tbuckley/cabot-search huggingface dataset:
Abstract 1524: The cancer specific intramembrane serine protease RHBDL2 serves as a master regulator of glutamine metabolism and chemoresistance in TNBC
Authors: Yosuke Matsushita, Kazumasa Okumura, Masato Komatsu, Tetsuro Yoshimaru, Masaya Ono, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri
Journal: Cancer Research (2025)

Abstract Glutamine metabolism is critical in cancer, driving cell proliferation and chemoresistance by supporting anabolic processes and energy production. This dependency offers a potential for therapeutic intervention; however, attempts to inhibit glutamine transporters and related enzymes have largely failed due to tumor plasticity, which enables cancer cells to adapt and bypass metabolic blockades. Our studies focus on RHBDL2, a cancer-specific intramembrane serine protease that regulates the glutamine metabolism in triple-negative breast cancer (TNBC).RHBDL2 plays two pivotal roles in glutamine metabolism. First, it binds and stabilizes ASCT2 at the plasma membrane, ensuring efficient glutamine uptake, which is crucial for ATP production and cell proliferation. Second, highlighting RHBDL2 localizes to the endoplasmic reticulum (ER), where it modulates N-glycosylation of ASCT2 by regulating glycosyltransferase activity. This glycosylation is essential for ASCT2 trafficking and stabilization. Collectively, these functions underscore RHBDL2’ pivotal roles in maintaining tumor metabolism of TNBC cells. In addition to regulating ASCT2, RHBDL2 forms complexes with other proteins and transporters involved in glutamine metabolism, enhancing cancer cells’ adaptability to metabolic stress. Our studies reveal that the RHBDL2-ASCT2 complex correlates with poor prognosis in cancer patients. Moreover, RHBDL2 upregulation has been associated with increased chemoresistance in TNBC, identifying it as a critical factor in therapeutic resistance. We successfully develop the RHBDL2 polyclonal antibody, which inhibits tumor growth by reducing glutamine uptake. Building on this, we are now developing monoclonal antibodies designed to disrupt RHBDL2 function, thereby reducing glutamine uptake and restoring chemotherapy sensitivity. This approach has the potential to impair cancer metabolism, suppress tumor growth, and improve outcomes in TNBC patients. Citation Format: Yosuke Matsushita, Kazumasa Okumura, Masato Komatsu, Tetsuro Yoshimaru, Masaya Ono, Mitsunori Sasa, Yasuo Miyoshi, Toyomasa Katagiri. The cancer specific intramembrane serine protease RHBDL2 serves as a master regulator of glutamine metabolism and chemoresistance in TNBC [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 1524.
Abstract 1819: Inhibition of the cell-scaffolding protein DLG5 sensitizes glioblastoma stem cells to radiotherapy
Authors: Somanath Kundu, Soham Mitra, Abigail Venskus, Harish Babu, Jason Horton, Mariano Viapiano
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is a fatal CNS tumor that responds poorly to conventional chemo- and radiotherapy. Although radiation achieves a significant adjuvant effect after surgical debulking, radioresistant tumor cells repopulate the tumor bed, resulting in unavoidable recurrence. GBM radioresistance has been largely associated with a population of GBM stem cells (GSCs) driven by Sonic Hedgehog (SHH) and Hippo pathways that promote metabolic reprogramming, DNA repair, and cell proliferation. We have previously described that GBM stemness pathways such as SHH are regulated by a cell-scaffolding member of the Scribble/DLG family, DLG5, which is a "high hierarchy" target that maintains a persistent GSC population. Given the related identity of stemness and post-treatment resistance in GSCs, we have investigated here if DLG5 can be targeted to increase the sensitivity of GSCs to conventional radiotherapy. Our results in cultured GSCs confirmed that DLG5 not only regulates the SHH pathway -as we have previously shown- but also the Hippo pathway. Specifically, DLG5 knockdown increased the expression of the Hippo-repressor kinases, MST-1/MST-2, and phosphorylation of the Hippo effector YAP; these alterations were accompanied by downregulation of Hippo-downstream genes (CTGF, BIRC5) as well as genes involved in DNA-damage repair (BRCA1, RAD51) and stemness (OCT4, NANOG). In agreement with these results, DLG5-deficient GSCs subjected to different irradiation regimes (2 - 8 Gy) showed decreased cell viability, reduced survival fraction in clonogenic assays, and reduced self-renewal ability compared to control GSCs. Irradiated DLG5-deficient cells had elevated cleaved Caspase-3 and PARP1 compared to control cells, increased long-term DNA damage, and accumulation in G2/M phase suggesting mitotic catastrophe. The sensitizing effects of DLG5 deficiency were also tested in intracranial GSC-derived tumors subjected to fractionated radiotherapy (5 x 2Gy q24h). Radiotherapy significantly increased the survival of animals implanted with DLG5-deficient tumor cells compared to controls. Overall, our work suggests that targeting DLG5 increases the efficacy of radiotherapy in GBM by disabling the ability of this cell-scaffolding protein to regulate signaling pathways that drive tumor stemness. Work in progress is currently focused on identifying critical functional domains of DLG5 and developing inhibitors to block DLG5-driven mechanisms in GBM tumors. Citation Format: Somanath Kundu, Soham Mitra, Abigail Venskus, Harish Babu, Jason Horton, Mariano Viapiano. Inhibition of the cell-scaffolding protein DLG5 sensitizes glioblastoma stem cells to radiotherapy [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 1819.
Abstract 1616: Artesunate-induced ferroptosis: A novel strategy to overcome chemoresistance in ovarian cancer
Authors: Yusanne Yung Sing Chan, Oscar Gee Wan Wong, Claire Ling Yang Cheung, Esther Shuk Ying Wong, Xu Cong, Annie Nga Yin Cheung
Journal: Cancer Research (2025)

Abstract The high propensity of ovarian cancer to develop chemoresistance contributes to its generally poor prognosis. Therefore, novel therapeutic approaches tackling this issue are highly sought after. Ferroptosis is a form of cell death characterized by iron dependency, increased lipid peroxidation, and disrupted cellular membranes. Many studies suggest that ferroptosis plays a crucial role in tumor suppression, thus providing new opportunities for cancer therapy. Artesunate is a well-known anti-malarial agent that can induce ferroptosis in multiple cancer types. Here in this study, we aim to investigate the potential of artesunate to induce ferroptosis and to attenuate cisplatin resistance in ovarian cancer cells. Cell viability assays indicated that artesunate effectively induced cell death. Cell death caused by artesunate was partially mitigated by the ferroptosis inhibitor ferrostatin-1 and the autophagy inhibitor chloroquine, suggesting the cytotoxic effects of artesunate are mediated through induction of both ferroptosis and autophagic cell death. Moreover, artesunate treatment significantly increased levels of reactive oxygen species (ROS) and lipid peroxidation (LPO), which are key hallmarks of ferroptosis. Western blot analysis also demonstrated that artesunate altered the expression of protein markers associated with increased ferroptosis, autophagy, and apoptosis in a time-dependent manner, suggesting a complex interplay between different cell death pathways. Co-treatment of artesunate with sub-cytotoxic concentrations of cisplatin significantly reduced cell viability after 48 hours, whereas ferrostatin-1 co-treatment partially rescued cell death. The combined treatment also led to an upregulation of ROS and LPO levels. Results suggested artesunate may enhance the cytotoxic effects of cisplatin by promoting ferroptotic cell death. These findings highlight the potential of artesunate as a novel agent to combat ovarian cancer chemoresistance through induction of ferroptosis, thereby enhancing therapeutic efficacy in clinical settings. Citation Format: Yusanne Yung Sing Chan, Oscar Gee Wan Wong, Claire Ling Yang Cheung, Esther Shuk Ying Wong, Xu Cong, Annie Nga Yin Cheung. Artesunate-induced ferroptosis: A novel strategy to overcome chemoresistance in ovarian 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 1616.
Abstract 2789: miR-6794-3p inhibits human pancreatic cancer metastasis by regulating the RBBP4/GRHL2 signaling pathway
Authors: Ha Gyeong Kim, Eun-Taex Oh, Yunmi Cho, Heon Joo Park
Journal: Cancer Research (2025)

Metastasis is a major cause of treatment failure in patients with pancreatic cancer, highlighting the urgent need for effective therapeutic strategies. Here, we focused on identifying novel miRNAs with key roles in metastasis of pancreatic cancer. Microarray analysis of miRNA expression in metastatic and non-metastatic pancreatic cancer samples revealed significantly lower expression of miR-6794-3p in the metastatic tumor group. Gain- and loss-of-function approaches using the pancreatic cancer cell lines MIA-PaCa-2 and HPAF-II expressing low and high levels of miR-6794-3p, respectively, indicated a role of miR-6794-3p in suppression of cell invasion, migration, and EMT signaling. Importantly, our results showed that miR-6794-3p exerts its effects by inhibiting expression of the chromatin remodeling factor, RBBP4. The resulting suppression of RBBP4 induced an increase in the levels of GRHL2 involved in regulating invasion, migration, and EMT signaling in metastatic pancreatic cancer cells. Consistent with these findings, low miR-6794-3p expression levels correlate with poor pancreatic cancer patient survival. Additional preclinical experiments on nude mice clearly demonstrated inhibitory effects of miR-6794-3p on pancreatic cancer cell metastasis. The collective results highlight the functional significance of miR-6794-3p as a suppressor of metastasis and support its predictive utility as a prognostic biomarker and therapeutic target in pancreatic cancer. Citation Format: Ha Gyeong Kim, Eun-Taex Oh, Yunmi Cho, Heon Joo Park. miR-6794-3p inhibits human pancreatic cancer metastasis by regulating the RBBP4/GRHL2 signaling pathway [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 2789.
Abstract 1822: O-GlcNAcylation of NDRG1 mediates radiation resistance in prostate cancer
Authors: Manish Thiruvalluvan, Sandrine Billet, Neil A. Bhowmick
Journal: Cancer Research (2025)

Prostate cancer (PCa) remains one of the most prevalent malignancies worldwide, with localized cases commonly treated through surgical resection and radiation therapy (RT). Both RT and androgen-targeted therapies can stimulate glutamine (L-Gln) secretion by the PCa-adjacent stroma, promoting tumor adaptation and resistance. Beyond its metabolic role, our findings revealed that L-Gln critically influences protein O-GlcNAcylation, a key process for DNA repair and therapy resistance. We hypothesized that targeting L-Gln signaling could enhance PCa sensitivity to RT. Our studies demonstrated that L-Gln starvation significantly increased RT sensitivity in both parental and radio-resistant PCa cell lines, a phenotype recapitulated by silencing OGT, the key enzyme mediating O-GlcNAcylation. Conditioned media from stromal fibroblasts elevated global O-GlcNAcylation and enhanced cell viability in PCa cells, highlighting the role of the tumor microenvironment. Sodium phenylbutyrate (SPB), a clinically available compound that sequesters L-Gln, effectively mimicked the effects of L-Gln depletion, contrasting with metabolic inhibitors of L-Gln that have failed to show clinical benefit. In subcutaneous xenograft models of PCa epithelia co-implanted with cancer-associated fibroblasts, the combination of SPB and RT markedly reduced tumor size compared to either treatment alone. Further, SPB significantly decreased plasma and intratumoral L-Gln concentrations. Mass spectrometry analysis of tumor tissues identified NDRG1 as a protein highly O-GlcNAcylated in response to RT, a modification suppressed by SPB. CRISPR/Cas9-mediated substitution of key O-GlcNAcylated serine residues in NDRG1 significantly enhanced RT sensitivity by destabilizing the protein and impairing its nuclear translocation. Mechanistically, NDRG1 dysfunction was associated with elevated endoplasmic reticulum (ER) stress, evidenced by increased CHOP and NRF2 expression and reduced Akt phosphorylation. RNA sequencing further revealed that SPB disrupted PCa cell metabolism by inhibiting fatty acid oxidation and reducing amino acid transporter activity, leading to diminished nucleotide pools and energy availability. This dual disruption of metabolic and O-GlcNAcylation processes compromised DNA repair and the detoxification of radiation-induced reactive oxygen species, thereby enhancing radiosensitivity. These findings suggest that targeting L-Gln bioavailability is a clinically viable strategy to overcome therapy resistance and improve therapeutic outcomes in PCa patients. Citation Format: Manish Thiruvalluvan, Sandrine Billet, Neil A. Bhowmick. O-GlcNAcylation of NDRG1 mediates radiation resistance in prostate 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 1822.
Abstract 1676: POLB as a novel synergistic target for combination therapy with niraparib
Authors: Joe Z. Wang, Hunain Alam, Rajarshi Choudhury, Ning Sun, Euan Stronach, David Alvarado, Benjamin Schwartz, Kelly Choi
Journal: Cancer Research (2025)

Abstract To identify novel drug targets for combination therapy with PARP inhibition, we performed a comprehensive niraparib x genome-wide (gw) CRISPR combination screen across 65 cancer cell lines representing multiple tumor indications. POLB was identified as a top synergy hit with niraparib, and was also confirmed by a targeted niraparib x CRISPR in vivo screen focusing on DNA damage repair pathways. POLB is a critical factor for the base excision repair (BER) pathway. Thus, we hypothesized that POLB loss results in disruption of the BER pathway, leading to accumulation of DNA damage in the presence of PARP inhibitor. Consistent with this hypothesis, POLB CRISPR knockout (KO) significantly increased niraparib sensitivity in DLD1 and HeLa cancer cell lines. This sensitivity was further amplified when single-strand DNA breaks were induced. Rescue experiments revealed that the lyase activity of POLB is a major driver of the synergy with niraparib. Mechanistic studies validated the hypothesis that POLB loss increases γH2AX foci and PARP1 trapping, indicating increased DNA damage. Our findings underscore POLB as a promising therapeutic target for combination with Niraparib, offering a potential avenue for enhancing cancer treatment efficacy. Citation Format: Joe Z. Wang, Hunain Alam, Rajarshi Choudhury, Ning Sun, Euan Stronach, David Alvarado, Benjamin Schwartz, Kelly Choi. POLB as a novel synergistic target for combination therapy with niraparib [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 1676.
Abstract 1672: Synergistic efficacy of FGFR4 inhibitor (H3B-6527) and oxaliplatin combination therapy in gastric cancer models
Authors: Nadeem Bhat, Mohammed Soutto, Ahmed Gomaa, Shoumin Zhu, Selma Maacha, Marwah Al-Mathkour, Mohammed Chwihne, Ahmed El-Rifai, Oliver McDonald, Wael El-Rifai
Journal: Cancer Research (2025)

Abstract Background: Resistance to chemotherapy remains a significant challenge in the treatment of gastric cancer. This study evaluates the therapeutic potential of a combination of the FGFR4 inhibitor H3B-6527 and Oxaliplatin in preclinical models, focusing on their synergistic effects on tumor suppression and cell death mechanisms. Material and Methods: To evaluate the efficacy of H3B-6527 and oxaliplatin combination, we employed IC50 analyses, colony formation assays, patient-derived xenograft (PDX) models, immunofluorescence (IF), immunohistochemistry (IHC), western blotting, and caspase-3/7 luminescence assays. These techniques were used to assess the impact of the drug combination on tumor cell proliferation, DNA damage, and apoptosis in gastric cancer cell lines (MKN28 and HGC27) and tumor tissues. Results: IC50 analyses demonstrated significantly enhanced sensitivity to the combination therapy in both MKN28 and HGC27 cell lines compared to either agent alone. Colony formation assays revealed that the combination therapy drastically reduced colony counts relative to monotherapies, highlighting its superior anti-proliferative effects. In PDX mouse models, the combination therapy led to pronounced tumor growth inhibition and significantly prolonged survival compared to controls. IF and IHC analyses showed marked increases in DNA damage, as evidenced by γH2AX expression, along with reduced proliferation (Ki67) and elevated apoptosis (cleaved caspase-3). Caspase-3/7 luminescence assays confirmed heightened apoptotic activity in treated cell lines. Western blot analysis revealed elevated levels of cleaved PARP and γH2AX in both gastric cancer cell lines and PDX tissues, corroborating the enhanced DNA damage and apoptotic response induced by the combination therapy. Conclusions: This study demonstrates the synergistic efficacy of H3B-6527 and oxaliplatin in promoting apoptosis, enhancing DNA damage, and inhibiting tumor proliferation in gastric cancer models. These findings provide compelling evidence for the potential clinical application of this drug combination as a promising therapeutic strategy for gastric cancer patients, especially those with chemoresistance. Citation Format: Nadeem Bhat, Mohammed Soutto, Ahmed Gomaa, Shoumin Zhu, Selma Maacha, Marwah Al-Mathkour, Mohammed Chwihne, Ahmed El-Rifai, Oliver McDonald, Wael El-Rifai. Synergistic efficacy of FGFR4 inhibitor (H3B-6527) and oxaliplatin combination therapy in gastric cancer 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 1672.
Abstract 695: Relative importance between DNA methylation and mutation in nonmalignant tissue for cancer risk
Authors: Harumi Yamada, Satoshi Yamashita, Yu-Yu Liu, Toshikazu Ushijima
Journal: Cancer Research (2025)

Abstract Cancer risk is correlated with the accumulation level of genetic (mutation) and epigenetic alterations (DNA methylation). Analysis of these alterations in nonmalignant tissue contributes to assessing cancer risk and to revealing environmental factors that induce the alterations. DNA methylation can be readily measured due to its high accumulation levels, while on the other hand, it is difficult to measure accumulation levels of mutations because of their rarity. To detect rare point mutations accurately and inexpensively, we developed a novel next generation sequencing (NGS) method, EcoSeq [Ueda, PNAS, 119:e2123241119, 2022]. Here, using EcoSeq, we aimed to evaluate the impact of DNA methylation and mutation for gastric cancer risk, and the mutational signatures of H. pylori (HP) infection, which is a mutagen for gastric cancer. Nonmalignant gastric mucosae were obtained from G1 (low risk; never infected with HP), G2 (intermediate; healthy people after HP eradication) and G3 (high; cancer patients after HP eradication). The mutation frequency was slightly increased by history of HP infection (p=&amp;lt;0.0001, G1vsG2), but not associated with cancer risk (p=0.50, G2vsG3). On the other hand, the DNA methylation level of miR124a-3 was strongly correlated with cancer risk (p&amp;lt;0.0001, G1vsG2; 0.00069, G2vsG3). Mutational signatures of SBS39 were observed in G2 and G3. These results showed that DNA methylation was more useful for assessing gastric cancer risk than point mutation frequency, and suggested that SBS39 is due to HP infection. Citation Format: Harumi Yamada, Satoshi Yamashita, Yu-Yu Liu, Toshikazu Ushijima. Relative importance between DNA methylation and mutation in nonmalignant tissue for cancer risk [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 695.
Abstract 1881: Bimodality in pan-cancer proteomics reveals new biomarker discovery opportunities
Authors: Wen Jiang, Damian Bikiel, Jan Zaucha, Jixin Wang, Sanddhya Jayabalan, Yongjin Li, Matthew Sung, James Harper, Jimmy Zhao, Krishna Bulusu, Wenyan Zhong
Journal: Cancer Research (2025)

Abstract Bimodal protein expression, characterized by a protein distribution with two modes, is linked to phenotypic variation across various biological systems. While previous studies focused on RNA expression data, we developed a bimodality model tailored for proteomics to enhance the identification of cancer-associated biomarkers and targets, facilitating precision oncology. We analyzed proteomics data from various cancer types and identified 2,401 tumor-associated bimodal proteins. These tumor-associated bimodal proteins were evaluated for pathway enrichment, revealing significant associations with critical cancer pathways, such as metabolism of non-essential amino acids, interaction between the extracellular matrix and its receptors on the surface of cells and central carbon metabolism in cancer. Utilizing an AI-enhanced knowledge graph, we further delineated common patterns among pan-cancer tumor-associated bimodal proteins. A case study on the bimodal expression of TROP2 in colon adenocarcinoma highlighted up-regulation of MYC and WNT-beta-catenin signaling pathways and down-regulation of inflammatory and interferon-related pathways in the TROP2-high group. The biological difference between TROP2-high and TROP2-low groups underscored its significance in determining cancer severity and informing potential treatment approaches. Our findings show the utility of proteomics in uncovering novel biomarkers and advancing precision medicine, setting a precedent for further multi-omics integration and clinical validation. Citation Format: Wen Jiang, Damian Bikiel, Jan Zaucha, Jixin Wang, Sanddhya Jayabalan, Yongjin Li, Matthew Sung, James Harper, Jimmy Zhao, Krishna Bulusu, Wenyan Zhong. Bimodality in pan-cancer proteomics reveals new biomarker discovery opportunities [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 1881.