclonal antibody (HuJ591), which binds to the extracellular domain of PSMA, conjugated to a proprietary cleavable topoisomerase I inhibitor exatecan linker-payload (LD038), with a drug-to-antibody ratio (DAR) of 8. Flow cytometry and immunofluorescence microscopy show TD001 is internalized and cleaved rapidly, colocalizing with lysosomes in PSMA-expressing tumor cells. TD001 (10-20 mg/kg IV) was evaluated in a human CRPC cell line-derived xenograft (CDX) model, LNCaP-abl with high PSMA expression, in castrated NSG mice, with a range of tumor sizes (from 150 to 700 mm3) at the time of treatment. TD001 gave dose-dependent and sustained potent activity (tumor growth inhibition [TGI] &amp;gt;80%) with single dosing. Sustained inhibition of regrowth for 20 days was observed after TD001 10 mg/kg even in large tumors up to 400 mm3. Strong antitumoral activity of a single dose of TD001 10 mg/kg was also observed even in tumors &amp;gt;400 mm3 at the time of treatment. Tumor regrowth was faster in larger tumors (mean volume ∼300-400 mm3) compared to smaller tumors (mean volume ∼200 mm3). PSMA expression was unchanged in tumor regrowth between treated and vehicle control in the CDX castrated mouse model after treatment with TD001 up to 20 mg/kg, indicating no impact on target expression. Fractionation of a single TD001 dose into 2 or 3 doses administered every 10 days resulted in a 2-3 fold higher therapeutic index (TGI &amp;gt;90%) compared to the equivalent higher single isodose. No mortality or weight loss was reported. Pharmacokinetics/pharmacodynamic correlations of TD001 are described separately. TD001 appears as a best-in-class anti-PSMA Topo I inhibitor ADC (exatecan payload), and exhibited potent and sustained antitumor activity, including in large tumors, and represents a promising new treatment for PSMA-expressing CRPC patients. Citation Format: Roberta Frapolli, Ezia Bello, Marina Meroni, Daniela Impellizzieri, Elisa Storelli, Carlo V. Catapano, Lavinia Morosi, Maurizio D'Incalci, Jemila Houacine, Esteban Cvitkovic. Dose-response and tumor size at time of treatment with TD001, a novel ADC against PSMA, drive potent tumor growth inhibition in a CRPC CDX castrated mouse 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 315.