tbuckley/cabot-search huggingface dataset:
Abstract 7091: Disparities in non small cell lung cancer treatment and outcomes among Native Hawaiian and other Pacific Islander populations
Authors: Chalothorn Wannaphut, Manasawee Tanariyakul, Jared Acoba
Journal: Cancer Research (2025)

Abstract Background: The American Cancer Society and National Cancer Institute, emphasize the critical need to disaggregate data for Asian, Native Hawaiian, and Other Pacific Islander (NHOPI) populations to better understand racial disparities in cancer. NHOPI populations are highly diverse, with distinct genetic, cultural, and socioeconomic backgrounds that can influence cancer outcomes. This study aims to analyze Native Hawaiian, and other Pacific Islander patients with non-small cell lung cancer (NSCLC) to identify disparities in prognostic factors, treatment, and outcomes. Methods: Data were abstracted from 4, 143 NSCLC patients treated at Queen's Medical Center in Honolulu, Hawaii, between 2000 and 2022. Patients were grouped by race: White, Asian, Native Hawaiian, and other Pacific Islander. Kaplan-Meier survival estimates, and Cox proportional hazards models were applied to adjust for demographic, clinical, and treatment-related factors. Results: Among the 4, 143 patients diagnosed with NSCLC, the racial distribution included 971 White patients, 2, 324 Asian patients, 637 Native Hawaiian (NH) patients, and 211 Pacific Islander (PI) patients. PI patients were generally younger, more likely to present with late-stage disease, and more often underinsured compared to other racial groups including Native Hawaiians. Median overall survival (OS) was 20.9 months for whites, 20.1 months for Asians, 15.8 months for NH, and 10.3 months for PI (p&amp;lt;0.001). Both NH and PI patients were less likely to undergo surgery despite having stage I disease (NH HR 0.52, 95% CI 0.33-0.84; PI HR 0.29, 95% CI 0.12-0.70). Additionally, PI patients less often received systemic therapy for advanced-stage disease (PI HR 0.56, 95% CI 0.38-0.81) compared to whites. In adjusted models without treatment, NH and PI patients exhibited worse survival compared to whites (NH HR 1.12, 95% CI 1.01-1.26; PI HR 1.16, 95% CI 0.97-1.39). However, when treatment was included in the model, these differences were no longer significant. Conclusion: Native Hawaiian (NH) and Pacific Islander (PI) patients with cancer should be studied independently due to their unique sociodemographic characteristics and treatment patterns. Both groups showed lower survival rates compared to whites, largely due to disparities in treatment. Citation Format: Chalothorn Wannaphut, Manasawee Tanariyakul, Jared Acoba. Disparities in non small cell lung cancer treatment and outcomes among Native Hawaiian and other Pacific Islander populations [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 7091.
Abstract 3698: A longitudinal investigation of temporal/intratumoral heterogeneity by plasma NGS profiling of mutation clones in metastatic colorectal cancer
Authors: Petra Kroupova, Barbora Minarikova, Andrea Chmelarova, Marek Minarik
Journal: Cancer Research (2025)

Abstract Intratumoral tumor heterogeneity characterized by the presence of genetically and phenotypically distinct cell populations (clones) within the same lesion, represents a significant obstacle to accurate diagnosis, prognosis, and therapeutic targeting based on molecular investigation, when biopsy may yield incorrect results due to insufficient representation of all tumor clones in the sample. Liquid biopsy, defined as the detection and quantification of somatic aberrations of circulating tumor DNA (ctDNA) in blood plasma, has long been considered an approach that can be effectively applied to obtain full spectrum of mutations without any bias. This assumption based on condition that the release of ctDNA fragments occurs quantitatively from all present cell populations. Our study aims to verify this hypothesis based on continuous liquid biopsies in patients undergoing treatment for advanced solid tumors. In the field of liquid biopsy, the use of ctDNA detection for continuous monitoring of ongoing therapy has recently come to the forefront. The so-called "tumor informed" approach, in which somatic mutations found in tumor tissue are subsequently detected in ctDNA. The procedure is characterized by relatively low costs, which allows repeated examinations based on frequent sampling for continuous monitoring of the disease and treatment. In ctDNA-positive patients, we subsequently perform broad-spectrum longitudinal profiling of mutational clones in ctDNA using an NGS panel based on the principle of hybrid capture of a panel covering a total of 127 genes. This method is used to monitor mutation profiles in ctDNA from plasma of patients with metastatic colorectal cancer undergoing multimodal treatment including surgical resection of metastatic tissue and chemotherapy. The results indicate that the response to treatment, which is manifested by a decrease or increase in ctDNA represented by different mutations, may not occur homogeneously in all present mutational clones. In fact, some clonal populations appear to indicate earlier response than others, characterized by shifts in mutation fraction dynamics. Citation Format: Petra Kroupova, Barbora Minarikova, Andrea Chmelarova, Marek Minarik. A longitudinal investigation of temporal/intratumoral heterogeneity by plasma NGS profiling of mutation clones in metastatic colorectal 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 3698.
Abstract 2318: Waist circumference and the risk of cancer: Two-sample mendelian randomization
Authors: Su Hyun Lee, Sun Ha Jee, Yoon-Jung Choi
Journal: Cancer Research (2025)

Abstract Background: The normal range of waist circumference for Asians is less than 90 cm for men and less than 85 cm for women, according to the Korean Society for the Study of Obesity (KSSO) guidelines. While observational studies have suggested an association between obesity and cancer, the causality of obesity in cancer development is not fully established. A two-sample Mendelian randomization (MR) analysis was used to assess whether a genetic predisposition index for waist circumference (WC) was associated with overall cancer and 10 site-specific cancer risk.While observational studies have suggested an association between obesity and cancer, the causality of obesity in cancer development is not fully established. A two-sample Mendelian randomization (MR) analysis was used to assess whether a genetic predisposition index for waist circumference (WC) was associated with overall cancer and 10 site-specific cancer risk. Methods: The MR method can assess potential causal relationships in various diseases. Summary-level data for WC were extracted from The Korean Cancer Prevention Study-II (KCPS-II) Biobank, and summary-level data for cancer were extracted from The Korean Genome Epidemiology Study (KoGES). Results: There was no causal relationship between WC and total cancer, but a positive correlation was found in colorectal cancer and thyroid cancer (total cancer OR=1.009, 95% CI=0.995-1.023; colorectal cancer OR=1.051, 95% CI=1.011-1.091; thyroid cancer OR=1.037, 95% CI=1.006-1.068). In cervical cancer and prostate cancer, protective results were shown for WC (cervical cancer OR=0.943, 95% CI=0.891-0.998; prostate cancer OR=0.874, 95% CI=0.766-0.998). Conclusion: The evidence supporting a causal relationship between WC and cancer was limited. Genetically predicted WC was positively correlated with colorectal cancer and thyroid cancer. The current study found causal detrimental effects of WC on several cancers. We propose to strengthen cancer screening in patients with large WC to enable early detection of cancer. Citation Format: Su Hyun Lee, Sun Ha Jee, Yoon-Jung Choi. Waist circumference and the risk of cancer: Two-sample mendelian randomization [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 2318.
Abstract 5429: NRF2 activation sensitizes the Fe-S cluster synthesis pathway to iron restriction
Authors: Maddison A. Olley, Nathan P. Ward
Journal: Cancer Research (2025)

Abstract Enhanced mitochondrial metabolism in human lung tumors relative to normal lung and lung tumorigenesis offers a potential therapeutic vulnerability in non-small cell lung cancer (NSCLC) due to the dependence on iron-sulfur (Fe-S) clusters. Recent data indicates that the incorporation of Fe-S clusters into recipient proteins is influenced by iron availability, with possible hierarchical loading when iron is limited. The labile iron pool which Fe-S clusters derive iron from is partly regulated by the transcription factor NRF2, which coordinates restriction of the labile iron pool through increased storage and efflux of free iron when activated. Given the aberrant activation of NRF2 in a significant proportion of NSCLC cases due to amplification or mutations in its negative regulator, KEAP1, we hypothesized that NRF2 regulation of intracellular iron availability may sensitize the Fe-S cluster synthesis pathway in NSCLC when iron is limiting. To investigate this potential vulnerability, we stratified 14 NSCLC lines based on the activation status of NRF2 and evaluated the sensitivity of Fe-S cluster biology to iron chelation with deferoxamine (DFO). Seahorse analyses of mitochondrial function showed that the decline in mitochondrial respiratory function under iron starvation is exacerbated in NRF2-high cells compared to NRF2-low counterparts. Furthermore, 13C-glucose tracing under DFO treatment revealed a significantly greater reduction in M+2 isotopologue enrichment of TCA cycle intermediates in NRF2-high cells relative to NRF2-low cells. In association with this enhanced mitochondrial metabolic dysfunction, we observe a more rapid loss of Fe-S protein activities such as aconitase and respiratory super complexes I-III and II-III in NRF2-high cells relative to NRF2-low cells following DFO treatment. Importantly, we find that NRF2 knockout protects against the loss of Fe-S protein function in response to iron restriction. Moreover, we find that the loss of mitochondrial iron in response to DFO treatment is dampened in NRF2 knockout cells, indicating that NRF2 coordinates mitochondrial iron availability in a manner relevant to Fe-S cluster biology. Overall, our data indicates that NRF2 activation augments the sensitivity of the Fe-S cluster synthesis pathway to iron restriction in NSCLC, presenting a vulnerability with potential therapeutic relevance. Citation Format: Maddison A. Olley, Nathan P. Ward. NRF2 activation sensitizes the Fe-S cluster synthesis pathway to iron restriction [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 5429.
Abstract 5248: Identification of a chromatin-remodeling peptide in diffuse midline glioma by immunopeptidomics
Authors: Niloofar Khairkhah, Ali Namvar, Arun Everest-Dass, Seeta Nyayapathy, Richard Jones, Julie M. Rumble, Christopher E. Whitehead, Judith S. Sebolt-Leopold, Stefanie Galban
Journal: Cancer Research (2025)

Abstract The identification of peptides presented by major histocompatibility complex class I (MHC-I) molecules on cancer cells is crucial for developing targeted immunotherapies, particularly for malignancies like pediatric diffuse midline gliomas (DMG), where therapeutic options remain limited. In this study, we applied advanced immunopeptidomics and mass spectrometry techniques to characterize the immunopeptidome of DMG H3K27M-altered. To identify DMG specific peptides, we included comparative studies to the immunepeptidome of adult glioblastoma (GBM). We identified a total of 454 peptides in DMG and U87 (glioblastoma) xenografts pertaining to 229 genes. Among these, 42 peptides were uniquely expressed in DMGs and 11 were shared with U87 xenografts, highlighting distinct antigen presentation profiles between these tumors. Notably, the peptide RSRKESYSVVYYKVLKQVHPD, which stems from the Histone H2B type 1-M (H2B1M) gene, is presented by the MHC-I molecule HLA-B*57:01, and is associated with chromatin remodeling, was enriched in DMG cells compared to GBM, revealing a potential immunotherapeutic target specific to DMG. To explore whether targeted therapies alter the identified immunopeptidome, we utilized MTX-241F, a previously described experimental compound that inhibits key proliferative pathways (EGFR/PI3K) in DMG and GBM. Comparative analysis of MTX-241F-treated DMGs and U87 xenografts revealed both overlapping and unique regulatory patterns of peptides, underscoring the tumor-specific effects of MTX-241F. MTX-241F selectively upregulated peptides in DMG stemming from the NCOA4, VATF and THOC2 genes that are linked to MHC-I presentation. In summary, our findings provide the first evidence of dynamic treatment dependent modulation of antigen presentation in DMGs and offer new insights into the tumor immunopeptidome. The distinct peptide profiles of DMG and U87 and their different responses to MTX-241F suggest potential therapeutic avenues for precision immunotherapy targeting DMG. In addition, the identification of a shared immunopeptidome presents an opportunity to develop a therapeutic for both pediatric and adult glioma. Citation Format: Niloofar Khairkhah, Ali Namvar, Arun Everest-Dass, Seeta Nyayapathy, Richard Jones, Julie M. Rumble, Christopher E. Whitehead, Judith S. Sebolt-Leopold, Stefanie Galban. Identification of a chromatin-remodeling peptide in diffuse midline glioma by immunopeptidomics [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 5248.
Abstract 6652: PDCD4/mTORC2 axis regulates tumorigenesis through PFKFB3 in NSCLC
Authors: Elham Zokaei, Qing Wang, Hsin-Sheng Yang
Journal: Cancer Research (2025)

Abstract Programmed cell death 4 (PDCD4) is a tumor suppressor whose expression is frequently downregulated in various cancers, including lung cancer. PDCD4 has been shown to suppress tumor cell proliferation, migration, invasion, and metastasis in cultured cells and in mouse models. It has also been suggested to play a role in regulating glucose metabolism; however, the detailed mechanisms remain unclear. Using reverse phase protein array, we found that knockdown of PDCD4 upregulated 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3), a critical enzyme in regulation of glycolysis. PFKFB3 converts fructose-6-phosphate to fructose-2, 6-bisphosphate to activate the rate-limiting enzyme, 6-phosphofructo-1-kinase, in glycolysis. PFKFB3 expression is upregulated in lung cancer and correlates with tumor stage progression. Inhibition or down-regulation of PFKFB3 in lung cancer cells induces cell apoptosis and inhibits tumor growth in nude mice. Given that PDCD4 inhibits mTORC2 activity, we next examined how mTORC2 affects PFKFB3 expression. We found that mTORC2 interacted with PFKFB3 in NSCLC cells. Using In vitro kinase assays demonstrated that can phosphorylate PFKFB3. Further analysis pinpointed a Ser residue as the target site, leading to the generation of phosphorylation-deficient (S to A) and phospho-mimetic (S to D) mutants. Stability assays revealed that phosphorylation at this specific Ser is essential for maintaining PFKFB3 protein stability; as the phosphorylation-deficient mutant underwent rapidly degradation, whereas the phospho-mimetic mutant showed increased it’s half-life. Functional assays showed that WT PFKFB3 promoted high proliferation rates, whereas the phosphorylation-deficient mutant impaired colony formation and proliferation. Taken together, these findings uncover a key mechanism of metabolic reprogramming in NSCLC, in which mTORC2 drives glycolysis by directly phosphorylating PFKFB3, highlighting the therapeutic potential of targeting the PDCD4/mTORC2/PFKFB3 axis in NSCLC treatment. Citation Format: Elham Zokaei, Qing Wang, Hsin-Sheng Yang. PDCD4/mTORC2 axis regulates tumorigenesis through PFKFB3 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 6652.
Abstract 1785: Development of dual-payload anti-GPC3 antibody-drug conjugate by dual-payload antibody conjugation (AD2C) platform for hepatocellular carcinoma treatment
Authors: Hao-Kang Li, Cheng-Wei Lai, Chien-Yu Lin, Yi-Jang Chen, Pei-Ju Leng, Chao-Min Cheng, Sai-Wen Tang, Shih-Chia Hsiao
Journal: Cancer Research (2025)

Abstract Glypican-3 (GPC3) has been reported as a promising target for the treatment of hepatocellular carcinoma (HCC). Although current therapies are available, tumor heterogeneity and the development of drug resistance continue to pose significant challenges to effective treatment. Therefore, combination therapy has emerged as a promising strategy to address these challenges. Acepodia successfully established a Dual-Payload Antibody Conjugation (AD2C) platform utilizing our proprietary bioorthogonal chemistry, which allows conjugating two (or multiple) different payloads to the antibody without requiring antibody engineering. In this study, we developed an anti-GPC3 antibody with dual payloads (anti-GPC3 AD2C) through our AD2C platform to enhance treatment efficacy of HCC. The anti-GPC3 AD2C exhibits comparable GPC3 binding affinity and internalization to the parental anti-GPC3 antibody. No significant degradation or aggregation was observed after long-term storage, demonstrating the stability of anti-GPC3 AD2C. In the pharmacokinetics study, anti-GPC3 AD2C showed a similar terminal half-life (T1/2) to the parental antibody, and its volume of distribution (Vss) was equivalent to the blood volume, indicating primary distribution in the blood. These findings suggest that the dual-payload conjugation has a limited impact on the in vivo stability and safety of the anti-GPC3 AD2C. The in vitro efficacy studies show that anti-GPC3 AD2C exhibits enhanced cytotoxicity compared to the mono-payload ADCs and parental antibody in GPC3-expressing cancer cell lines but not in the GPC3 negative cell lines and primary normal cells. The HCC xenograft study further demonstrated that the anti-GPC3 AD2C completely suppressed tumor growth at doses of up to 10 mg/kg, with no significant body weight change observed. In conclusion, the dual-payload ADC produced by AD2C platform offers a potential strategy to overcome tumor heterogeneity and drug resistance while maintaining an ideal safety profile, supporting its potential clinical application in HCC treatment. Citation Format: Hao-Kang Li, Cheng-Wei Lai, Chien-Yu Lin, Yi-Jang Chen, Pei-Ju Leng, Chao-Min Cheng, Sai-Wen Tang, Shih-Chia Hsiao. Development of dual-payload anti-GPC3 antibody-drug conjugate by dual-payload antibody conjugation (AD2C) platform for hepatocellular carcinoma treatment [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 1785.
Abstract 4726: ETC-501, a novel brain penetrant MNK kinase inhibitor, potentiates TMZ-induced senescence and sensitizes glioblastoma cells to senolytic therapy
Authors: Giselle Nah, Yuk Kien Chong, Fatin Nasha Sulaimi, Kian Leong Lee, See Wee Lim, Kassoum Nacro, Jeffrey Hill, Alex Matter, Henry Yang, Beng Ti Ang, Carol Tang, Sin Tiong Ong
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM), the most lethal primary brain tumor in adults, has a median survival of only 15 months, with fewer than 10% of patients surviving beyond five years. Despite aggressive multimodal therapies, including maximal surgical resection, radiation, and temozolomide (TMZ) chemotherapy, recurrence is almost inevitable. Contributing factors include incomplete resection, elevated levels of O6-methylguanine DNA methyltransferase that repair TMZ-induced DNA damage, therapy-resistant glioma stem cells, intratumoral heterogeneity, and the restrictive blood-brain barrier. Additionally, therapy-induced senescence from chemoradiation poses further challenges, as senescent glioma cells secrete pro-tumorigenic senescence-associated secretory phenotype (SASP) factors and may escape senescence, potentially facilitating recurrence. To evaluate the clinical relevance of MNK kinases in gliomas, we analyzed data from The Cancer Genome Atlas (TCGA), showing that elevated MNK1 and MNK2 expression correlates with increased tumor aggressiveness and poor prognosis. Genetic knockdown experiments confirmed that MNK1/2 are essential for GBM growth in vitro and drive aggressive behavior in vivo. To exploit their therapeutic potential, we developed ETC-501, a potent, selective, brain-penetrant MNK inhibitor. ETC-501 inhibited critical GBM processes, including MYC-driven transcriptional programs, DNA replication, ribosome biogenesis, inflammatory responses, and coagulation. Importantly, in combination with TMZ, ETC-501 significantly enhanced TMZ-induced senescence and reduced tumor-promoting SASP factors in GBM cells, acting both as a senescence inducer and senomorphic. Leveraging this enhanced senescence, we increased the susceptibility of GBM cells to the senolytic agent navitoclax, enabling targeted clearance of residual senescent cells. This “one-two punch” therapeutic strategy effectively eradicated cells that could otherwise act as reservoirs for recurrence. Our findings underscore the therapeutic potential of MNK inhibition in GBM, advancing our approach to managing GBM and potentially other malignancies characterized by senescence and SASP. Citation Format: Giselle Nah, Yuk Kien Chong, Fatin Nasha Sulaimi, Kian Leong Lee, See Wee Lim, Kassoum Nacro, Jeffrey Hill, Alex Matter, Henry Yang, Beng Ti Ang, Carol Tang, Sin Tiong Ong. ETC-501, a novel brain penetrant MNK kinase inhibitor, potentiates TMZ-induced senescence and sensitizes glioblastoma cells to senolytic 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 4726.