tbuckley/cabot-search huggingface dataset:
Abstract 4368: Selective targeting of oncogenic KRAS G12D using complementary peptide nucleic acid oligomers
Authors: Jayati Mondal, Dennis Lam, Mary E. Gerritsen, Tilmann M. Brotz, Jodi G. Kennedy, Bruce Rehlaender, Arthur J. Ross, Daniel E. Levy, Christopher A. Bonagura, William Lanzilotta, Frank McCormick, Jeffrey H. Rothman, Andrew L. Wolfe
Journal: Cancer Research (2025)

KRAS is a proto-oncogene that has activating mutations in ∼15-30% of all cancers. Conventional therapies non-selectively target tumor and normal cells which may cause high toxicities, and programmable mutant-selective targeted inhibitors are lacking. Peptide nucleic acids (PNAs) have base sequences analogous to DNA, except they have modified peptide backbones instead of sugar-phosphate backbones, allowing them to hybridize with DNA with high avidity to suppress transcription. Here, we developed KRAS G12D-selective PNA oligomers with novel cell-penetrating peptides (CPP) flanking regions. Immunofluorescently labeled PNA-CPP oligomers had high uptake rates in cells and nuclei. Complementary PNA-CPP treatment resulted in repression of KRAS G12D RNA and protein expression within 2 hours, lasting up to 48 hours. Alternative end modifications and lengths of complementary KRAS sequence were tested using dose-response cell viability assays. These experiments identified modifications to PNA oligomer sequence composition and length that were most effective at selectively preventing growth of on-target KRAS G12D cells, while relatively sparing off-target KRAS G12C cells. These PNA-CPPs were effective against a panel of pancreatic ductal adenocarcinoma cell lines and patient derived xenografts in vivo. These results indicate that PNA-CPPs show promise as both a tool for studying tumors driven by oncogenic point mutations, and as a possible therapeutic strategy capable of sparing normal cells while selectively targeting mutant cancer cells. Citation Format: Jayati Mondal, Dennis Lam, Mary E. Gerritsen, Tilmann M. Brotz, Jodi G. Kennedy, Bruce Rehlaender, Arthur J. Ross, Daniel E. Levy, Christopher A. Bonagura, William Lanzilotta, Frank McCormick, Jeffrey H. Rothman, Andrew L. Wolfe. Selective targeting of oncogenic KRAS G12D using complementary peptide nucleic acid oligomers [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 4368.
Abstract 5004: Application of a comprehensive multi-omic immune profiling strategy achieves superior checkpoint immunotherapy response prediction in lung cancer
Authors: Helen M. McGuire, Natalie Smith, Michael Cohen, Julien Hedou, Grégoire Bellan, Xavier Durand, Erika L. Smith-Mahoney, Julie Alipaz, Jennifer Snyder-Cappione, Brice Gaudilliere, Christina Loh, David King, Michael Hinterberg, Clare Paterson, Barbara Fazekas de St Groth
Journal: Cancer Research (2025)

Abstract Immune checkpoint inhibitors (ICIs) are currently the most effective treatment for late-stage lung cancer. However, most patients fail to mount a durable response, and the mechanisms underlying non-responsiveness remain elusive. Here, we apply a universal omics approach to identify correlates of non-responsiveness to ICIs in lung cancer. In-depth characterization of the plasma proteome was performed using the SomaScan™ platform on pretreatment and longitudinal blood samples from 40 ICI-treated patients, resulting in quantification of 10, 000 unique proteins. In parallel, comprehensive immune phenotyping was achieved with matched pretreatment PBMC for 90% of patients (36/40) through CyTOF™ technology, with a 38-plex panel describing over 150 immune populations in circulation. To enhance clinical outcome predictability of cellular and plasma-based immune relationships, cross-platform data integration was achieved with Stabl, a sparse, reliable omic biomarkers analysis strategy. Stabl identified key predictive features from both CyTOF and SomaScan technology, providing insight into immune deficits present in non-responsive patients. The combined model demonstrated a stronger capability to predict non-response from a pretreatment blood sample (AUROC = 0.79, p-value = 1.7e-2, Mann-Whitney non-parametric test) compared with individual platforms alone. Additionally, this multi-omic strategy is compatible with Imaging Mass Cytometry™ technology, unlocking another layer of clinical investigation via spatial biology. This study ultimately demonstrates both the clinical impact and utility of blood- and imaging-based CyTOF technology and the benefit of combining SomaScan and multi-omic-appropriate analysis approaches. Overall, robust treatment prediction, attributed to biomarker features, provides insights into mechanisms for non-response and highlights the potential for better treatment options in lung cancer. Citation Format: Helen M. McGuire, Natalie Smith, Michael Cohen, Julien Hedou, Grégoire Bellan, Xavier Durand, Erika L. Smith-Mahoney, Julie Alipaz, Jennifer Snyder-Cappione, Brice Gaudilliere, Christina Loh, David King, Michael Hinterberg, Clare Paterson, Barbara Fazekas de St Groth. Application of a comprehensive multi-omic immune profiling strategy achieves superior checkpoint immunotherapy response prediction in lung 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 5004.
Abstract 3499: Engineering and construction of anti-B7-H3 antibody-based T cell engagers (TCEs) and antibody-drug conjugates (ADCs) for cancer therapy
Authors: Chuan Chen, Yue Wu, Liang Tian, Chenpeng Su, Xiaoou Xu, Xiaoqian Chen, Dandan Liu, Yang He, Jiyuan Tian, Jian Peng, Zhenping Zhu
Journal: Cancer Research (2025)

Abstract B7-H3 (CD276), an immunomodulatory protein of the B7 superfamily, is overexpressed in a wide range of solid tumors. Various antibody-based therapeutic modalities targeting B7-H3 have shown antitumor response in preclinical and clinical studies. Ifinatamab deruxtecan (I-DXd), a B7-H3-directed DXd antibody drug conjugate (ADC) has demonstrated promising efficacy in patients with pretreated ES-SCLC in phase II clinical study. Further, several bispecific T-cell engagers (TCE) targeting B7-H3 and CD3 have also entered early phase clinical trials. In this study, leveraging our streamlined AI-guided antibody engineering platform, we generated several biparatopic TCEs targeting B7-H3 and CD3 as well as a number of biparatopic anti-B7-H3 ADCs constructed with various linkers and cytotoxic payloads. Our biparatopic TCEs were designed to simultaneously target two distinct epitopes on B7-H3 and with monovalent binding to CD3 on T cells with moderate to low affinity, in an attempt to enhance T cell-mediated specific cytotoxicity while mitigating the risk of cytokine release syndrome (CRS). The lead biparatopic TCE molecule demonstrated a robust B7-H3-specific T cell-dependent cellular cytotoxicity towards multiple B7-H3-positive tumor cells with various B7-H3 expression levels. The biparatopic ADCs demonstrated high avidity-driven binding activity to B7-H3 positive cancer cells and were capable of mediating strong internalization activity with higher tumor cell killing efficiency compared to their counterpart ADCs targeting to a single binding epitope. Further in vitro assays and in vivo efficacy studies for the lead biparatopic TCE and ADC molecules in xenografted tumor animal models are being investigated. Taken together, our studies provide support for the further development of the biparatopic B7-H3-targeting ADCs and TCEs for the treatment of B7-H3-expressing solid cancers. Citation Format: Chuan Chen, Yue Wu, Liang Tian, Chenpeng Su, Xiaoou Xu, Xiaoqian Chen, Dandan Liu, Yang He, Jiyuan Tian, Jian Peng, Zhenping Zhu. Engineering and construction of anti-B7-H3 antibody-based T cell engagers (TCEs) and antibody-drug conjugates (ADCs) for cancer therapy [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 3499.
Abstract 4349: Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling for VVD-130037, a novel, first-in-class covalent small molecule Kelch-like ECH-associated protein 1 (KEAP1) activator
Authors: Conrad Housand, Nil Roy, Tine Wyseure, Christie Eissler, Hauke Ruehs, Christoph Niederalt, Carsten Zieschang, Marielena Mata, Ramin Samadani, John Bothos, Lawrence Lu, Jenna Goldberg, Peter N. Morcos
Journal: Cancer Research (2025)

Introduction: The KEAP1-nuclear factor erythroid 2 (NRF2) pathway provides homeostatic mechanisms for oxidative stress response which can be activated in cancers. Vividion Therapeutics has developed novel allosteric molecular glues of the Keap1-CUL3 E3-ligase complex. Preclinically, these agents covalently target KEAP1-CUL3 E3 ligase and allosterically increase the affinity between KEAP1 and CUL3, promoting the formation of active KEAP1-CUL3 E3 ligase complexes and enhancing NRF2 degradation (Mol Cancer Ther (2023) 22 (12_Suppl): PR011). We established a translational PK/PD model for KEAP1 target engagement (TE) for the clinical candidate, VVD-130037. Methods: VVD-130037 PK/PD modeling leveraged an initially developed framework (Mol Cancer Ther (2023) 22 (12_Suppl): C126). Compartmental PK models are used to describe VVD-130037 plasma and tumor exposure and are coupled to a mechanistic TE model capturing intracellular covalent binding to KEAP1 and KEAP1/NRF2 synthesis, degradation and complex formation. The PK models were parameterized using mouse experiments; the predicted tumor concentration provided the input to the TE model. Predictive accuracy of the TE model was made by comparison to experimental TE. A physiologically-based PK (PBPK) model incorporating human physiology was linked to the TE model for human PK-TE predictions. Results: The PK model captures mouse plasma and tumor PK across dose levels. Similarly, the mechanistic TE model adequately predicts in vitro and in vivo TE profiles at various drug concentrations. Sensitivity analyses reveal KEAP1 turnover as a key parameter influencing VVD-130037 TE. Biologically plausible ranges facilitate predictions of efficacious dose regimens to saturate TE. The VVD-130037 human PBPK model predicted a rapid plasma half-life, however when coupled with the TE model predict sustained peripheral and tumor TE with once and twice daily dosing regimens. Conclusions: A translational PK/PD model is developed for VVD-130037; supporting efficacious doses during clinical development. Citation Format: Conrad Housand, Nil Roy, Tine Wyseure, Christie Eissler, Hauke Ruehs, Christoph Niederalt, Carsten Zieschang, Marielena Mata, Ramin Samadani, John Bothos, Lawrence Lu, Jenna Goldberg, Peter N. Morcos. Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling for VVD-130037, a novel, first-in-class covalent small molecule Kelch-like ECH-associated protein 1 (KEAP1) activator [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 4349.
Abstract 4345: BH3120, a PD-L1x4-1BB bispecific antibody, exhibits favorable safety profiles in distinct in vivo and ex vivo liver toxicity evaluations
Authors: Jing Wang, Jiangcheng Xu, Jun Wang, Jiangwang Liu, Kyoungwoo Lee
Journal: Cancer Research (2025)

Abstract BH3120 is a novel bivalent PD-L1/4-1BB bispecific antibody targeting both inhibitory (PD-1/PD-L1) and co-stimulatory (4-1BB clustering) signaling. In multiple non-clinical safety evaluations, BH3120 consistently showed minimal modulation of T cell functions in the blood or normal tissues resulting in favorable safety profiles. Clinical evaluation of BH3120 as a monotherapy and in combination with a PD-1 inhibitor is underway (NCT06234397). While early stage clinical evaluations of 4-1BB agonists as a monotherapy or in combination with PD-1/PD-L1 inhibitors are generally associated with certain level of liver abnormalities, the potential biomarkers or patient’s backgrounds that can pre-determine the risk of liver toxicity have not been discussed in details. In the meantime, treatment discontinuation or disruption, and administration of corticosteroid due to liver toxicity would be the limitations of 4-1BB agonists in tumor management, and the mode of action and impact of 4-1BB agonists on liver inflammation need to be further investigated. To understand potential risks of liver toxicity with BH3120, sensitive in vivo and ex vivo models for liver toxicity evaluations were established: a mice model with mild liver inflammation induced by Concanavalin A, and human liver organoids co-cultured with immune cells to mimic the histological and physiological changes in patient's liver tissues. In both models, BH3120 was not associated with significant elevation of liver inflammation markers, indicating minimal risk of liver toxicity that is in line with the safety results we previously reported. The property of BH3120 to minimize systemic immune modulation enables de-coupling of anti-tumor efficacy from systemic toxicities, and would provide flexibility in combination with different anti-tumor treatments. Citation Format: Jing Wang, Jiangcheng Xu, Jun Wang, Jiangwang Liu, Kyoungwoo Lee. BH3120, a PD-L1x4-1BB bispecific antibody, exhibits favorable safety profiles in distinct in vivo and ex vivo liver toxicity evaluations [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 4345.
Abstract 3350: Prognostic importance of physical activity in the chemotherapy of esophagogastric cancer; associations with skeletal muscle, systemic inflammation, and lifestyle
Authors: Koichi Hayano, Natsiko Arimatsu, Yasunori Matsumoto, Yoshihiro Kurata, Ryota Otsuka, Akira Nakano, Tadashi Shiraishi, Nobufumi Sekino, Takeshi Toyozumi, Masaya Uesato, Gaku Ohira, Hisahiro Matsubara
Journal: Cancer Research (2025)

Abstract Background: Physical activity (PA) must be an important intervention in the treatment of cancer. However, it is unknown what kinds of PAs can improve patients’ outcome in the chemotherapy of esophagogastric cancer (EGC). Methods: Unresectable or recurrent EGC patients treated with chemotherapy were prospectively investigated. PA was measured using an accelerometer for 1 week before and after the chemotherapy administration. PA was classified as sedentary behavior (&amp;lt; 1.5METs, SB), light-intensity PA (1.6-2.9 METs, LPA), and moderate-to-vigorous PA (≥ 6.0 METs, MVPA). PA parameters were compared with disease specific survival (DSS), inflammatory and nutritional markers, subsequent skeletal muscle (SM) volume change, and lifestyle. Results: Thirty-nine patients were evaluated. In Cox regression analyses, better DSS was significantly correlated with longer times of LPA (P=0.02), but not with MVPA (P=0.2). LPA showed significant negative correlations with WBC, CRP, and modified GPS score (P=0.03, 0.03, 0.004, respectively), and positive correlations with serum total protein (TP) and albumin (Alb) levels and SM change (P=0.01, 0.003, 0.01, respectively). The longer times of LPA was significantly associated with better socialization with neighbors (P=0.001). Conclusions: LPA would be recommended during the chemotherapy of advanced EGC patients, keeping their better inflammatory and nutritional status and preventing SM loss. Socialization might play a key role in increasing LPA. Citation Format: Koichi Hayano, Natsiko Arimatsu, Yasunori Matsumoto, Yoshihiro Kurata, Ryota Otsuka, Akira Nakano, Tadashi Shiraishi, Nobufumi Sekino, Takeshi Toyozumi, Masaya Uesato, Gaku Ohira, Hisahiro Matsubara. Prognostic importance of physical activity in the chemotherapy of esophagogastric cancer; associations with skeletal muscle, systemic inflammation, and lifestyle [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 3350.
Abstract 3127: An mRNA-encoded masked IL-12 improves systemic tolerability while maintaining anti-tumor efficacy in preclinical studies
Authors: Kanchana Ravichandran, Erwan LeScolan, Na Cai, Bruce Howng, Robert Lau, Lisa Clark, Joshua Millet, Pankaj Kumar, Sushma Gurumurthy, Raghava Sriramaneni, Sean McAllister, Vangipuran Rangan, Olga Vasiljeva, Madan Paidhungat, Dylan Daniel, Marcia Belvin, Lin Guey
Journal: Cancer Research (2025)

Abstract IL-12 is a potent pro-inflammatory cytokine that has shown promising anti-tumor activity through its ability to activate both innate and adaptive immune cells. However, systemically administered IL-12 has limited clinical utility due to striking inflammatory toxicity and short half-life leading to a narrow therapeutic margin. Alternative strategies to reduce systemic exposure or restrict IL-12 activity to the tumor microenvironment and limit activity in circulation and non-tumor tissues have been explored. Using CytomX proprietary PROBODY® Therapeutics masking technology and Moderna mRNA technology, we describe a novel product concept of an mRNA encoded masked IL-12 molecule that is designed to have reduced activity systemically. Masked IL-12 is activated by elevated protease activity associated with the tumor microenvironment (TME), leading to preferential IL-12 activity in the tumor microenvironment. mRNA-encoded masked IL-12 protein showed 200X lower cell-based potency relative to an unmasked IL-12 counterpart and regained full activity upon protease-mediated cleavage of the mask in vitro. In an in vivo MC-38 tumor-bearing mouse model, systemically administered LNP encapsulated mRNA encoding masked IL-12 showed significantly improved tolerability (&amp;gt;30X) compared to unmasked IL-12. Consistently, masked IL-12 mRNA led to significantly lower serum IFNγ levels relative to unmasked IL-12 mRNA dosed at 10X lower dose. Most importantly, masked IL-12 mRNA dosed systemically resulted in complete remission of tumors in all dose levels and demonstrated protease-dependent intra-tumoral activation and efficacy. Taken together, these data show a novel and attractive engineering approach to develop an mRNA-encoded IL-12 therapeutic that significantly improves tolerability while maintaining potent anti-tumor activity. Citation Format: Kanchana Ravichandran, Erwan LeScolan, Na Cai, Bruce Howng, Robert Lau, Lisa Clark, Joshua Millet, Pankaj Kumar, Sushma Gurumurthy, Raghava Sriramaneni, Sean McAllister, Vangipuran Rangan, Olga Vasiljeva, Madan Paidhungat, Dylan Daniel, Marcia Belvin, Lin Guey. An mRNA-encoded masked IL-12 improves systemic tolerability while maintaining anti-tumor efficacy in preclinical 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 3127.
Abstract 4030: Uncovering psychosocial and physical challenges in colorectal cancer: findings from a comprehensive patient and survivor survey
Authors: Kimberly Lynn Newcomer, David Fenstermacher
Journal: Cancer Research (2025)

Abstract Background: Colorectal cancer (CRC) is the third most diagnosed cancer and the second leading cause of cancer-related deaths globally among men and women combined. While survival rates for CRC have improved, limited knowledge exists about the specific unmet needs of CRC patients and survivors. These needs include emotional support, information on treatment options, and strategies for coping. CRC significantly impacts patients' emotional well-being, quality of life (QoL), and healthcare experiences. Beyond the stress of a cancer diagnosis, patients endure the physical and emotional toll of rigorous treatments, even in cases where no signs of the disease remain. Methods: The Colorectal Cancer Alliance conducted a comprehensive survey of CRC patients, survivors, and caregivers to better understand their experiences and needs. This IRB-approved, cross-sectional study included over 150 questions addressing patient profiles, diagnosis, access to care, treatment experiences, resources, and QoL. The survey was distributed through the Alliance’s social media, email, and web-based platforms, reflecting a collaborative effort to address the multifaceted challenges faced by the CRC community. Results: Insights from 283 CRC patients and survivors highlighted critical unmet needs. The median age group of respondents was 46-55. Key findings included 74% struggling to find someone who shared similar experiences, 41% reporting reduced support after treatment, 54% feeling fatigued, and 51% experiencing stress. Cancer significantly disrupted personal and social aspects of life: 64% reported adverse effects on careers, 51% on dating, 43% on family planning, 58% on spousal relationships, 80% on sexual health, and 65% on social participation. Although patients felt well-informed pre-treatment, 46% identified gaps in knowledge about complementary or alternative therapies. These findings underscore the importance of addressing psychosocial and physical needs to improve care outcomes. Conclusions: CRC patients and survivors face profound psychosocial and physical challenges that reshape their lives. By identifying these needs, healthcare providers can develop more personalized treatment plans and support systems, offering hope for better patient experiences and outcomes. The Alliance aims to use these findings to guide clinical practices, care programs, and survivorship support, driving transformative improvements in CRC care. Citation Format: Kimberly Lynn Newcomer, David Fenstermacher. Uncovering psychosocial and physical challenges in colorectal cancer: findings from a comprehensive patient and survivor survey [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 4030.