tbuckley/cabot-search huggingface dataset:
Abstract 2217: Commensal bacteria are internal triggers of chronic inflammation and B-cell lymphoma development in myeloid cell-specific TRAF3-deficient mice
Authors: Jaeyong Jung, Sining Zhu, Almin I. Lalani, Judith Shakarchi, Brygida Matracz, Guojun G. Wu, Wei-Xing Zong, Liping Zhao, Ping Xie
Journal: Cancer Research (2025)

Abstract Myeloid cells are central players in innate immunity and inflammation. Their function is regulated by the adaptor protein TRAF3. We previously reported that aging myeloid cell-specific TRAF3-deficient (M-Traf3-/-) mice spontaneously develop chronic inflammation and B-cell lymphoma (BCL). In the present study, we aimed to identify the internal trigger of this disease phenotype in these mice. We first detected gut dysbiosis and transmigration of commensal bacteria to the liver in aging M-Traf3-/- mice. Interestingly, depletion of commensal bacteria using antibiotics effectively prevented chronic inflammation and BCL development in these mice. Systemic IgG responses against commensal bacteria were induced and the IgH CDR3 sequences of malignant B-cell clones of M-Traf3/- mice showed high homology to prevalent bacteria-reactive Ig clonotypes. Furthermore, M-Traf3-/- mice with BCL exhibited high titers of antibodies against commensal bacteria in their serum. Together, our findings suggest that commensal bacteria dysbiosis and transmigration can promote chronic inflammation and BCL development in individuals with compromised innate immunity. Accordingly, targeting relevant commensal bacteria may serve as a therapeutic strategy for preventing and treating chronic inflammation and BCL in these patients. This study was supported by the National Cancer Institute Grant R01CA293055, the National Institute of Allergy and Infectious Diseases Grant R21AI128264, a HealthAdvance Award, the Grossman Innovation Prize, and a New Jersey Commission on Cancer Research (NJCCR) grant DCHS19CRF005. Citation Format: Jaeyong Jung, Sining Zhu, Almin I. Lalani, Judith Shakarchi, Brygida Matracz, Guojun G. Wu, Wei-Xing Zong, Liping Zhao, Ping Xie. Commensal bacteria are internal triggers of chronic inflammation and B-cell lymphoma development in myeloid cell-specific TRAF3-deficient mice [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 2217.
Abstract 4340: DM1 pharmacokinetics in combination with tucatinib in patients with HER2+ LA/M breast cancer
Authors: Ariel R. Topletz-Erickson, Diqiong Xie, Flavia Storelli, Julie Meyer, Shawna Hengel, Wentao Feng, Lauren Farr, Amit Garg
Journal: Cancer Research (2025)

Abstract Background: HER2CLIMB-02 (NCT03975647) is a randomized, double-blinded, placebo-controlled, global phase 3 study designed to evaluate the efficacy and safety of tucatinib in combination with T-DM1 (ado-trastuzumab emtansine) in patients with HER2+ locally advanced/metastatic breast cancer (LA/mBC) who received prior treatment with trastuzumab and a taxane in any setting. Tucatinib is a strong cytochrome P450 3A4 (CYP3A4) inhibitor. The T-DM1 unconjugated payload DM1 is primarily metabolized by CYP3A4. Though T-DM1 is contraindicated for concomitant use with strong CYP3A4 inhibitors, no clinical drug-drug interaction studies have been conducted in patients to assess the impact of strong CYP3A4 inhibitors on DM1 PK. Thus, DM1 PK with and without tucatinib was characterized in HER2CLIMB-02. Methods: Patients in HER2CLIMB-02 were randomized to either tucatinib+T-DM1 or placebo+T-DM1 arms. PK samples were collected on Days 1, 2, 3, and 5 in Cycle 2 (intensive PK substudy) and Day 1 of Cycles 3-6 (all patients). DM1 plasma concentrations were analyzed using validated mass spectrometry methods. DM1 PK parameters following T-DM1 administration, including plasma area under the concentration-time curve up to the last time point (AUClast, Cycle 2 only) and maximal concentrations (Cmax, end of T-DM1 infusion), were calculated using Phoenix (WinNonlin v8.2). Statistical summaries were produced using SAS version 9.4 or later. Results: PK data were available for 196 (substudy: n=27) and 206 (substudy: n=20) patients in the tucatinib and placebo arms, respectively. Geometric mean (GM, CV%) Cycle 2 DM1 AUClast values were 4.93 (34%) and 4.37 (23%) day*ng/mL in the tucatinib (n=11) and placebo (n=11) arms, respectively. Cycle 2 GM (CV%) DM1 Cmax values were 2.38 (26%) and 2.75 (24%) ng/mL in the tucatinib (n=23) and placebo (n=20) arms. Geometric mean ratios for Cycle 2 DM1 AUClast and Cmax were 1.13 (CI90% 0.92-1.4) and 0.86 (CI90% 0.76-0.98), respectively, in the tucatinib versus placebo arms. Likewise, DM1 Cmax GM values for Cycles 3-6 in all study patients were similar between tucatinib and placebo arms. Conclusions: DM1 plasma PK was not impacted by tucatinib in patients with HER2+ LA/mBC. Citation Format: Ariel R. Topletz-Erickson, Diqiong Xie, Flavia Storelli, Julie Meyer, Shawna Hengel, Wentao Feng, Lauren Farr, Amit Garg. DM1 pharmacokinetics in combination with tucatinib in patients with HER2+ LA/M breast 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 4340.
Abstract 191: Functional role of chromosome 1q loci on breast cancer progression
Authors: Alakesh Bera, Eric Russ, Hai Hu, Craig D. Shriver, Meera Srivastava
Journal: Cancer Research (2025)

Abstract Several studies have identified differential expression at various loci on the long arm of chromosome 1 (1q) as the most frequent cytogenetic abnormalities associated with human breast carcinoma. To investigate the impact of genetic alterations on chromosome 1q, we analyzed data from over thirteen thousand human breast tumors (n=13, 146 samples; corresponding to 12, 229 patients across 30 studies) using cBioPortal, which included comprehensive datasets like The Cancer Genome Atlas(TCGA). Our findings revealed that eight genes exhibit significant copy number alterations (12-15%), predominantly amplifications. These genes include TRIM67 (1q42.2, 14%), DISC1 (1q42.2, 14%), REN (1q32.1, 15%), DNM3 (1q24.3, 12%), ATP1B1 (1q24.2, 12%), VSIG8 (1q23.2, 14%), SPTA1 (1q23.1, 14%) and MUC1 (1q22, 14%). In contrast, analysis across more than 100, 000 samples from over 35 different cancers (n=105, 424samples; 101, 597 patients across 226 studies) showed that these genes have much lower alteration frequencies, approximately 3%. Besides, these genes also exhibited notably low expression levels at both RNA and protein levels in normal breast tissues. We further explored the clinical relevance of these genes, examining their roles in breast cancer prognosis and survival outcomes. Our mutual exclusivity and co-occurrence analyses revealed distinct patterns of genetic interplay, indicating a probable collective gain-of-function that drives breast cancer progression. Specifically, TP53 was found to co-occur with MUC1, SPTA1, and VSIG8, while REN exhibited mutual exclusivity. The driver gene PIK3CA co-occurred with DISC1, TRIM67, and REN, whereas ERBB2 showed co-occurrence with all eight genes. These findings suggest a complex network of genetic interactions that may underlie invasive and metastatic breast cancer phenotypes. Additionally, we observed that some of the above mentioned gene products (proteins) including REN (Renin) are detectable in serum, suggesting potential as biomarkers for recurrence or prognosis. Our ongoing studies are focused on validating these proteins as diagnostic and therapeutic targets. Collectively, this study underscores the importance of multi-locus evaluation on chromosome 1q, which could pave the way for novel diagnostic and therapeutic strategies in breast cancer management. Citation Format: Alakesh Bera, Eric Russ, Hai Hu, Craig D. Shriver, Meera Srivastava. Functional role of chromosome 1q loci on breast cancer progression [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 191.
Abstract 1704: Overcoming resistance in HER2-positive gastric and breast cancers: Efficacy of disitamab vedotin in preclinical models resistant to trastuzumab emtansine and trastuzumab deruxtecan
Authors: Negar Pourjamal, Vadim Le Joncour, György Vereb, Cilla Honkamaki, Jorma Isola, Jeffrey V Leyton, Pirjo Laakkonen, Heikki Joensuu, Mark Barok
Journal: Cancer Research (2025)

BACKGROUND: HER2-positive gastric and breast cancers often develop resistance to the approved antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). Disitamab vedotin (DV), a novel anti-HER2 ADC, binds to a distinct epitope on HER2 compared to trastuzumab. This study investigated the therapeutic potential of DV in preclinical models of gastric and breast cancer, including those resistant to T-DM1 and T-DXd and explored whether combining DV with these ADCs could enhance anti-tumor efficacy. METHODS: We evaluated the efficacy of DV, T-DM1, and T-DXd individually and in combination using AlamarBlue cell proliferation assays in HER2-positive gastric and breast cancer cell lines, including models resistant to T-DM1 and T-DXd. We assessed the in vivo efficacy of DV in SCID mouse xenograft models of gastric and breast cancer that had progressed on T-DM1 and/or T-DXd. We examined dual combinations of the three ADCs in xenograft models to evaluate potential synergistic effects. RESULTS: DV demonstrated significant anti-tumor activity in both in vitro and in vivo models, including cell lines and xenografts that were resistant to T-DM1 and T-DXd. In xenograft models, DV effectively inhibited tumor growth in cancers that had progressed following treatment with T-DM1 and/or T-DXd. Notably, combining DV with either T-DM1 or T-DXd resulted in superior anti-tumor effects compared to the use of single agents alone, both in cell culture and in xenograft studies. CONCLUSIONS: This study highlights the effectiveness of DV in overcoming resistance to T-DM1 and T-DXd in preclinical models of HER2-positive gastric and breast cancer. The combination of DV with these ADCs demonstrated enhanced efficacy, underscoring the potential of dual ADC strategies to improve outcomes in HER2-positive cancers. Citation Format: Negar Pourjamal, Vadim Le Joncour, György Vereb, Cilla Honkamaki, Jorma Isola, Jeffrey V Leyton, Pirjo Laakkonen, Heikki Joensuu, Mark Barok. Overcoming resistance in HER2-positive gastric and breast cancers: Efficacy of disitamab vedotin in preclinical models resistant to trastuzumab emtansine and trastuzumab deruxtecan [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 1704.
Abstract 1390: Dysregulation of microtubule dynamics caused by <i>LOXL3</i> knockout triggers mitosis catastrophe and senescence in U87MG and U251 cells
Authors: Talita de Souza Laurentino, Roseli da Silva Soares, Ricardo Cesar Cintra, Antonio Marcondes Lerario, Suely Kazue Marie, Sueli Mieko Oba-Shinjo
Journal: Cancer Research (2025)

The amine oxidase LOXL3 has been implicated in tumor development and progression, with elevated expression in glioblastoma (GBM), the most malignant central nervous system tumor. This enzyme influences adhesion, migration, and proliferation of GBM cells. Furthermore, LOXL3 upregulation contributes to poorer GBM patient outcomes, and its expression is correlated with genes encoding tubulins. Microtubules, the major component of the cytoskeleton, are crucial for the cell cycle and mitotic progression. In this study, LOXL3 knockout was performed using CRISPR-Cas9 in two GBM cell lines, U87MG and U251, which resulted in decreased cell viability and migration in both cell lines. Transcriptome enrichment analysis revealed downregulation of genes associated with tubulin acetylation, which was subsequently confirmed by western blot and immunofluorescence analyses. Both U87MG and U251 cells exhibited downregulation of cell cycle- and proliferation-related genes. Functional assays confirmed that LOXL3-knockout cells exhibited delayed cell cycle progression and significant alterations in mitotic spindles during the metaphase-anaphase transition. Nuclear analysis revealed morphological changes indicative of mitotic catastrophe in U87MG cells (with wild-type TP53) and senescence in U251 cells (with mutated TP53). U87MG cells with LOXL3 knocked out presented increased apoptotic cells, which was enhanced after TMZ treatment. Our results suggest that LOXL3 is a potential therapeutic target for GBM treatment, especially in those with higher LOXL3 expression. LOXL3 inhibition can induce tumor cell senescence in GBM with TP53 mutation and apoptosis in cases with wild-type TP53 boosting TMZ treatment, improving GBM patients´ outcome. Citation Format: Talita de Souza Laurentino, Roseli da Silva Soares, Ricardo Cesar Cintra, Antonio Marcondes Lerario, Suely Kazue Marie, Sueli Mieko Oba-Shinjo. Dysregulation of microtubule dynamics caused by LOXL3 knockout triggers mitosis catastrophe and senescence in U87MG and U251 cells [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 1390.
Abstract 2246: VISTA-induced tumor suppression and immunosuppression by shared cell-intrinsic mechanisms
Authors: Yan Zhao, Tina Andoh, Ishrat Durdana, Joshua Gruber
Journal: Cancer Research (2025)

Abstract VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth, even without a functioning immune system. To understand if similar principles underlie VISTA-mediated immunosuppression we engineered mice with targeted mutations in the VISTA NPGF motif. These animals had increased T cell signaling and proliferation leading to improved control of tumor growth. These results define a generalizable mechanism by which VISTA represses NUMB to control cell signaling across disparate cell types that could be exploited for immunotherapies. Citation Format: Yan Zhao, Tina Andoh, Ishrat Durdana, Joshua Gruber. VISTA-induced tumor suppression and immunosuppression by shared cell-intrinsic mechanisms [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 2246.
Abstract 1392: Mechanism of chemoresistance in esophageal squamous cell carcinoma based on mitochondrial DNA copy number
Authors: Koji Tanaka, Yuto Kubo, Kotaro Yamashita, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Hidetoshi Eguchi, Yuichiro Doki
Journal: Cancer Research (2025)

Abstract Epithelial-to-mesenchymal transition (EMT) has been reported to be associated with metastasis and resistance to therapy in various carcinomas. However, the mechanism of EMT induction and its regulation remain unresolved. Esophageal cancer is one of the most difficult-to-treat cancers that metastasize and are refractory to therapy. In this study, we focused on mitochondrial DNA to elucidate the mechanism of EMT induction in esophageal cancer and to search for therapeutic targets. We established a resistant strain (TE11-R) by long-term exposure of an esophageal cancer cell line (TE11) to chemotherapy (CDDP), and found that TE11-R acquired mesenchymal characteristics. We also observed that the mtDNA copy number was decreased in TE11-R. Next, we established ESCC with reduced mtDNA copy number (TE11-shT) by knockdown of mitochondrial transcription factor A (sh-TFAM). First, mtDNA copy number was reduced to 60% in TE11-shT. Complex IV activity and membrane potential (MMP) were reduced in TE11-shT compared to control TE11. Next, exposure of TE11 to depolarizing agents (CCCP) decreased expression of epithelial markers (CDH1) and increased expression of mesenchymal markers (CDH2, Vimentin, ZEB1) by qPCR and WB. Exposure of TE11-shT and CCCP to DNMT inhibitors increased expression of E-cadherin, decreased expression of N-cadherin and Vimentin, and improved CDDP sensitivity. and CDDP sensitivity were observed. Decreased mtDNA copy number in esophageal squamous cell carcinoma induced EMT via increased DNMT expression, suggesting that DNMT inhibitors may be therapeutic targets for treatment-resistant esophageal cancer cells. Citation Format: Koji Tanaka, Yuto Kubo, Kotaro Yamashita, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Hidetoshi Eguchi, Yuichiro Doki. Mechanism of chemoresistance in esophageal squamous cell carcinoma based on mitochondrial DNA copy number [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 1392.
Abstract 1712: CD36 enrichment in HER2+ mesenchymal stem cells potentiates therapy refractoriness in HER2+ breast cancer
Authors: Lorenzo Castagnoli, Valeria Cancila, Martina Bigliardi, Matteo Dugo, Paola A. Corsetto, Claudia Chiodoni, Viola Regondi, Michela Francesconi, Antonino Belfiore, Andrea Vingiani, Giancarlo Pruneri, Francesca Ligorio, Elda Tagliabue, Claudio Tripodo, Claudio Vernieri, Tiziana Triulzi, Serenella M. Pupa
Journal: Cancer Research (2025)

Abstract Approximately 15-20% of breast cancers (BCs) are characterized by amplification/overexpression of HER2. Although the introduction of anti-HER2 drugs has improved the prognosis of HER2-positive (HER2+) BC patients, a considerable number of tumors fail to respond to or acquire resistance to targeted therapies, highlighting the need for new strategies. Emerging evidence shows that the reprogramming of fatty acid (FA) metabolism plays a key role in the aggressiveness and therapeutic resistance of HER2+ BC. HER2+ BC has been defined as a "lipogenic disease" due to the functional reciprocal crosstalk occurring between HER2-mediated oncogenic signaling and fatty acid (FA) biosynthesis via fatty acid synthase activity. Once lipid biosynthesis is inhibited by anti-HER2 agents, cancer cells could enhance their ability to uptake extracellular FAs to guarantee their supply. In this context, the functional role of the reprogramming of CD36-mediated FA uptake in HER2+ BC progression remains unclear. Our study provides an in-depth molecular, biological and functional characterization of the transmembrane FA transporter CD36 in epithelial (MET-like)- and mesenchymal (EMT-like) HER2+ breast cancer stem cell (CSC) subsets, selected HER2+ BC cell lines and patients treated with neoadjuvant trastuzumab. We reveal consistent enrichment of CD36 in HER2+ EMT-like CSCs from all tested preclinical and clinical therapy-refractory BC models. Notably, we demonstrate the functional interplay occurring between Wnt signaling regulation/activation and CD36 enrichment in HER2+ BC cells. Dual blockade of CD36 and HER2 increases the anti-CSC efficacy of anti-HER2 drugs. Additionally, expression of CD36 in intratumor HER2+ mesenchymal CSCs is significantly associated with resistance to trastuzumab in HER2+ BC patients. These results support the critical role of CD36-mediated FA uptake in HER2+ therapy-refractory BC. Our study provides evidence that targeting CD36 might be an effective therapeutic strategy for this malignancy. (Supported by AIRC) Citation Format: Lorenzo Castagnoli, Valeria Cancila, Martina Bigliardi, Matteo Dugo, Paola A. Corsetto, Claudia Chiodoni, Viola Regondi, Michela Francesconi, Antonino Belfiore, Andrea Vingiani, Giancarlo Pruneri, Francesca Ligorio, Elda Tagliabue, Claudio Tripodo, Claudio Vernieri, Tiziana Triulzi, Serenella M. Pupa. CD36 enrichment in HER2+ mesenchymal stem cells potentiates therapy refractoriness in HER2+ breast 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 1712.
Abstract 3468: Intratumoral interleukin-7 delivery via human iPS cell-derived neural stem cells for glioblastoma immunotherapy
Authors: Yi Fu, Irfaan Karim, Hernando Lopez-Bertoni, Mingyao Ying
Journal: Cancer Research (2025)

Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor characterized by severe immunosuppression and a poor response to conventional treatments. The immunologically "cold" tumor microenvironment of GBM makes immunotherapy still challenging. Here, we studied the immunostimulatory cytokine interleukin-7 (IL7) for GBM immunotherapy. We first showed that IL7 delivery to GBM tumors effectively induced an immune-active tumor microenvironment and anti-tumor immunity. Next, we developed a therapeutic strategy based on intratumoral IL7 delivery via human iPS cell-derived neural stem cells (iNSCs). This iNSC-IL7 treatment in two mouse syngeneic GBM models (CT2A and GL261) led to robust tumor regression with a complete response rate (CR) of 40%. It also significantly extended the survival of animals with partial responses. This treatment induced an immune-active microenvironment, as evidenced by increasing cytotoxic CD8+ T cell infiltration and activity and established anti-tumor immunity. Following RNA-sequencing analysis, we defined transcriptomic changes of tumors in response to iNSC-IL7 treatment, including various tumor microenvironment modulators and the upregulation of immune checkpoint pathways (e.g., PD-1 and CTLA4). This discovery guided the combination regimens using iNSC-IL7 and immune checkpoint inhibitors (anti-PD1 or anti-CTLA4 monoclonal antibody). These two combination regimens led to CR of 80% (iNSC-IL7 + anti-PD1) and 60% (iNSC-IL7 + anti-CTLA4), more effective than monotherapies (iNSC-IL7: 40%; anti-PD1: 40%; anti-CTLA4: 30%). Our results demonstrate that IL7 is a potent immunostimulatory cytokine for GBM immunotherapy. They support iNSC-IL7 treatment for future clinical translation as an autologous cellular immunotherapy for GBM and likely other solid tumors based on human iPS cell-derived cell progenies. The transcriptomic analysis dataset will facilitate the future development of an optimal iNSC-IL7 therapy through combination strategies with other immunotherapy regimens, such as immune checkpoint inhibitors. Citation Format: Yi Fu, Irfaan Karim, Hernando Lopez-Bertoni, Mingyao Ying. Intratumoral interleukin-7 delivery via human iPS cell-derived neural stem cells for glioblastoma immunotherapy [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 3468.