tbuckley/cabot-search huggingface dataset:
Abstract 4287: GBC-11004: an AI-driven novel kinase target with potential to overcome osimertinib resistance in NSCLC
Authors: Hat Nim Jeon, Ji Young Bae, Hyunsun Na, Ji Hwan Park, Seung Hyun Ahn, Bada Pyo, Jihye Ryu, Jinguen Rheey
Journal: Cancer Research (2025)

Abstract Osimertinib resistance poses a significant clinical challenge in the treatment of non-small cell lung cancer (NSCLC), with diverse mechanisms complicating patient outcomes. Conventional next-generation sequencing (NGS) analysis methods often fall short in identifying effective therapeutic targets due to the complexity and heterogeneity of resistance mechanisms. To address this issue, we have developed an artificial intelligence (AI)-driven target discovery platform designed to identify novel and effective drug target genes capable of overcoming Osimertinib resistance in NSCLC, thereby surpassing the capabilities of traditional NGS analysis. Our platform integrates three key components: deep learning (G-TAC), statistical significance testing (G-SET), and a large language model (G-LAT). G-TAC and G-SET evaluate and rank genes according to their responsiveness to Osimertinib and tumor-specific expression. G-LAT assesses these genes based on publications and clinical trials to ensure novelty and efficacy of the identified targets. We identified a novel kinase target named GBC-11004, as one of the top-ranked target genes that were found to be overexpressed in patient-derived organoids (PDOs) resistant to Osimertinib. To ascertain the functional impact of GBC-11004, target validation was conducted using PDOs and CRISPR/Cas9-based gene editing. Gene editing in Osimertinib resistant PDOs resulted in a significant decrease in cell viability corresponding to increased indel frequency. Furthermore, we have initiated lead compound optimization by preliminary IC50 analyses using compounds targeting GBC-11004 and observed significantly enhanced sensitivity in the combination therapy group (Osimertinib + GBC-11004 inhibitor) compared to the Osimertinib monotherapy group in resistant PDO models. Our results demonstrate the potential of GBC-11004 as a novel therapeutic target for overcoming Osimertinib resistance in NSCLC treatment and emphasize the capability of our PDO-based AI-driven target discovery platform in identifying high-priority novel targets. Citation Format: Hat Nim Jeon, Ji Young Bae, Hyunsun Na, Ji Hwan Park, Seung Hyun Ahn, Bada Pyo, Jihye Ryu, Jinguen Rheey. GBC-11004: an AI-driven novel kinase target with potential to overcome osimertinib resistance in NSCLC [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 4287.
Abstract 4432: mRNA-based restoration of pomalidomide sensitivity in multiple myeloma
Authors: Joseph U. Ogbede, Michael S. Rogers, Robert J. D'Amato, Bruce R. Zetter
Journal: Cancer Research (2025)

Abstract Multiple myeloma (MM) remains an incurable hematologic malignancy, and immunomodulatory imide drugs (IMiDs) have been used as an effective treatment option. A significant challenge with IMiDs such as pomalidomide, as with other treatment options, is the development of drug resistance. This has become a substantial impediment to extending patients' lives. Currently, no effective strategy exists for overcoming IMiD resistance in MM patients. Exploring alternative approaches that could improve the efficacy of pomalidomide might help myeloma patients live longer. Genetic alterations in cereblon (CRBN) contribute to more than one-third of clinical cases of pomalidomide resistance. This study aims to restore sensitivity to pomalidomide-resistant cells through mRNA-based wildtype CRBN restoration. First, we repeatedly exposed multiple myeloma cell lines (MM1.S) to pomalidomide at increasing doses, starting from 2 nM to 10 μM. Following six months of pomalidomide exposure, we generated MM1.S cells that are resistant to pomalidomide and confirmed the absence of CRBN with RNA sequencing and western blotting. Through in vitro transcription, we synthesized CRBN mRNA and electroporated it to the resistant cells. We found restoration of wildtype cereblon and subsequent pomalidomide sensitivity compared to cells without CRBN mRNA treatment. As electroporation is impractical beyond laboratory studies, we are designing a polymer-lipid hybrid nanoparticle to efficiently deliver the mRNA to the cells. Additionally, to ensure targeted delivery of the nanoparticle-coated CRBN mRNA to plasma cells, we applied phage display peptide library screens and identified a cyclic peptide with a high affinity for B-cell maturation antigen (BCMA), a protein known to be almost exclusively expressed by plasma and myeloma cells. This peptide is being validated for BCMA binding, and will be conjugated with the nanoparticle-coated CRBN mRNA for targeted delivery to the malignant plasma cells. Findings from this work will advance mRNA-based therapeutics for overcoming drug resistance caused by genetic alterations in target proteins. Citation Format: Joseph U. Ogbede, Michael S. Rogers, Robert J. D'Amato, Bruce R. Zetter. mRNA-based restoration of pomalidomide sensitivity in multiple myeloma [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 4432.
Abstract 6136: Efficacy of LPS, flagellin, IFN-g, and sCD40L treated bone marrow-derived macrophages in murine mammary carcinoma
Authors: Robert A. Kurt, Joshua Finn, Melissa Lass, Ernesto Oviedo-Bermudez
Journal: Cancer Research (2025)

Abstract Previously we reported that treating bone marrow-derived macrophages (BMDM) with poly(I:C), IFN-γ, and sCD40L generated BMDM with more consistent anti-tumor activity than BMDM generated with the agonists alone. These BMDM also showed significant anti-tumor activity against the EMT6 and 168 murine mammary carcinoma models. However, the BMDM showed no activity against the 4T1 murine mammary carcinoma model. Here we asked whether BMDM generated with IFN-γ and sCD40L in combination with other TLR agonists would have greater anti-tumor activity than the poly(I:C) generated BMDM. For this purpose we generated BMDM and then activated them with IFN-γ, sCD40L, and either LPS, flagellin or R848. BMDM generated with a combination of four agonists (IFN-γ, sCD40L, LPS and flagellin) were also evaluated. Based on in vitro analysis these treatments led to a significant increase in nitrite and IL-12 production, and the levels of nitrite and IL-12 were significantly greater than the levels produced by the poly(I:C) generated BMDM. All treatments also led to a significant increase in expression of il-1b, il-6, tnf-a, il-18, ccl5, cxcl9, cxcl10 and cxcl11. Moreover, the LPS, flagellin and R848 generated BMDM often expressed a significantly higher level of cytokines than the poly(I:C) generated BMDM. All treatments led to a significant increase in MHC Class II or CD80 expression, but only BMDM generated with IFN-γ, sCD40L, LPS, flagellin and BMDM generated with IFN-γ, sCD40L and LPS showed a significant increase in both MHC Class II and CD80 expression. Furthermore, BMDM generated by these same treatments showed significant anti-tumor activity against all three murine mammary carcinoma models; EMT6, 168, and 4T1. Depletion studies revealed that the BMDM exerted anti-tumor activity against the 4T1 and EMT6 tumors by recruiting CD8+ T cells and NK cells suggesting that expression of ccl5, cxcl9, cxcl10, and cxcl11 may be critical for the in vivo anti-tumor activity of these BMDM. Citation Format: Robert A. Kurt, Joshua Finn, Melissa Lass, Ernesto Oviedo-Bermudez. Efficacy of LPS, flagellin, IFN-g, and sCD40L treated bone marrow-derived macrophages in murine mammary carcinoma [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 6136.
Abstract 6128: Targeting DHX9 helicase with the novel small-molecule inhibitor ATX968 induces replication stress and innate immunity in small cell lung cancer
Authors: Takahiko Murayama, Jun Nakayama, Xueying Ma, Siddharth Balachandran, Matthew H. Daniels, Jennifer Castro, Israel Cañadas
Journal: Cancer Research (2025)

Abstract Small cell lung cancer (SCLC) is the most lethal type of lung cancer. The uniqueness of this tumor lies in its initial exquisite response to chemotherapy, due to its high level of genomic instability. However, most patients experience relapse within 6 to 12 months. Although the addition of immune checkpoint blockade (ICB) therapy to standard chemotherapy has been approved by the FDA, only a small fraction of SCLC patients responds to immunotherapy because of an immunologically “cold” tumor microenvironment. Recently, using genetic depletion methods, we have demonstrated that targeting DExD/H-box helicase 9 (DHX9) in SCLC cells triggers tumor-intrinsic innate immunity, enhancing immunotherapy response and suggesting an effective and unexplored strategy to convert immunologically “cold” SCLCs into “hot”. DHX9 is a multi-functional RNA helicase capable of unwinding both RNA and DNA duplexes and more complex nucleic acid structures and has been considered an undruggable nuclear protein. Here, using SCLC models we characterized ATX968, an orally bioavailable DHX9 tool inhibitor developed by Accent Therapeutics. In vitro treatment with ATX968 induced an aberrant accumulation of R-loops (DNA/RNA hybrids), resulting in replication stress and an increase in DNA damage-derived cytoplasmic DNA in SCLC cells. In addition, ATX968 treatment led to an accumulation of cytoplasmic double-stranded RNA (dsRNA), which mainly derived from repetitive element sequences. Both cytoplasmic nucleic acids contributed to the induction of an innate immune response in SCLC cells. Notably, oral treatment with ATX968 monotherapy resulted in robust and durable tumor regression in SCLC mouse xenograft models, which was tolerable over a 28-day treatment period. Together, these findings suggest that DHX9 is a crucial repressor of tumor-intrinsic innate immunity and replication stress, and inhibitors of DHX9 represent a promising new therapeutic strategy for SCLC treatment and potentially other “cold” tumors characterized by replication stress and genomic instability. Citation Format: Takahiko Murayama, Jun Nakayama, Xueying Ma, Siddharth Balachandran, Matthew H. Daniels, Jennifer Castro, Israel Cañadas. Targeting DHX9 helicase with the novel small-molecule inhibitor ATX968 induces replication stress and innate immunity in small cell 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 6128.
Abstract 3768: Development of novel MHC-II-restricted TCR-STEM CD4+ T cell immunotherapy for solid cancers
Authors: Jiayi Zhang, Chen Qian, Xin Liu, Tianhao Duan, Rongfu Wang
Journal: Cancer Research (2025)

Abstract Despite recent advances in immune checkpoint inhibitors (ICI) for treating solid tumors, most patients fail to respond to ICI therapy, eventually relapse and die without further treatment options. Hence, the development of novel immunotherapy is urgently needed. While most studies focus on MHC-I-restricted T cell receptor (TCR)-engineered CD8+ T cell immunotherapy, we recently developed a novel MHC-II-restricted TCR-engineered CD4+ T cell immunotherapy. Because CT83 (KK-LC-1), a cancer-testis antigen, is highly expressed in 40-60% of lung and breast cancers, but not in normal tissues except testis, we used single-cell sequencing and identified a novel HLA-DR13-restricted CT83-specific TCR for tumor recognition. To improve the therapeutic potential of CD4+ TCR-T cells, we further engineered TCR with several novel technologies, including Synthetic TCR-signaling Enhancing for Memory T cells (STEM), thus markedly improving T cell persistence. We demonstrated that CD4+ TCR-STEM T cells specifically recognized and killed breast and lung cancer cells, with no T cell reactivity against a panel of HLA-DR13+ CT83- tumor cells. Surprisingly, we found that CD4+ TCR-STEM T cells could eliminate both breast and lung cancer cells in animal models. In contrast, TCR-engineered CD8+ T cells could only eliminate lung cancer, but not breast cancer, in an animal model. Notably, significantly high percentages (30-40%) of CD4+ TCR-STEM T cell infiltration were detected in the tumors by flow cytometry and immunohistochemistry. Imaging mass cytometry further revealed a substantial number of Th1 cells and M1 macrophages at the tumor site, suggesting a dual mechanism of action of CD4+ TCR-STEM T cells through direct tumor killing and indirect killing via recruitment of other immune cells. Indeed, we showed that CD4+ TCR-STEM T cells could kill antigen-negative tumor cells in a mixture of antigen-positive and negative tumor cells. In conclusion, we have developed a novel MHC-II-restricted CT83-specific CD4+ TCR-STEM T cell immunotherapy showing robust and therapeutic anti-tumor immunity against solid tumors. Given the high prevalence of HLA-DR13 expression across different ethnic groups (20-30%), particularly in African Americans (29.7%), CD4+ TCR-STEM T cells represent an entirely innovative approach to developing therapeutic T cell immunotherapy drugs for solid cancers and addressing cancer disparities. Citation Format: Jiayi Zhang, Chen Qian, Xin Liu, Tianhao Duan, Rongfu Wang. Development of novel MHC-II-restricted TCR-STEM CD4+ T cell immunotherapy for solid cancers [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 3768.
Abstract 4435: PRAME-mediated retinoid resistance is overcome by EZH2 inhibition in keratinocyte carcinoma
Authors: Brandon Liam Ramchatesingh, Ivan V. Litvinov
Journal: Cancer Research (2025)

Abstract Retinoids have exhibited efficacy as treatments and prophylactics for both types of keratinocyte carcinoma (KC): basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC). However, the practical efficacy of these compounds is limited by retinoid resistance mechanisms. Preferentially Expressed Antigen in Melanoma (PRAME) is a cancer-testis antigen ectopically expressed in a subset of BCC and cSCC tumors. In gametes, PRAME binds Enhancer of Zeste Homologue 2 (EZH2), an epigenetic silencer, selectively targeting transcriptional repression to retinoic acid response elements (RARE) in gene promoters. The functions and therapeutic relevance of PRAME expression in KC tumors have not been investigated. A combination of transcriptomic analyses, 2D and 3D cell culture approaches were undertaken to evaluate the contributions of PRAME to KC pathogenesis and treatment response. Pharmacological retinoid sensitization strategies were also investigated. Epidermal differentiation and cytokine signaling pathways were downregulated in high PRAME-expressing tumors and in PRAME overexpressing (OE) cell lines. Conversely, low-PRAME tumors and PRAME depleted cell lines exhibited an enrichment of epidermal differentiation and cytokine signaling gene signatures. PRAME OE impaired epidermal differentiation in 3D organotypic skin culture models. Additionally, PRAME OE impaired RARE activation and conferred resistance to retinoid-induced growth suppression. PRAME depletion restored RARE activation and restored retinoid-induced growth suppression. Mechanistically, PRAME was determined to abrogate the anti-keratinization effect of retinoid treatment in SCC cells and organoid models. PRAME also abrogated the cell death promoting effect of retinoid treatment in BCC cells. Targeting of EZH2, using pharmacological or genetic strategies, in combination with retinoid treatment, resulted in a selective repression of cell growth in KC cell lines. Similar effects were observed when performing co-treatments using cell lines representative of cutaneous melanoma and lung squamous cell carcinoma. This study illustrates potential roles for PRAME in modulating differentiation programs and demonstrates a role for PRAME in conferring resistance to retinoid-based therapeutics. Furthermore, this study offers a preclinical demonstration of a drug repurposing strategy including retinoid compounds and EZH2 inhibitors to suppress the growth of PRAME-expressing cells. Citation Format: Brandon Liam Ramchatesingh, Ivan V. Litvinov. PRAME-mediated retinoid resistance is overcome by EZH2 inhibition in keratinocyte carcinoma [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 4435.
Abstract 5665: Targeted cell killing: a versatile platform for cell therapy and cytotoxicity assays in diverse cell lines
Authors: Nicholas J. Hess, Brock Binkowski, Julia Gilden, Gopal Krishnan, Mei Cong, Marjeta Urh
Journal: Cancer Research (2025)

Abstract The HiBiT Target Cell Killing Assay (HiBiT TCK Assay) is a streamlined, sensitive method for selectively quantifying target cell lysis in coculture experiments with effector cells. HiBiT is an 11AA peptide that binds with high affinity to LgBiT, forming a bright, luminescent enzyme. For HiBiT TCK, target cells are engineered to express a HiBiT-tagged protein, and release of this protein by dead/dying cells leads to complementation with the cell impermeable LgBiT. This gain-of-signal approach enables precise measurements of target cell killing induced by various effectors, including CAR-T cells and cell killing mediated by bispecific antibodies. Here we demonstrate the use of HiBiT TCK with ADCC, ADCP, TDCC and CAR-T applications. Furthermore, we present data of mRNA transfection to transiently express HiBiT in a variety of target cells, allowing for the rapid and uniform labeling of both dividing and non-dividing cells. This approach extends the HiBiT TCK products beyond use of stable cell lines alone and allows users to screen a variety of cell lines. Citation Format: Nicholas J. Hess, Brock Binkowski, Julia Gilden, Gopal Krishnan, Mei Cong, Marjeta Urh. Targeted cell killing: a versatile platform for cell therapy and cytotoxicity assays in diverse cell lines [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 5665.
Abstract 4291: Inhibition of FANCM helicase activity confers synthetic lethality in alternative lengthening of telomeres (ALT) positive cancers
Authors: Youyou Zhang, Raghuvar Dronamraju, Tom Berrodin, Kevin Coleman, Benjamin Schwartz
Journal: Cancer Research (2025)

Abstract FANCM (Fanconi anemia, complementation group M) is a human gene that encodes a protein that plays a key role in DNA repair and genome maintenance. Alternative lengthening of telomeres (ALT) is a mechanism that allows cancer cells to maintain telomere length without using telomerase. A synthetic lethal relationship between ALT status and FANCM levels was uncovered by analyzing CRISPR Screens in DepMap database. By using telomerase (TERT) as a biomarker which is negative in ALT positive tumors, cell lines without TERT or ALT+ were found to be sensitive to FANCM knockdown. This synthetic lethal relationship was validated in cell lines with different status of ALT by targeting FANCM with siRNA pool and CRISPR-Cas9. Knock-in of K117K silent mutation, but not K117A/R mutations in catalytic domain of FANCM “rescued” the growth of ALT positive FANCM KO SAOS2 cell. Depletion or deletion of FANCM using siRNA/ CRISPR Cas9 led to the increase in the intensity/distribution of PML and TRF foci. ALT positive cell lines have significantly higher amount of C circle DNA compared to telomerase positive or ALT negative cell lines. Loss of FANCM leads to increase in the levels of C circles. Our results further validate FANCM as a target for ALT cancers and suggest inhibiting its helicase activity as a strategy to treat ALT cancer. Citation Format: Youyou Zhang, Raghuvar Dronamraju, Tom Berrodin, Kevin Coleman, Benjamin Schwartz. Inhibition of FANCM helicase activity confers synthetic lethality in alternative lengthening of telomeres (ALT) positive cancers [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 4291.
Abstract 4530: mTOR inhibition augments antitumor T cell response by modulating the expression of immune regulatory molecules
Authors: Priyatosh Nath, Alok Khandelwal, Ivan Alvarez, Chun Li, Srivatsa Vasudevan, Tara Moore-Medlin, Cherie-Ann Nathan
Journal: Cancer Research (2025)

Abstract The mechanistic target of rapamycin (mTOR) is a protein kinase that plays a critical role in regulating immune responses by modulating the growth, differentiation, activation and migration of various immune cells. Dysregulation of mTOR signaling, which is common in various cancers, can potentially disrupt the immune cell function, leading to weakened immune surveillance. This study evaluates the antitumor activity of an mTOR inhibitor drug, everolimus, focusing on its impact on antitumor immunity. Treatment with everolimus inhibited the growth of PD-1 resistant and poorly immunogenic ROC-1 syngeneic grafts, potentially through the activation of T cell-mediated immunity. Flow cytometry analysis of single cell suspension of tumor cells revealed increased CD8+ T cell infiltration and increased expression of class-I MHC in tumor cells in mice treated with everolimus when compared to vehicle. Moreover, everolimus reduced the number of exhausted (PD1+) CD4+, CD8+ T cells in tumors, indicating a more potent immune response against the cancer cells. The CD8+ tumor infiltrated lymphocytes (TILs) magnetically sorted and cocultured with the tumor cells showed significantly higher T cell cytotoxicity for the group of mice who received everolimus in comparison to vehicle. These findings suggest the potential of everolimus in boosting anti-tumor immunity, providing a rationale for further investigation. Citation Format: Priyatosh Nath, Alok Khandelwal, Ivan Alvarez, Chun Li, Srivatsa Vasudevan, Tara Moore-Medlin, Cherie-Ann Nathan. mTOR inhibition augments antitumor T cell response by modulating the expression of immune regulatory molecules [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 4530.