tbuckley/cabot-search huggingface dataset:
Abstract 833: A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal cancer therapy
Authors: Ming-Heng Wu, Yao-Tsung Tsai, Chee Voon Yap
Journal: Cancer Research (2025)

Abstract Antibody-drug conjugates (ADCs) are "biological missiles" that utilize a chemical linker to connect monoclonal antibodies (mAbs) with cytotoxic drugs, which induces the precise killing of targeted tumor cells and causes the death of surrounding untargeted cancer cells through the bystander effect. However, current ADCs are too specific to certain cancer subtypes and not specific enough to accurately target a cancer-specific protein, which limits the therapeutic populations and induces unwanted side effects. We developed a heavy-chain antibody (HCAb) from a llama immune library, which recognizes glycosylated CEACAM6 (Carcinoembryonic antigen-related cell adhesion molecule 6), a broad-surface marker of epithelial-type cancers. The anti-CEACAM6 HCAb showed a higher affinity (KD: sub-nanomolar), better thermal stability, unique tissue penetration and epitope-recognition abilities compared to the conventional antibodies. The anti-CEACAM6 HCAb-drug conjugate (HCAb-ADC), which links the HCAb and tubulin inhibitors via hydrophilic linkers, specifically killed CEACAM6-expressing colorectal (CRC), lung, pancreas, and bile duct carcinoma cells at sub-nanomolar concentrations and had a better anti-cancer effect than current FDA-approved ADCs. In xenograft models, a single administration of HCAb-ADC completely abolished colorectal and pancreatic tumors. Notably, HCAb-ADC can effectively inhibit tumor growth even at very low doses (0.2 mg/Kg) and demonstrated a superior therapeutic effect over current therapeutic regimens. Meanwhile, it exhibited minimal toxicity to normal epithelial and peripheral blood mononuclear cells. In summary, the excellent anti-tumor activity across different epithelial cancers and minimal toxicity to normal tissues support the clinical development of the novel HCAb-ADC for treating multiple epithelial-type cancers, including CRC, lung, pancreatic, and bile duct carcinoma. Citation Format: Ming-Heng Wu, Yao-Tsung Tsai, Chee Voon Yap. A novel anti-CEACAM6 heavy-chain antibody-drug conjugate for gastrointestinal 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 833.
Abstract 3672: High-sensitivity CRISPR-Cas12a detection of prostate-specific antigen based on computationally optimized aptamers
Authors: Peizhi Ma, Jing Wu, Yichen Zhang, Fangyue Guo, Mengying Liu, Shuying Sun, Shize Xiao, Shanfeng Zhang, Pei Li
Journal: Cancer Research (2025)

Abstract Background: Prostate cancer (PCa) is one of the most common malignant tumors worldwide. Early detection of PCa via Prostate-Specific Antigen (PSA) blood testing is essential for efficient and accurate screening. However, current diagnostic approaches are costly, labor-intensive, require large sample volumes and have relatively low interference capability. Additionally, the limitations of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) technology often result in PSA aptamers with insufficient affinity, compromising the sensitivity of some aptamer-based detection methods. Methods: In this study, we developed a PSA detection strategy based on the trans-cleavage mechanism of the CRISPR-Cas12a-aptamer system, integrating computationally optimized PSA aptamers with CRISPR-Cas12a-based technology. A series of experiments were conducted, including the optimization of PSA aptamers, the design of crRNA, the optimization of aptamer concentration, the establishment of the CRISPR-Cas12a-aptamer detection system, and the validation of clinical samples. Results: Through sequence alignment and structural analysis of existing PSA aptamers, we identified conserved and potential binding sequences, enabling the construction of optimized aptamers. Molecular docking revealed aptamers with lower ΔG values and higher ZDOCK scores, which were selected as candidates. Optimal aptamer concentrations were identified experimentally, and the system's sensitivity and specificity were assessed using PSA standards and non-specific controls. Comparative studies demonstrated enhanced detection sensitivity with optimized aptamers, exhibiting a linear PSA detection range of 1.44-23 ng/ml with steeper slopes and higher R2 values compared to original aptamers. In the validation of clinical samples, the detection values of this method showed good consistency with the data provided by hospitals. Conclusions: This study demonstrates the ultrasensitivity and rapidity of the CRISPR-Cas12a-aptamer detection system and presents a robust strategy for improving aptamer affinity through sequence analysis and molecular docking, offering significant potential for diagnostic applications. Citation Format: Peizhi Ma, Jing Wu, Yichen Zhang, Fangyue Guo, Mengying Liu, Shuying Sun, Shize Xiao, Shanfeng Zhang, Pei Li. High-sensitivity CRISPR-Cas12a detection of prostate-specific antigen based on computationally optimized aptamers [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 3672.
Abstract 498: In melanoma, disruption of the NF1/SPRED1 RAS inactivating complex cooperates with mutant KIT necessitating combined KIT and MEK inhibition to suppress tumor growth
Authors: Meng Kian Tee, Jia Yang, Jiafang Ma, Meng Wang, Dirk Schadendorf, Boris C. Bastian, Iwei Yeh
Journal: Cancer Research (2025)

Abstract We previously identified concurrent loss of function mutations of either NF1 or SPRED1 with activating mutations in KIT in primary acral and mucosal melanomas. We hypothesized the positive selection for NF1 or SPRED1 inactivation in the context of KIT mutations reflects a functional cooperation that may impact response to therapy targeting KIT. We find that contrary to each of the alterations alone, combined loss of either NF1 or SPRED1 in the presence of mutant KIT transforms immortalized mouse melanocytes. Because loss of NF1 and SPRED1 each activates RAS acting downstream of KIT, it could subvert the effect of KIT inhibitors. In patient-derived melanoma cell lines with KIT mutations and loss of NF1 or SPRED1, combination treatment with a KIT inhibitor (imatinib or avapritinib) and a MEK inhibitor (trametinib) acted synergistically. Combined KIT and MEK inhibition also reduced tumor growth and prolonged survival of mice xenografted with KIT-mutant melanoma cell lines. Our findings suggest that combination therapy with KIT and MEK inhibitors would be beneficial for melanoma patients with activating KIT mutations and concomitant loss of function NF1/SPRED1 mutations. Citation Format: Meng Kian Tee, Jia Yang, Jiafang Ma, Meng Wang, Dirk Schadendorf, Boris C. Bastian, Iwei Yeh. In melanoma, disruption of the NF1/SPRED1 RAS inactivating complex cooperates with mutant KIT necessitating combined KIT and MEK inhibition to suppress tumor growth [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 498.
Abstract 796: Incidence of depression and anxiety in kidney cancer survivors: A nationwide population-based cohort study
Authors: Minji Jung, Mingyi Li, Eunjung Choo, Sukhyang Lee, David Spiegel, Mike Baiocchi, Zhengyi Deng, Jinhui Li, Marvin E. Langston, Melissa L. Bondy, Benjamin I. Chung
Journal: Cancer Research (2025)

Abstract Depression and anxiety are highly prevalent among kidney cancer survivors, yet limited evidence exists on their cumulative incidence following kidney cancer diagnosis and their associations with the diagnosis. We conducted a nationwide, population-based retrospective cohort study using the Korean National Health Insurance and Medical Checkup Linkage Database. Adults, over 20 years, diagnosed with kidney cancer from 2010 to 2020 were included, along with age- and sex-matched non-cancer comparators. Individuals with prior cancer, depression, or anxiety were excluded. We 1) quantified the empirical risk trajectories of depression and anxiety in kidney cancer survivors for up to five years post-diagnosis, and 2) estimated the time-dependent associations between kidney cancer diagnosis and the incidence of these conditions within three post-diagnosis intervals (0-1, 1-3, and 3-5 years) using inverse-probability weighted Cox regressions. Until five years post-diagnosis, survivors (n=24, 310) consistently had a higher cumulative incidence of depression (2.8% vs 2.2%) and anxiety (3.3% vs 2.6%) compared with comparators (n=173, 471). Additionally, survivors (n=16, 049) had an increased hazard of depression (hazard ratio (HR)=1.92, 95% confidence interval (CI): 1.52-2.42) and anxiety (HR=1.63, 95% CI: 1.31-2.02) compared to comparators (n=100, 782) within the first year. During the subsequent 1-3 years, the hazard of anxiety remained increased (HR=1.32, 95% CI: 1.07-1.62). In conclusion, kidney cancer survivors experienced a higher rate of depression and anxiety, especially in the early post-diagnosis period, compared to the non-cancer population. Our findings emphasize the need for proactive prevention and management of psychiatric disorders in kidney cancer patients. Citation Format: Minji Jung, Mingyi Li, Eunjung Choo, Sukhyang Lee, David Spiegel, Mike Baiocchi, Zhengyi Deng, Jinhui Li, Marvin E. Langston, Melissa L. Bondy, Benjamin I. Chung. Incidence of depression and anxiety in kidney cancer survivors: A nationwide population-based cohort study [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 796.
Abstract 880: Accumulation of cytosolic single-stranded DNA triggers innate immune responses via a novel sting-independent mechanism
Authors: Jing Zhang
Journal: Cancer Research (2025)

Abstract Immune checkpoint blockade (ICB) has shown durable responses in a subset of patients with hypermutated cancers. Although some non-hypermutated cancer patients have also demonstrated clinical responses to ICB, the majority do not respond, prompting research into novel combination immunotherapies. Ongoing clinical trials have explored such combinations, but challenges like hematological toxicities and resistance have limited their effectiveness. Therefore, there is an urgent need for more effective therapies. Recent studies suggest that mislocalized cytoplasmic DNA may serve as a potent mediator of innate immune responses, potentially enhancing ICB efficacy. However, the mechanisms by which intracellular single-stranded DNA (ssDNA) activates the innate immune system remain poorly understood. In this study, we report that accumulation of cytosolic ssDNA in cancer cells by silencing TREX1 improves ICB response and promotes the infiltration of immune cells via DDX3X. Additionally, we further developed mRNA-based therapeutic agents HIM-mRNA-001 to enhance tumor sensitivity to ICB with minimal toxicities. These findings suggest that targeting cytosolic ssDNA accumulation could provide a new therapeutic strategy for non-hypermutated cancers, offering a promising alternative to current immunotherapies. Citation Format: Jing Zhang. Accumulation of cytosolic single-stranded DNA triggers innate immune responses via a novel sting-independent mechanism [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 880.
Abstract 511: Neratinib monotherapy in advanced non-small cell lung cancer with EGFR exon 18 mutations in China
Authors: Wenfeng Fang, Ning Li, Runxiang Yang, Ying Cheng, Baogang Liu, Haiyong Wang, Lin Wu, Qiming Wang, Steve Shen
Journal: Cancer Research (2025)

Abstract Background: In NSCLC patients, EGFR exon 18 mutations account for approximately 3-5% and are associated with a poor prognosis. In phase 2 SUMMIT global trial, 29 metastatic NSCLC patients with EGFR exon 18 mutations received neratinib monotherapy, having good result. The objective response rate (ORR) was 35%. However, only 1 (4.5%) Asian individual is enrolled in study. Therefore, there is an urgent need to explore the effect of neratinib monotherapy in Chinese NSCLC patients with EGFR exon 18 mutation. Methods: Planned 14 patients with EGFR exon 18-mutated NSCLC who had failed first-line standard chemotherapy were enrolled in this study(NCT06029816). The primary endpoint is the ORR by the investigator according to RECISTv1.1 and the secondary endpoints are DCR (Disease Control Rate), PFS (Progression-Free Survival). Results: To date, 7 advanced NSCLC patients with exon 18 mutations after receiving Neratinib treatment following the failure of standard first-line therapy. The ORR is 42.9% (3 PR, 4 SD) and DCR is 100.0%. The common 1-2 grade treatment-related adverse events (AEs) occur in 82% of patients. 28.6% of patients have Diarrhea (CTCAE Grade 2), and that can be managed after loperamide intervention within 3 days. To date, there have been no grade 4- 5 AEs in any of the patients. Conclusion: Neratinib monotherapy has demonstrated tolerable safety and encouraging preliminary efficacy in NSCLC with EGFR exon 18 mutations. This study is expected to provide more treatment options for Chinese patients with NSCLC who have EGFR exon 18 mutations. Citation Format: Wenfeng Fang, Ning Li, Runxiang Yang, Ying Cheng, Baogang Liu, Haiyong Wang, Lin Wu, Qiming Wang, Steve Shen. Neratinib monotherapy in advanced non-small cell lung cancer with EGFR exon 18 mutations in China [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 511.
Abstract 401: HDBNJ3049: A novel EGFR-targeting PROTAC to overcome C797S-mediated osimertinib resistance in NSCLC
Authors: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Ji Min Park, Hye Mi Kim, Jae June Dong, Byoung Gon Moon
Journal: Cancer Research (2025)

The emergence of C797S-driven Osimertinib resistance represents a major hurdle in the treatment of non-small cell lung cancer (NSCLC). This study presents a novel series of proteolysis-targeting chimeras (PROTACs) designed to overcome resistance by potently and selectively degrading EGFR mutants, including the C797S variant. These next-generation EGFR PROTACs demonstrated significant anti-proliferative activity across a broad spectrum of EGFR mutations, achieving subnanomolar potency in cellular proliferation and protein degradation assays alike. Notably, these compounds effectively targeted not only C797S mutants but also other clinically relevant mutations such as Exon19Del and L858R/T790M variants. The lead candidate, HDBNJ3049, exhibited superior activity across all tested EGFR mutant cell lines, including potent growth inhibition of C797S-mutant Ba/F3, and H1975 cells (GI50 as low as 17 nM and 50 nM for L858R/T790M/C797S Ba/F3 and H1975, respectively), and robust degradation of Del19/T790M/C797S mutant EGFR (DC50: 13 nM, Dmax: 98%). In vivo pharmacokinetic and pharmacodynamic studies further validated the therapeutic potential of HDBNJ3049, establishing it as a highly promising lead candidate for overcoming osimertinib resistance in NSCLC and offering new hope for patients with limited treatment options. Citation Format: Mohammad Hassan Baig, Yun Seong Jo, Sagar Dattatraya Nale, Chang Joong Kim, Tae Hwan Park, Ju Han Bok, Dong Min Kim, Ji Min Park, Hye Mi Kim, Jae June Dong, Byoung Gon Moon. HDBNJ3049: A novel EGFR-targeting PROTAC to overcome C797S-mediated 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 401.
Abstract 84: Dimerization of MACC1: A newly identified feature and its role in cancer metastasis
Authors: Malti Dumbani, Benedikt Kortüm, Simona Kostova, Fabian Zincke, Alexandra Forrai, Dennis Kobelt, Wolfgang Walther, Erich Wanker, Oliver Daumke, Christoph Buhlheller, Ulrike S. Stein
Journal: Cancer Research (2025)

Abstract Cancer metastasis remains the most lethal characteristic of tumors mediating the majority of cancer-related deaths and continues to be a leading cause of mortality. Exemplified for colorectal cancer (CRC) metastasis results in around 0.9 million deaths annually worldwide. Identifying key molecules responsible for metastasis, understanding their biological functions and therapeutically targeting these molecules is therefore of tremendous value. Metastasis Associated in Colon Cancer 1 (MACC1), a gene first described in 2009, is such a key driver of metastatic processes, initiating cellular proliferation, migration, invasion, and metastasis in vivo. Since its discovery, the value of MACC1 as a prognostic biomarker has been confirmed and linked to poor overall outcome in more than 20 cancer types. Despite numerous studies identifying MACC1 as a promising target for solid cancer, little is known about the structural features of MACC1 protein and its oligomeric states. Therefore, we asked whether MACC1 can form protein complexes and if so, which region is critical for complexation/oligomerization. Using AlphaFold-Multimer, the MACC1 homodimer structure was predicted and the residues involved in dimerization were evaluated. The notion of MACC1 dimerization was validated further using bioluminescence resonance energy transfer (BRET) in HEK293 and HCT116 cell system. To our surprise, BRET revealed that MACC1 exists as homodimer in living cells. Further, we report that mutation of the predicted dimer interface residues Val212, Ile214 and Cys216 close to the N-terminus of MACC1 in the ZU5 domain hinders homodimerization and affects MACC1-mediated cell migration in vitro and metastasis formation in vivo. Taken together, these findings identify an important role of MACC1 dimers for the MACC1-mediated metastasis phenotype. We provide with this study a framework to better understand the MACC1 signaling landscape and to facilitate the rational development of novel therapies aiming at MACC1 oligomerization to intervene in MACC1-mediated metastasis. Citation Format: Malti Dumbani, Benedikt Kortüm, Simona Kostova, Fabian Zincke, Alexandra Forrai, Dennis Kobelt, Wolfgang Walther, Erich Wanker, Oliver Daumke, Christoph Buhlheller, Ulrike S. Stein. Dimerization of MACC1: A newly identified feature and its role in cancer metastasis [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 84.
Abstract 863: A novel SIRPA based FiCAR T cells therapy targeting TYRP1 to treat melanoma patients
Authors: Henrik Paavilainen, Sakari Pöysti, Veera Nikoskelainen, Marie Nyman, Anil K. Thotakura
Journal: Cancer Research (2025)

Abstract Background: The first-generation immune checkpoint inhibitors anti-PD1/PDL1 and anti-CTLA-4 either alone or in combination have shown tremendous clinical success in BRAF wild type melanoma cancer patients. However, there is still a high unmet need as great proportion of melanoma patients relapsed after treatment with first generation immune checkpoint inhibitors and BRAF mutant patient relapsed after treatment BRAF inhibitors. Chimeric antigen receptor (CAR) expressing T cells have shown clinical success in hematological malignancies, recent studies have shown that CAR Ts cells were detected in circulation a decade after the first CD19 CART cell injection. Here, we generated a novel SIRPa based extracellular extension TYRP1 targeting CAR T cell, here onwards referred as TYRP1 FiCAR, that work independent of the tumor mutation burden and BRAF status. TYRP1 targeting FiCARs could be an alternative and attractive therapeutic strategy for treatment relapsed melanoma patients. Methods &amp; Results: A well-known anti-TYRP1 binder flanvotumab’s scfv was inserted into FiCAR-structure containing CD28 and CD3zeta intra cellular signaling domain and those CAR T cells were studied for both in vitro and in vivo function. TYRP1 based FiCAR grew normally and good transduction rates with low vector copy numbers were achieved. In addition, upon co-culture of TYRP1 FiCAR T cells with tumor cells expressing TYRP1 a rapid and significant release of pro-inflammatory cytokines was detected. Moreover, killing of the target cells were observed by the TYRP1 FiCAR T cells. To study the in vivo functionality of the TYRP1 FiCAR-T cells, NSG mice were inoculated with melanoma cells subcutaneously. Three weeks after the inoculation mice were intravenously injected with a single dose of TYRP1 FiCAR T cells. Discussion: The data presented here shows a proof-of-concept study for the FiCAR structure to work against TYRP1 antigen. TYRP1 FiCAR T cells upon co-culture with TYRP1 expressing tumor elicited a significant increase in effector cytokines production and has not shown any signs of tonic signaling. Additionally, TYRP1 FiCAR T cells were able to kill tumor cells efficiently reaching 100% maximal killing. In vivo, TYRP1 FiCAR T cells significantly delayed tumor growth. However, full regression of the tumors was not achieved in vivo. Collectively, the in vitro and in vivo data support further optimization of TYRP1 FiCAR T cells to treat melanoma patients refractory to immunotherapy and BRAF inhibitors. Citation Format: Henrik Paavilainen, Sakari Pöysti, Veera Nikoskelainen, Marie Nyman, Anil K. Thotakura. A novel SIRPA based FiCAR T cells therapy targeting TYRP1 to treat melanoma patients [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 863.