tbuckley/cabot-search huggingface dataset:
Abstract 7268: A novel immunocompetent tumor model reveals the immunomodulatory effects of trastuzumab deruxtecan
Authors: Julia Steele, Justin Balko
Journal: Cancer Research (2025)

Abstract The αHER2 antibody-drug conjugate, trastuzumab deruxtecan (T-DXd), has revolutionized the treatment of breast cancer. However, it is being combined with immunotherapy in clinical trials without rigorous preclinical validation. Few studies have explored T-DXd’s immunologic impact, and comprehensive preclinical data supporting immunotherapy combinations is lacking. This gap stems from trastuzumab’s inability to bind to rodent HER2. Consequently, many existing models rely on human-derived cell lines or xenografts transplanted into immune-deficient mice, thus overlooking T-DXd’s adaptive immunologic effects. Other strategies involve inoculating murine tumors expressing human HER2 into immunocompetent mice; however, this approach increases the immunogenicity of the model and often leads to tumor rejection or delayed growth due to xenoantigens arising from sequence differences between mouse and human HER2. To address this, we have developed a robust, immunocompetent tumor model to study trastuzumab-based therapies by minimally editing the mouse HER2 trastuzumab binding region. This tumor model, which we termed HER2X, binds trastuzumab, is nonimmunogenic, and is sensitive to T-DXd treatment. Here we demonstrate the use of this HER2X tumor model to elucidate the immunologic effects of T-DXd. Cytometry by time of flight (CyTOF) analysis revealed significant shifts to proinflammatory, antitumor immune populations, including T cells, NK cells, and M1-like macrophages, in T-DXd treated versus untreated EMT6 HER2X tumors from immunocompetent mice. Accordingly, the proportion of M2-like macrophages, neutrophils, and monocytes were significantly lower in the T-DXd treated tumors. Notably, 60% of T-DXd complete responder mice were also resistant to rechallenge with EMT6 HER2X tumor cells, indicating immunologic memory and potential involvement of adaptive immunity. Furthermore, T-DXd treatment potentiated EMT6 HER2X antitumor responses in immunocompetent mice compared to athymic nude mice. Finally, co-administration of αPD-L1 and T-DXd treatment further increased survival and response compared to either monotherapy in HER2X tumors. Together, these data suggest T-DXd induces a proinflammatory tumor-immune microenvironment, necessitates adaptive immunity for effective antitumor response, and may provide combinatorial benefit with immunotherapy in clinical settings. Further work is needed to determine the mechanism behind these immunomodulatory effects, and how we can leverage this knowledge to inform and improve treatment strategies in patients. Citation Format: Julia Steele, Justin Balko. A novel immunocompetent tumor model reveals the immunomodulatory effects of 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 7268.
Abstract 6819: TOMM40/FADS2 expression ratio predicts the sensitivity to mTOR inhibitors in triple-negative breast cancer
Authors: Salman Mohamed Farah, Yuan-Feng Lin
Journal: Cancer Research (2025)

Abstract Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that does not express the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Because of the negative to ER, PR and HER2, the current targeted therapy is not fully working for TNBC. Deregulated mTOR signaling has been reported to have implications in several human diseases, including cancer. This study aimed to explore the prognostic significance of the mTORC1 gene set and identify potential biomarkers for predictive the therapeutic effectiveness of mTOR inhibitors on TNBC. Methods: The transcriptional profile of normal tissues and primary tumors derived from TNBC patients was obtained from The Cancer Genome Atlas (TCGA) database and used to generate the differentially expressed genes (DEGs) of mTORC1 gene set from Molecular Signatures Database. Cox regression analysis for the DEGs against overall survival of TNBC patients was employed to identify independent prognostic factors. The Chi-square test of independence was used to study the association among the identified prognostic genes and the clinicopathological characteristics of TNBC patients. RT-PCR, immunohistochemistry (IHC) staining and Western blot experiments were used to detect endogenous expression levels of the identified prognostic genes in a panel of TNBC cell lines. MTT assay were used to assess the sensitivity/resistance of TNBC cells to mTOR inhibitors. Results: Two potential prognostic genes FADS2 and TOMM40 were identified from 56 differentially expressed genes (DEGs) between normal tissues and primary tumors of TCGA TNBC patients. Where FADS2 is a protective factor (HR= 0.652), TOMM40 (HR= 2.243) serves as a risk factor under overall survival condition. The signature of TOMM40 downregulation and FADS2 upregulation was associated with a favorable overall survival; conversely the higher TOMM40/FADS2 ratio was referred to a poor outcome in TNBC patients. Under overall survival condition, the TOMM40/FADS2 ratio was shown to significantly (p &amp;lt; 0.05) associate with age, tumor size, lymph node metastasis, pathologic stage and overall survival event. Notably, cell-based cytotoxicity assay revealed that TNBC cells harboring a higher TOMM40/FADS2 ratio compared to TNBC cells with a lower TOMM40/FADS2 ratio are more sensitive to mTOR inhibitor treatment. Conclusion: Our results provide the expression ratio of TOMM40/FADS2 genes as a useful biomarker to predict the therapeutic efficacy of mTOR inhibitors in TNBC. Citation Format: Salman Mohamed Farah, Yuan-Feng Lin. TOMM40/FADS2 expression ratio predicts the sensitivity to mTOR inhibitors in triple-negative 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 6819.
Abstract 5282: New insights into the roles of transcriptional regulation and differentiation state in rhabdomyosarcoma cell migration
Authors: Andrea Largent, Yadong Wang, Abraham Hengyucius, Eleanor Chen
Journal: Cancer Research (2025)

The differentiation state of a tumor cell has been known to impact the cell’s pro-tumor and pro-metastatic abilities; for example, in epithelial tumors like lung cancer, epithelial-mesenchymal transitions (EMT) involve a conversion from a differentiated phenotype to a stem-like state, allowing for increased tumor cell motility and successful metastasis. In rhabdomyosarcoma (RMS), a pediatric soft tissue sarcoma, tumors are heterogeneous for cells at different stages of myogenesis or muscle cell differentiation, but it is not fully clear whether certain myogenic cell types have a propensity towards metastatic migration than others. In both development and RMS, master regulatory factors (MRFs) are essential for transcriptional regulation of genes involved in myogenesis. One of these MRFs is myogenin, a transcription factor expressed during mid-differentiation that leads to a more committed myocyte state. Myogenin-positive RMS cells in a zebrafish model have been shown to exhibit many metastasis-promoting abilities, such as increased migratory velocity compared to stem-like RMS cells, the ability to enter the bloodstream, and the capacity to seed tumor-free areas surrounding the tumor. This indicates that metastasis in RMS may rely heavily on transcriptional regulation and likely involves cells of a myocyte-like state. Knowing this, our lab carried out a human cell line knockdown (KD) scratch assay screen of multiple epigenetic factors to investigate if any may also be involved in RMS cell movement. From this screen, BRD1, a bromodomain-containing transcriptional regulator, emerged as a driver of RMS cell migration, and subsequent quantitative PCR (qPCR) analysis of BRD1 KD cells additionally indicated a significant role in MRF and stem cell marker expression. Immunofluorescent staining of untreated RMS cells 24 hours post-scratch revealed that migratory cells exhibit increased BRD1 and myogenin expression as well as decreased MyoD expression (an earlier MRF), suggesting that migratory RMS cells are at a later differentiation state. These results and future experiments would significantly impact the field, as the metastatic functions of BRD1 and myogenin were previously unknown and understudied, respectively. Citation Format: Andrea Largent, Yadong Wang, Abraham Hengyucius, Eleanor Chen. New insights into the roles of transcriptional regulation and differentiation state in rhabdomyosarcoma cell migration [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 5282.
Abstract 6594: Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial cancer
Authors: Jussi Nikkola, Lauri Ryyppö, Juuso Vuorinen, Lauri Moilanen, Maarit Ahtiainen, Kirsi Pylvänäinen, Hanna Selin, Tuomo Virtanen, Matti Nykter, Thea Veitonmäki, Jukka-Pekka Mecklin, Toni T. Seppälä, Matti Annala
Journal: Cancer Research (2025)

Abstract Lynch syndrome (LS) is a hereditary cancer syndrome characterized by a defective DNA mismatch repair (MMR) system and a high frequency of different cancers, including urothelial cancers (UC) of the upper urinary tract and bladder. We studied the somatic landscape of LS-associated UCs (LS-UC) by analysing 41 tumor samples and 3 urine DNA samples collected from 34 LS-UC patients. We demonstrate that mutations of the telomerase reverse transcriptase (TERT) promoter are present in 83% of sporadic UC and are scarcely present (5%) in LS-UC (p &amp;lt; 0.00001). As a substitute, all LS-UC patients possessed a 5-methylcytosine deamination (CG&amp;gt;TG) and microsatellite instability driven mutation landscape with highly frequent ARID1A (82%), FGFR3 (80%), and KMT2D (78%) mutations. We suggest that the scarcity of TERT promoter mutations in LS-UC is due to an inability to create the required GABP binding motif (5’-GGAA) through CG&amp;gt;TG mutation or microsatellite instability. Our data indicates that LS-UC is a distinct disease entity characterized by unique genomic features. Citation Format: Jussi Nikkola, Lauri Ryyppö, Juuso Vuorinen, Lauri Moilanen, Maarit Ahtiainen, Kirsi Pylvänäinen, Hanna Selin, Tuomo Virtanen, Matti Nykter, Thea Veitonmäki, Jukka-Pekka Mecklin, Toni T. Seppälä, Matti Annala. Constrained hypermutation and absence of TERT promoter mutations in Lynch syndrome-associated urothelial 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 6594.
Abstract 6812: The third-generation FLT-3 inhibitor, PLM-102, is a promising therapeutic option for venetoclax-resistant AML
Authors: Yun Sun Lee, Min Ji Park, Bongki Ko, Soo Jin Kim, Miran Moon, Soo Yeon Jang, Yong-Chul Kim
Journal: Cancer Research (2025)

Abstract Venetoclax, a selective inhibitor of the anti-apoptotic protein Bcl-2, has been used as a first-line treatment for acute myeloid leukemia (AML). However, the long-term administration of the drug generally leads to the development of resistance, thereby limiting its therapeutic efficacy. This study aims to evaluate whether PLM-102, an orally available selective and potent FLT3 inhibitor, can overcome venetoclax resistance (VR) in a drug-resistant AML model. To prepare venetoclax-resistant AML cells, the FLT3-ITD-positive MOLM-14 cell line was exposed to increasing concentrations of venetoclax, starting from 10 nM to 1 μM over a period sufficient to induce appreciable resistance. The venetoclax-resistant (VR) cells showed increased phosphorylation of FLT3, AKT, and STAT3 compared to the parental cells. Treatment of the VR cells with PLM-102 ameliorated all activated signaling pathways, restoring them to basal levels more effectively than either tuspetinib or gilteritinib. Additionally, venetoclax, an inhibitor of the anti-apoptotic protein Bcl-2, is known to upregulate MCL-1 as a bypass mechanism. Treatment with PLM-102 reduced MCL-1 and Bcl-2 expression levels and concurrently led to a significant increase in cleaved caspase-3, indicating that PLM-102 induces apoptosis in VR cell lines. In-vivo anti-cancer activities of venetoclax, various FLT3 inhibitors and PLM-102 were compared in the MOLM-14 VR xenograft mouse model. In contrast to the in-vivo study with the parental MOLM-14 model, venetoclax did not show anti-cancer activity in the MOLM-14 VR model, confirming the resistance of VR AML cells in vivo. Notably, PLM-102 demonstrated the highest tumor growth inhibitory (TGI) efficacy compared with those of other FLT3 inhibitors including tuspetinib, gilteritinib and PHI-101. In conclusion, PLM-102 completely inhibited FLT3 kinase and its downstream signaling including AKT and STAT3, inducing apoptosis in VR AML cells along with significant inhibition of the tumor growth in the VR xenograft mouse model. These findings suggest that PLM-102, a third-generation FLT-3 inhibitor, is a promising candidate for overcoming venetoclax resistance and could serve as a therapeutic option for venetoclax-resistant AML. Citation Format: Yun Sun Lee, Min Ji Park, Bongki Ko, Soo Jin Kim, Miran Moon, Soo Yeon Jang, Yong-Chul Kim. The third-generation FLT-3 inhibitor, PLM-102, is a promising therapeutic option for venetoclax-resistant AML [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 6812.
Abstract 6811: Overcoming temsirolimus resistance in renal cell carcinoma: The potential of bAP15 inhibitor combination therapy
Authors: YI-JU Kao, Kuan-Lin Kuo, Shih-Ming Liao, Chen-Hsun Hsu, Yen-ling Chiu, Wei-Chou Lin, Kuo-How Huang, Po-Ming Chow
Journal: Cancer Research (2025)

Abstract Renal cell carcinoma (RCC) is a prevalent form of kidney cancer with a high mortality rate, especially in advanced stages. While treatments like tyrosine kinase inhibitors, mTOR inhibitors, and immune checkpoint inhibitors exist, they often have limited efficacy. Temsirolimus, a clinically used mTOR inhibitor, provides a therapeutic option for advanced RCC by hindering cell growth and proliferation, but resistance to this drug can emerge. This study investigated the role of deubiquitylating enzymes UCHL5/USP14 in RCC progression and the potential of their inhibitor, bAP15, to overcome Temsirolimus resistance. bAP15 demonstrated potent anti-cancer activity in RCC cells by inducing apoptosis and cell cycle arrest. Importantly, bAP15 synergized with Temsirolimus in vitro, likely by inhibiting proliferating cell nuclear antigen (PCNA), and enhanced Temsirolimus efficacy in vivo. This combination therapy suppressed tumor growth more effectively than either agent alone. These preclinical findings highlight the potential of bAP15 to overcome Temsirolimus resistance in RCC by targeting UCHL5/USP14. Further research, including clinical trials, is necessary to evaluate the safety and efficacy of bAP15 in RCC patients. Citation Format: YI-JU Kao, Kuan-Lin Kuo, Shih-Ming Liao, Chen-Hsun Hsu, Yen-ling Chiu, Wei-Chou Lin, Kuo-How Huang, Po-Ming Chow. Overcoming temsirolimus resistance in renal cell carcinoma: The potential of bAP15 inhibitor combination 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 6811.
Abstract 6926: Targeting plasma membrane KCa3.1 channels reduces tumor size and mitigates gemcitabine-induced fibrosis in a PDAC mouse model
Authors: Zoltan Pethö, Ilka Neumann, Weronika Wilczak, Micol Rugi, Sarah Sargin, Sandra Schimmelpfennig, Elke Nass, Gonçalo Mesquita, Dominika Ciechanska, Andrea Oeckinghaus, Serena Pillozzi, Natalia Prevarskaya, V’yacheslav Lehen’kyi, Albrecht Schwab, Benjamin Soret
Journal: Cancer Research (2025)

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer marked by extensive fibrosis and limited therapeutic options. The calcium-activated potassium channel KCa3.1 has been implicated in cancer progression. with Its elevated expression correlatesing with poor survival in PDAC patients. Here, we explored the in vivo therapeutic potential of targeting KCa3.1 channels using selective inhibitors in PDAC. Experimental procedures: Tumor-bearing KPfC (Kraswt/LSL-G12D Tp53fl/+ PDX1Cre+) mice were treated with TRAM-34 or maurotoxin, inhibitors of KCa3.1, either alone or in combination with gemcitabine. KCa3.1 expression, and markers of epithelial-to-mesenchymal transition (EMT) were assessed via immunohistochemistry. Tumor progression was evaluated by histological analysis, measuring tumor node size and Sirius Red staining to quantify fibrosis. Distinct effects of plasma membrane and mitochondrial KCa3.1 inhibition were determined by comparing maurotoxin with the membrane-permeable TRAM-34. Results: KCa3.1 channels were expressed in CK18+ tumor cells and α-SMA+ cancer-associated fibroblasts. Maurotoxin reduced the tumor node size as compared to vehicle treatment, especially in combination with gemcitabine. In contrast, TRAM-34 and gemcitabine in monotherapy showed no significant impact on tumor node size. Gemcitabine alone induced a marked increase in fibrosis within tumor nodes, an effect not observed with other treatments. Notably, co-treatment with KCa3.1 inhibitors prevented gemcitabine-induced fibrosis and reversed EMT marker expression. Conclusions: Selective targeting of plasma membrane KCa3.1 channels with maurotoxin reduces tumor node size and mitigates gemcitabine-induced fibrosis in PDAC. These findings highlight the therapeutic potential of KCa3.1 inhibition as a strategy to enhance the efficacy of gemcitabine and limit desmoplasia. Citation Format: Zoltan Pethö, Ilka Neumann, Weronika Wilczak, Micol Rugi, Sarah Sargin, Sandra Schimmelpfennig, Elke Nass, Gonçalo Mesquita, Dominika Ciechanska, Andrea Oeckinghaus, Serena Pillozzi, Natalia Prevarskaya, V’yacheslav Lehen’kyi, Albrecht Schwab, Benjamin Soret. Targeting plasma membrane KCa3.1 channels reduces tumor size and mitigates gemcitabine-induced fibrosis in a PDAC mouse model [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 6926.
Abstract 6907: Novel TACC3 protein-protein interaction inhibitor, AO-252, shows potent activity in prostate, gastric cancers, and triple negative breast cancer with brain metastasis
Authors: Sridhar Vempati, Chaemin Lim, Robbin Frnka, Edward Painter, Sotirios G. Stergiopoulos
Journal: Cancer Research (2025)

Abstract TACC3 (Transforming Acidic Coiled-Coil-Containing 3) is a key player in microtubule and centrosomal processes and is considered to have an important role in causing chromosomal instability, leading to aggressive cancer. TACC3 overexpression is found in multiple cancers and strongly associated with a poor prognosis in those cancer types. TACC3 is a pleiotropic gene which binds to multiple proteins and plays an important role in DNA damage response mechanisms, hematopoiesis, epigenetics, and immune functions. While TACC3 is essential for cancer cells but it is dispensable for normal cells based on conditional knockout in adult mice, making it an ideal treatment target for highly aggressive cancers. We had previously shown that AO-252, a novel small molecule TACC3 protein-protein interaction (PPI) inhibitor, exhibited strong in vivo efficacy in triple negative breast cancer (TNBC) and ovarian cancer. In the present work, we show in vitro and vivo assays that AO-252 shows exceptional efficacy in prostate, gastric cancers and TNBC with brain metastases. In all these cancers, AO-252 exhibited dose dependence on tumor growth inhibition and complete responses in xenograft models. In addition, these responses demonstrated to be durable even after stopping the treatment with AO-252. We also show that AO-252 exerts its activity by destabilizing the C-terminus of TACC3 and disrupting the protein-protein interactions occurring in the C-terminus (EGFR, NOTCH, BRCA1, HIF1b/ARNT, KIFC1, HDAC2, MBD2, DNAPK etc) without blocking the N-terminus interactions. AO-252 is currently in first-in-human (FIH), Phase I clinical trial in TNBC, ovarian and endometrial cancers (NCT06136884). We are in the process of expanding our trial to include prostate, gastric cancer and TNBC with brain metastases. Citation Format: Sridhar Vempati, Chaemin Lim, Robbin Frnka, Edward Painter, Sotirios G. Stergiopoulos. Novel TACC3 protein-protein interaction inhibitor, AO-252, shows potent activity in prostate, gastric cancers, and triple negative breast cancer with brain 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 6907.