tbuckley/cabot-search huggingface dataset:
Abstract 1560: SCR-A0011, a novel bispecific ADC targeting cMET and B7H3, exhibits potent anti-tumor efficacy
Authors: Yayuan Fu, Guangcun Cheng, Hui Zheng, Shuai Wang, Lei Jiang, Chunlei Xia, Huipeng Guo, Xiyuan Wang, Renhong Tang
Journal: Cancer Research (2025)

Abstract Background: The HGF/cMET signaling pathway plays an important role in the regulation of cell proliferation, differentiation, migration and other normal physiological functions. cMET is expressed in many different normal tissues but is usually expressed at low levels. Abnormal expression and dysfunction of cMET have been found in a variety of tumors. cMET is a well-established target in clinical, but its clinical application is limited, because clinical efficacy was mainly observed in cMET signaling driving tumor or cMET-high expression tumors. To extend the potential therapeutic population and anti-tumor activity, we searching for some new approaches, such as bispecific antibody drug conjugates. Bioinformatics analysis and translational research showed that cMET and B7H3 are co-expressed in multiple types of solid tumors without high expression in normal tissues. Therefore, targeting both B7H3 and cMET could be a new and powerful strategy in pan-tumor therapy. Methods &amp; Results: We developed a novel B7H3xcMET targeted bispecific antibody-drug conjugate (ADC) called SCR-A0011, which is comprised of B7H3/cMET bispecific antibody conjugated with novel topoisomerase 1 inhibitor (CPT116). SCR-A0011 specifically bind B7H3 and cMET with high affinity, and showed enhanced internalization and binding capacity compared to parental monoclonal antibody ADC separately in the B7H3/cMET co-expressing cell line. SCR-A0011 induced tumor cell lysis in various tumor cell types including NSCLC, CRC, OC, HNSCC, etc. SCR-A0011 showed remarkable anti-tumor efficacy in several CDX models in a dose dependent manner. SCR-A0011 exhibits significantly stronger anti-tumor activity than their parental monoclonal-ADC or clinical ADC in B7H3+cMET+ double positive tumor cells. SCR-A0011 also have very good stability and favorable developability. Conclusion: These findings illustrated SCR-A011 could be a potential First-in-Class BsADC to conquer the resistance or non-response of current treatment in broad cancer types and may provide a new therapeutic approach for B7H3 and cMET positive cancer patients in the future. Citation Format: Yayuan Fu, Guangcun Cheng, Hui Zheng, Shuai Wang, Lei Jiang, Chunlei Xia, Huipeng Guo, Xiyuan Wang, Renhong Tang. SCR-A0011, a novel bispecific ADC targeting cMET and B7H3, exhibits potent anti-tumor efficacy [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 1560.
Abstract 1000: Impact of <i>GSTP1 Ile105Val</i> genetic polymorphism on cervical cancer risk among Bangladeshi female population
Authors: Md. Mustafizur Rahman, Md Mehedi Hasan, Abdur Rahman Munna, Amir Hossain
Journal: Cancer Research (2025)

Background and aim: Worldwide, cervical cancer is both the fourth-most common cause of cancer and the fourth-most common cause of death from cancer in women. Approximately 90% of deaths from cervical cancer occurred in low- and middle-income countries. Glutathione S-transferase P1 (GSTP1) is a xenobiotic metabolizing (detoxifying) enzyme. Studies have suggested that GSTP1 genetic polymorphism in exon 5 (Ile105Val, GSTP1 A313G) may play important role in determining susceptibility to cervical cancer, though the data have often been inconsistent. Objective: This study aimed to investigate the association of the GSTP1 Ile105Val polymorphism with the prevalence and risk of cervical cancer in Bangladeshi females. We also aimed at finding any correlation between demographic variables and polymorphic genotypes in cervical cancer patients. Materials and Methods: Polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) were performed to genotype GSTP1 polymorphism (Ile105Val). Genomic DNA was isolated from venous blood collected from 117 pathologically diagnosed squamous cell cervical cancer patients and 150 healthy females. Results: The homozygous variant (G/G) genotypes and heterozygous plus variant (A/G+G/G) genotypes showed 3.17 fold (OR= 3.1746, 95% CI= 1.037 to 9.7187, p=0.043) and 1.71 fold (OR= 1.7143, 95% CI= 1.0425 to 2.8189, p=0.0337) increased risk of cervical cancer when compared to homozygous wild type (A/A) genotypes, respectively. The allele frequency distribution of A and G in cases and controls also associated with increased cervical cancer risk (OR= 1.677, 95% CI= 1.1129 to 2.5271) and the result is statistically significant (p&amp;lt;0.05). However, there was no significant combined effects of demographic variables (p&amp;gt;0.05) and GSTP1 genotypes in cancer development. Conclusion: GSTP1genetic polymorphism (Ile105Val) could influence susceptibility to cervical cancer among Bangladeshi women. Citation Format: Md. Mustafizur Rahman, Md Mehedi Hasan, Abdur Rahman Munna, Amir Hossain. Impact of GSTP1 Ile105Val genetic polymorphism on cervical cancer risk among Bangladeshi female population [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 1000.
Abstract 1858: Nanoformulation strategy for oral delivery of KRAS inhibitor (sotorasib): pH-independent dissolution to mitigate PPI drug interaction
Authors: Henis Patel, Akanksha Patel, Ketan Patel
Journal: Cancer Research (2025)

Abstract Biovariability poses a significant challenge in the oral administration of sotorasib (AMG 510), an FDA-approved KRAS G12C inhibitor for non-small cell lung cancer (NSCLC). Sotorasib, a weakly basic drug with limited aqueous and pH-dependent solubility, necessitates a high daily dose (960 mg; 8 tablets). In general, high doses, pill burdens, and poor solubility often result in poor patient compliance and therapeutic outcomes. Co-administration with proton pump inhibitors (PPIs) in cancer patients significantly reduces the bioavailability of weakly basic drugs including sotorasib. To address these limitations, we developed a pH-independent nanocrystalline formulation through wet media milling, aiming to achieve a stable formulation with enhanced bioavailability, improved redispersibility, and minimized fasted/fed variability. The nanosuspension, formulated using anionic surfactant and non-ionic polymer as stabilizers, achieved a high drug load (45% w/w) with uniformly distributed nanocrystals (173 ± 21.54 nm) and a negative zeta potential (-36.0 ± 0.57 mV). Cryoprotectants hydroxypropyl-β-cyclodextrin (HPβ-CD) and trehalose were effective in preventing aggregation, ensuring excellent redispersibility across pH conditions in both simulated gastric (pH 4.0) and intestinal (pH 6.8) environments. In vitro dissolution studies demonstrated &amp;gt; 95% drug release within 5 minutes at both pH levels, indicating rapid dissolution and robust stability. Solid State Characterization studies, including X-ray diffraction (XRPD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), and cryo-TEM, confirmed the preserved crystallinity, reduced particle size, and improved homogeneity. Additionally, BET surface area analysis indicated an increased surface area for the lyophilized nanosuspension, supporting enhanced dissolution. The in-silico model predicted increased absorption in the intestinal region, particularly the duodenum and jejunum due to improved saturation solubility and minimized drug precipitation. In vivo pharmacokinetic studies in SD rats revealed superior systemic exposure, with a significant increase in Cmax (3529 ± 564.57 ng/mL) and AUClast (8294.5 ± 1346.66 h*ng/mL) compared to the physical mixture. It may address the challenges of high dosing requirements and drug interactions with acid-reducing agents, offering a promising solution to enhance therapeutic outcomes for lung cancer patients. Citation Format: Henis Patel, Akanksha Patel, Ketan Patel. Nanoformulation strategy for oral delivery of KRAS inhibitor (sotorasib): pH-independent dissolution to mitigate PPI drug interaction [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 1858.
Abstract 1561: Antitumor effect of farletuzumab ecteribulin in molecular subtypes of endometrial cancer patient-derived xenograft models
Authors: Shigehiro Yagishita, Sho Sato, Daisuke Shintani, Tadaaki Nishikawa, Aiko Ogasawara, Masanori Yasuda, Hironori Ishii, Keiji Furuuchi, Toshimitsu Uenaka, Hiroshi Yoshida, Kosei Hasegawa, Akinobu Hamada
Journal: Cancer Research (2025)

Abstract Background: Endometrial cancer (EC) represents a significant health burden globally, particularly in postmenopausal women. Current treatment options for advanced-stage EC remain limited, emphasizing the need for novel therapeutic strategies. This study aimed to investigate farletuzumab ecteribulin (FZEC), an antibody-drug conjugate (ADC) targeting folate receptor alpha (FRα), as a potential new therapeutic agent for EC using tumor models. Methods:We utilized a panel of 24 patient-derived xenograft (PDX) models, representing various histological and molecular subtypes of EC with different levels of FRα expression, to evaluate the antitumor effect of FZEC. FZEC was administered intravenously at doses of 5 mg/kg and 12.5 mg/kg. Intratumoral accumulation of eribulin, the payload of FZEC, was visualized using phosphor-integrated dot imaging. Results:FZEC demonstrated dose-dependent antitumor effects across the EC-PDX panel. At 5 mg/kg, the FZEC efficacy was associated with FRα expression, with 100% of FRα 3+ models exhibiting tumor shrinkage compared to 27.2% of FRα-negative models. FZEC also demonstrated broad activity across both histological and molecular subtypes of EC. Intratumoral eribulin accumulation was highly correlated with antitumor effects, even in models with low FRα expression. Follow-up studies confirmed FRα-dependent antitumor effects, while also indicating potential FRα-independent mechanisms of action. Conclusion:FZEC demonstrated robust antitumor effect against the FRα high EC-PDX models. Importantly, significant antitumor effects were observed, even in FRα-low or negative models. Intratumoral eribulin accumulation exhibited a stronger correlation with efficacy than with FRα expression alone. These results support further clinical development of FZEC for EC treatment and highlight the complexity of ADC mechanisms of action. Citation Format: Shigehiro Yagishita, Sho Sato, Daisuke Shintani, Tadaaki Nishikawa, Aiko Ogasawara, Masanori Yasuda, Hironori Ishii, Keiji Furuuchi, Toshimitsu Uenaka, Hiroshi Yoshida, Kosei Hasegawa, Akinobu Hamada. Antitumor effect of farletuzumab ecteribulin in molecular subtypes of endometrial cancer patient-derived xenograft 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 1561.
Abstract 2310: Food environment index is inversely associated with cancer survival in North Carolina
Authors: Shenghui Wu, Sarah Ulrich, Tinghao Feng, Yanning Liu, Leilani Tseng
Journal: Cancer Research (2025)

Background: Exploring the potential role of the food environment on cancer survival could facilitate prevention and control approaches to improve cancer survivorship. This study examined the associations between food environment index (FEI) and survival for overall cancer in North Carolina. Methods: This retrospective cohort study included 1,292,991 patients diagnosed with overall cancer from January 1, 2000 to December 31, 2022 from the North Carolina Cancer Central Registry. The individual-level demographic, tumor, and treatment information were provided by the North Carolina Cancer Central Registry. FEI and other county-level exposures were obtained from the County Health Rankings &amp; Roadmaps databases. The county-level food environment index is an indicator of access to healthy foods (0 is worst, 10 is best). Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between FEI and cancer survival after adjusting for individual-level and county-level covariates. Results: Higher levels of FEI were associated with a statistically significant better survival for overall cancer (fully adjusted HR for every score increase=0.983, 95% CI 0.979, 0.988; P &amp;lt;0.0001; adjusted HR for the 3rd quartile vs. 1st quartile = 0.98, 95% CI 0.94, 0.99; and adjusted HR for the 4th quartile vs. 1st quartile = 0.95, 95% CI 0.94, 0.96). Conclusion: These results suggest that a healthy food environment, as measured by FEI, may be a protective factor for cancer survival in North Carolina. To improve cancer survival, further strategies to improve food environment at the county level are warranted. Citation Format: Shenghui Wu, Sarah Ulrich, Tinghao Feng, Yanning Liu, Leilani Tseng. Food environment index is inversely associated with cancer survival in North Carolina [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 2310.
Abstract 1755: Discovery of a novel, selective WRN inhibitor, DAT-5000A, in the treatment of microsatellite-unstable tumors
Authors: Jingxi Zhang, Huixian Chen, Dan Yan, Xi Chen, Jincong Zhuo, Kevin Zhou
Journal: Cancer Research (2025)

Abstract Werner syndrome ATP-dependent helicase (WRN) is a member of RecQ helicase involved in DNA replication and repair and is identified as a synthetic lethal target in microsatellite instability-high (MSI-H) tumors. MSI-H feature has been found in a variety of tumor types including colorectal, gastric and endometrial cancers. The clinical benefits of immune checkpoint inhibitor (ICI) such as anti-PD-1 or anti-PD-L1 antibodies on MSI-H cancers have been well documented; however, nearly 20-50% of these cancer patients are intrinsically resistant to PD-(L)1 therapies or develop acquired resistance with prolonged treatment. Thus, agents targeting MSI-H tumors are of great interest. Here we described the discovery of a novel non-covalent WRN inhibitor, DAT-5000A, with excellent potency and PK profile. DAT-5000A potently inhibited WRN in vitro activity both on ATPase and unwinding assays and showed good selectivity over BLM, another member of RecQ helicase. DAT-5000A also showed selective killing of MSI-H SW48 but not MSS (microsatellite stability) SW620 tumor cell line. In addition, DAT-5000A demonstrated good drug-like properties including high cell permeability and microsomal metabolic stability, as well as favorable PK profile with low in vivo clearance and optimal oral bioavailability, across multiple species. DAT-5000A exhibited single-agent activity with tumor regression on MSI-H cell-line derived xenograft (CDX) tumor models, meanwhile DAT-5000A did not cause any abnormality on these mice. Our data demonstrated that DAT5000A is a potent, selective WRN inhibitor with sufficient in vivo exposure and acceptable preliminary safety profile, which supports DAT-5000A to be further evaluated in human clinical trials. Citation Format: Jingxi Zhang, Huixian Chen, Dan Yan, Xi Chen, Jincong Zhuo, Kevin Zhou. Discovery of a novel, selective WRN inhibitor, DAT-5000A, in the treatment of microsatellite-unstable tumors [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 1755.
Abstract 3220: PD-1 antibody-bound progenitor-exhausted CD8+T cells in lymph nodes enhance PD-1 blockade anti-tumor immunity in gastrointestinal cancer
Authors: Takuro Saito, Yohei Nose, Yoshiaki Yasumizu, Naganari Ohkura, Hisashi Wada, Hidetoshi Eguchi, Yuichiro Doki
Journal: Cancer Research (2025)

Abstract Introduction: Progenitor-exhausted T (Tpex) cells, marked by TCF1 and PD-1 expression, are essential for the efficacy of immune checkpoint inhibitors (ICIs) like anti-PD-1 antibodies. These cells serve as precursors to intratumoral exhausted T (Tex) cells and may play a pivotal role in maintaining immune responses during cancer therapy. While Tpex cells are recognized for their importance, the detailed mechanisms by which ICIs influence their activation, proliferation, and migration remain unclear. Specifically, the dynamics of ICI-bound Tpex cells across lymph nodes (LNs) and tumors have not been fully characterized. To address this point, we investigated the spatial and functional behavior of Tpex cells in gastrointestinal cancer patients, focusing on how ICIs reprogram these cells to exert anti-tumor immunity. Methods: We collected tumor, lymph node (LN), and blood samples from gastrointestinal cancer patients treated with or without anti-PD-1 antibodies. Purified lymphocytes were analyzed with flowcytometry and sequencing analysis. To identify ICI-binding T cells, we developed a method using IgG4 detection, which allowed us to detect cells directly bound by therapeutic anti-PD-1 antibodies. We further used combined sequencing technique including single-cell RNA sequencing, T cell receptor sequencing and CITE-sequencing for IgG4 detection (scRNA/TCR/CITE-seq) to profile 29, 388 T cells across tissue compartments, including LNs, tumors, and blood. Results: Our flowcytometry analysis revealed that CD8-Tpex cells were enriched in proximal LNs and exhibited significant proliferation following ICI treatment. Using IgG4 detection and sequencing, we confirmed that PD-1+ Tpex cells in LNs directly bound therapeutic anti-PD-1 antibodies and underwent clonal expansion. Notably, these ICI-bound Tpex cells shared TCR clonotypes with intratumoral Tex cells, suggesting that Tpex cells migrate from LNs to tumors after treatment. Conclusion: ICIs primarily target PD-1+ Tpex cells in proximal LNs, driving their proliferation and migration to tumors, where they differentiate into Tex cells and contribute to sustained tumor destruction. These results not only deepen our understanding of the mechanisms underlying ICI therapy but also provide a robust methodological framework for tracking ICI-binding T cells across tissues. Citation Format: Takuro Saito, Yohei Nose, Yoshiaki Yasumizu, Naganari Ohkura, Hisashi Wada, Hidetoshi Eguchi, Yuichiro Doki. PD-1 antibody-bound progenitor-exhausted CD8T cells in lymph nodes enhance PD-1 blockade anti-tumor immunity in gastrointestinal 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 3220.
Abstract 319: Testing of trispecific antibodies for treating multiple myeloma using the Membrane Proteome Array
Authors: Lewis Joe Stafford, J. Tabb Sullivan, Carmen T, None Navia, Amelia M. Snyder, Diana M. Norden, Benjamin J. Doranz
Journal: Cancer Research (2025)

Abstract Background: Assessment of off-target antibody reactivity is a regulatory requirement prior to clinical development; however, conventional screening methods are frequently ineffective in screening newer therapeutic modalities including multispecifics and CAR-T cell therapies. This presents an issue for T-cell engaging therapeutics that require exquisite specificity, as even minimal cross-reactivity could result in non-target cell killing accompanied by serious or even life-threatening consequences. Methods: We developed the Membrane Proteome Array (MPA)—containing 6, 000 human proteins—as a comprehensive approach to identify off-target protein interactions. The MPA is a cell-based protein array that assesses binding interactions in native, unfixed cells, allowing for quantitative and high sensitivity detection using flow cytometry. The MPA has been used to test specificity of over 1000 therapeutic molecules, including conventional MAbs and newer biotherapeutic modalities, including scFv, VH/VHH, and bispecific molecules, as well as other protein modalities. Results: We used the MPA to evaluate the specificity of several multispecific antibody candidates targeting the G protein-coupled receptor GPRC5D, a promising target for multiple myeloma. Here we tested a panel of GPRC5D bispecifics using a CD3 targeting arm, as well as trispecific antibodies targeting GPRC5D, BCMA, and CD3. The MPA was successfully able to assess specificity of these molecules, showing compatibility with screening trispecifics. As a result, lead candidates devoid of cross-reactivity were identified for further development. The MPA has also been used to rapidly evaluate the specificity of novel CAR-T cell therapies for cancer and autoimmunity. Conclusions: The MPA is compatible with screening of multispecifics, has been used for lead selection, and has been used in numerous successful regulatory applications for antibody-based therapies. The MPA is currently being developed as an FDA-qualified Drug Development Tool. Citation Format: Lewis Joe Stafford, J. Tabb Sullivan, Carmen T, Navia, Amelia M. Snyder, Diana M. Norden, Benjamin J. Doranz. Testing of trispecific antibodies for treating multiple myeloma using the Membrane Proteome Array [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 319.