tbuckley/cabot-search huggingface dataset:
Abstract 2576: Crosstalk between cancer-associated fibroblasts and sympathetic nerves promotes pancreatic ductal adenocarcinoma progression
Authors: Ariana Sattler, Parham Diba, Tetiana Korzun, Marigold Kuykendall, Kevin MacPherson-Hawthorne, Mara Sherman, Teresa A. Zimmers, Sebnem E. Eksi
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a 5-year survival rate of 12.8%. This aggressive malignancy is composed of a heterogenous tumor microenvironment (TME), including cancer-associated fibroblasts (CAFs) and sympathetic neurons. The abundance of CAFs and sympathetic neurons correlates with tumor progression and is often associated with poor prognosis of PDAC patients. However, the precise role of CAF-nerve interactions in cancer progression and metastasis remains unclear. To explore our hypothesis that these bidirectional interactions can be tumor-supportive, we used advanced imaging and sequencing techniques, an in vivo tumor denervation murine model, and in vitro CAF-sympathetic neuron coculture systems. Compared to human PDAC tumors, we affirmed that sympathetic innervation is recapitulated in murine PDAC tumors, and these intratumor nerves are similarly surrounded by an abundance of CAFs. To focus on the interaction between CAFs and sympathetic nerves, we developed and optimized in vitro coculture systems. These cocultures initially revealed that CAFs consistently interact with nerve fibers and significantly increase sympathetic nerve outgrowth. Transcriptional analysis of these co-cultures further identified genes upregulated in CAFs that promote adhesion, ECM deposition, and neuroactive ligand-receptor interactions, while sympathetic nerves upregulated pathways associated with nerve injury response. To further interrogate the impact of sympathetic innervation in the PDAC TME, we specifically and locally ablated sympathetic nerves in murine orthotopic PDAC tumors and spatially evaluated the cellular and molecular changes in response. Collectively, our findings suggest that the crosstalk between sympathetic nerves and CAFs may modulate CAF behavior, enhance tumor innervation, and drive tumor-promoting phenotypes in PDAC progression. Citation Format: Ariana Sattler, Parham Diba, Tetiana Korzun, Marigold Kuykendall, Kevin MacPherson-Hawthorne, Mara Sherman, Teresa A. Zimmers, Sebnem E. Eksi. Crosstalk between cancer-associated fibroblasts and sympathetic nerves promotes pancreatic ductal adenocarcinoma 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 2576.
Abstract 5384: Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer
Authors: Caleb Cheng, Jasmine Wisniewski, Sydney Peters, Rüya Pakkan, Jennifer P. Morton, Pietro Morlacchi, Yuanyuan Qiao, Costas A. Lyssiotis, Arul M. Chinnaiyan
Journal: Cancer Research (2025)

Abstract Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning, as a novel and targetable vulnerability in PDAC. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in numerous preclinical human and mouse models, including endogenous genetically engineered models. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC. Citation Format: Caleb Cheng, Jasmine Wisniewski, Sydney Peters, Rüya Pakkan, Jennifer P. Morton, Pietro Morlacchi, Yuanyuan Qiao, Costas A. Lyssiotis, Arul M. Chinnaiyan. Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic 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 5384.
Abstract 3797: Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of CD3-bispecifics and mitigate T cell exhaustion
Authors: Latifa Zekri, Nisha Prakash, Monika Engel, Timo Manz, Stefanie Müller, Jonas Heitmann, Sebastian Hörner, Ilona Hagelstein, Martin Pflügler, Gundram Jung, Helmut R. Salih
Journal: Cancer Research (2025)

Bispecific antibodies (bsAbs) that stimulate CD3 (bsAbsCD3) have emerged as promising therapeutic compounds and effectively induce T cell responses by providing “signal 1" for T cell activation. However, the efficacy of these reagents is often limited by T cell exhaustion that is caused by excessive TCR/CD3 signaling in the absence of a costimulatory "signal 2". We recently developed a PSMAxCD3 bsAb (CC-1) and currently evaluate this bsAbCD3 in patients with metastatic, castration-resistant prostate carcinoma (NCT04104607). While treatment with CC-1 significantly reduced PSA levels in the heavily pretreated patients, the induced T cell activity as well as PSA reduction was rather transient. Using blood samples of our study patients in ex vivo analyses, we here show that T cells loose responsiveness and cytotoxic capacity over time upon exposure to PSMAxCD3 treatment. To overcome this limitation, we generated novel bispecific costimulatory antibodies for tumor-restricted activation of CD28 (BiCos) to sustain the efficacy of bsAbCD3 such as CC-1. A lead construct directed to Endoglin (BiCo-1) was identified based on producibility, minimal aggregation tendency and, most importantly, fully target cell-restricted CD28-stimulatory activity. We demonstrate in various in vitro and in vivo models that BiCo-1 alone exhibits neither therapeutic effects nor toxicity. However, in combination with bsAbCD3 including CC-1, BiCo-1 induced sustained T cell proliferation and memory formation, and profoundly increased the antitumor efficacy of bsAbCD3. Finally, and perhaps most importantly, BiCo-1 also reverted T cell exhaustion induced by CC-1 single agent treatment in patient-derived T cells ex vivo. Taken together, these data demonstrate that the combinatorial use of bsAbCD3 and Bicos may profoundly enhance the sustainability and specificity of therapeutically induced T cell responses against tumors. The GMP-compliant production of BiCo-1 as well as preclinical evaluation in non-human primates has been completed, and a first-in-human clinical trial in prostate cancer patients is will begin recruitment in 2025. Citation Format: Latifa Zekri, Nisha Prakash, Monika Engel, Timo Manz, Stefanie Müller, Jonas Heitmann, Sebastian Hörner, Ilona Hagelstein, Martin Pflügler, Gundram Jung, Helmut R. Salih. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of CD3-bispecifics and mitigate T cell exhaustion [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 3797.
Abstract 4650: The impact of GLI3 mutations and expression on prognosis in gastric cancer
Authors: Wanfu Zhang, Wendi Jin, Hongwei Wan, Chao Niu, Chu Yan, Chunxiao Wang, Juanjuan Liu, Xiaogang Li, Qinglan Zong, Ning Gao, Ding Zhang
Journal: Cancer Research (2025)

Abstract Background: GLI3, a member of the GLI zinc finger family, has been extensively investigated in various cancers, including gastric cancer. It has been observed that GLI3 is significantly upregulated in solid cancer types. These findings suggest the involvement of GLI3 in the malignant progression of different cancers. However, the precise impact of GLI3 mutations and expression on the prognosis of gastric cancer patients remains unclear. Further investigation is warranted to elucidate the prognostic significance of GLI3 alterations in gastric cancer. Methods: This study included 269 gastric cancer patients from TCGA and 2903 patients from China. The mutation rate of GLI3 was analyzed using Excel. Additionally, the survival rates of gastric cancer patients with GLI3 mutations were compared to those with wild-type using KM survival curves in the TCGA cohort. In addition, the impact of high and low expression of GLI3 on survival was analyzed using a 50% threshold. The expression of GLI3 in tumor tissues were evaluated using Mann-Whitney analysis to compare with those in normal tissues. Results: The mutation rate of GLI3 was 13.55% in the TCGA cohort, whereas it was significantly lower at 7.79% in the Chinese cohort. KM curve analysis demonstrated that patients with GLI3 mutations in the TCGA cohort had a significantly higher survival rate than those with the wild group (p &amp;lt; 0.05). Additionally, GLI3 expression was significantly higher in tumor tissues compared to normal tissues (p &amp;lt; 0.01). Furthermore, based on GLI3 expression analysis, patients with a 30% higher expression of GLI3 had a significantly worse prognosis compared to the remaining 70% of patients (p &amp;lt; 0.05). The analysis of GLI3 mutations and expression revealed that patients with GLI3 mutations had significantly lower RNA expression compared to those with the wild-type. Conclusion: The mutation rate of GLI3 was found to be higher in the TCGA cohort compared to the Chinese cohort. Both GLI3 mutations and expression were closely associated with the prognosis of gastric cancer patients. These findings highlight the significance of GLI3 as a potential prognostic indicator in gastric cancer. Further research is needed to elucidate the underlying mechanisms and validate these observations in larger and more diverse patient populations. Citation Format: Wanfu Zhang, Wendi Jin, Hongwei Wan, Chao Niu, Chu Yan, Chunxiao Wang, Juanjuan Liu, Xiaogang Li, Qinglan Zong, Ning Gao, Ding Zhang. The impact of GLI3 mutations and expression on prognosis in gastric 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 4650.
Abstract 3293: Exploiting PEGylation of CCN5 for tumor immunity and therapy of triple-negative breast cancer: A new and effective approach for TNBC therapy
Authors: Sunil P. Upadhyay, Axel H. Breier, Inamul Haque, Archana De, Snigdha Banerjee, Mohiuddin Quadir, Sushanta K. Banerjee
Journal: Cancer Research (2025)

Abstract Triple-negative breast cancer (TNBC) is defined by a lack of expressions of three receptors. These include estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor rector 2 (HER2). TNBC accounts for ∼15-17% of all breast cancers (BC) and is the most aggressive subtype of metastatic BC. TNBC incidence is high among BRCA1 mutation carriers, women with the age of 50 or below, and African American descent. The therapeutic opportunities for TNBC are limited to chemotherapy as targeted options are deficient, resulting in elevated risk of recurrence and mortality risk. Over the last five years, new strategies for treating TNBC have transformed significantly by introducing PD-1/PD-L1-immune checkpoint inhibitors (ICIs) and others. However, only eighteen-20% of PD-L1 positive TNBC patients with metastasis respond to ICIs with or without chemotherapy and enhance the antitumor response of therapeutic CD8+ T cells. The low overall response rate of ICIs in TNBC patients is due to insufficient PD-L1/PD-1 interaction blockade. Consequently, an unmet need exists to revolutionize treatment regimens by replacing or modifying them with ones that are more effective and less toxic. Previous studies demonstrate that CCN5 (also known as WISP-2), which is family of cellular communication Network (CCN) factors, is considered a tumor suppressor and anti-invasive protein as it promotes the growth arrest and progression of TNBC cells. Our previous studies showed that recombinant CCN5 (hrCCN5) therapy is weak for systemic delivery due to poor bioavailability. Thus, only intratumoral injection of CCN5 was considered and found effective with no toxicity in animal studies, but this is not an ideal therapeutic strategy for progressive BC therapy. To overcome this limitation, we implemented the protein PEGylation/PEG conjugation technique that increased the bioavailability and activities of CCN5 and reverses tumor growth and metastasis and increases prolonged overall survival in an MDA-MB-231tumor xenograft model. Further, we found that PEGCCN5 significantly increased CD8+ T cells decreased myeloid infiltration and PD-L1 expression in tumor cells. Thus, we consider PEGCCN5 can emerge as a new, beneficial immunotherapeutic drug for TNBC treatment alone or in combination with αPD-1, chemotherapy, or both. Citation Format: Sunil P. Upadhyay, Axel H. Breier, Inamul Haque, Archana De, Snigdha Banerjee, Mohiuddin Quadir, Sushanta K. Banerjee. Exploiting PEGylation of CCN5 for tumor immunity and therapy of triple-negative breast cancer: A new and effective approach for TNBC 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 3293.
Abstract 2539: Imaging heterogeneity in pre-clinical models of soft-tissue sarcoma with multi-parametric MRI
Authors: Ellen O'Sullivan, Clémentine Lesbats, Paul H. Huang, James P. O'Connor, Simon P. Robinson
Journal: Cancer Research (2025)

Abstract Soft tissue sarcomas (STS) are highly aggressive and heterogeneous cancers. There is a clinical need for techniques to image inter- and intratumoral heterogeneity of STS for personalized adaptation of treatment and to improve diagnostic accuracy. Multiparametric MRI (mpMRI) quantitatively maps spatial variations of functional and structural features of tumors in vivo. mpMRI data was acquired from mice bearing subcutaneous ICR-LMS-1, SK-UT-1 (both leiomyosarcoma, LMS) or HS-SY-II (synovial sarcoma, SS) xenografts. Biomarkers included quantification of the tumor apparent diffusion coefficient (ADC), native T1 and T2 relaxation times, magnetisation transfer ratio (MTR), the transverse relaxation rate R2*, and the complex shear modulus |G*| using MR elastography to assess tumor stiffness. Pathology correlates were sought from MRI-aligned histological sections. Frequency histograms visualized the distribution of values to assess statistical dispersion. Median ADC and T2 were significantly higher in the two LMS models compared to the more cellular dense HS-SY-II tumors (table Table ICR-LMS-1 (n=7) SK-UT-1 (n=8) HS-SY-II (n=10) Tumor volume (mm3) 374 ± 116 343 ± 26 405 ± 52 ADC (x10-6mm3/s) 1303 ± 139 1083 ± 91 629 ± 30 *** T1 (ms) 2549 ± 42 2607 ± 49 2496 ± 33 T2 (ms) 110 ± 14 96 ± 4.6 73 ± 2 *** MTR (%) 16.5 ± 6 20 ± 0.46 22 ± 0.41 * R2* (s-1) 31.7 ± 14.5 26 ± 1.5 43.7 ± 3.4 * G* (kPa) 3.46 ± 0.45 2.87 ± 1.02 4.06 ± 0.22 ). Significantly higher MTR in the HS-SY-II tumors suggests greater macromolecule (e.g protein) content. Tumor R2*, a proxy for blood vessels, was slowest in the SK-UT-1 cohort, consistent with their low CD31 positivity. All three models exhibited a relatively soft biomechanical phenotype. HS-SY-II tumors displayed unimodal histograms, suggesting homogeneously distributed MRI biomarkers, and had little inter-tumor variation. In contrast, both LMS models exhibited bi- or trimodal distributions and higher interquartile range values, particularly for ADC, indicating pronounced intratumor heterogeneity and marked inter-tumour variation. mpMRI can inform on and assess differences in tissue heterogeneity within STS subtypes. Quantification of tumor ADC may provide a sensitive MRI biomarker to assess differential response of LMS and SS to therapy, which has clear translational potential. Citation Format: Ellen O'Sullivan, Clémentine Lesbats, Paul H. Huang, James P. O'Connor, Simon P. Robinson. Imaging heterogeneity in pre-clinical models of soft-tissue sarcoma with multi-parametric MRI [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 2539.
Abstract 5386: Metabolic regulation of PARP inhibitor response in ovarian cancer cells
Authors: Subin Myong, Hardik Shah, Benedikt Nagele, Anh Q. Nguyen, Sridevi Challa
Journal: Cancer Research (2025)

Abstract Ovarian cancer (OvCa) is the most lethal gynecologic cancer due to high mortality from therapeutic resistance. Recently, PARP inhibitors (PARPi) have shown efficacy in treating OvCa, and patients with DNA repair pathway defects are now on PARPi maintenance. However, heterogeneous responses and resistance to therapy limit the clinical efficacy of PARPi treatment. Catalytic activation of the PARP1 enzyme consumes NAD+, a metabolite coenzyme for redox reactions and a key regulator of energy metabolism. PARP inhibitors can change the metabolic state of cells by inhibiting PARP1 activation and altering cellular NAD+ levels, but the role of metabolic dysregulation in PARPi resistance remains unclear. Here, we show that PARPi-resistant ovarian cancer cells have elevated NAD+ biosynthesis through the NAD+ salvage pathway. Gene expression analysis using RNA sequencing and metabolomic analysis using metabolic profiling have identified key pathways downstream of NAD+ biosynthesis that contribute to PARPi resistance. We also demonstrated that the metabolic changes caused by high NAD+ biosynthesis in PARPi-resistant cells cause cell cycle arrest at the G0/G1 phase and increase cellular quiescence and cell motility. Inhibition of the NAD+ salvage pathway and reduction of NAD+ levels within PARPi-resistant cells reverse cellular quiescence and cell migration, ultimately increasing the PARPi response in these cells. In summary, our results demonstrate that elevated NAD+ biosynthesis in ovarian cancer cells causes PARP inhibitor resistance by altering the metabolic state of these cells. Furthermore, inhibition of the NAD+ salvage pathway enhances the efficacy of PARP inhibitor-mediated control of ovarian cancer growth. Supported by grants from the NCI SPORE and CRF to S.C. Citation Format: Subin Myong, Hardik Shah, Benedikt Nagele, Anh Q. Nguyen, Sridevi Challa. Metabolic regulation of PARP inhibitor response in ovarian cancer 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 5386.
Abstract 2252: ASO targeting of intratumoral human FOXP3+ Tregs in humanized SGM3-IL15 mice
Authors: Wayne W. Hancock, Tatiana Akimova, Liqing Wang, Zhanna Bartosh, Lanette M. Christensen, Pali Kaur, Veenu Aishwarya
Journal: Cancer Research (2025)

Abstract Introduction: Humanized mice are an indispensable tool for pre-clinical cancer immunotherapy research, but there are limited data regarding human antitumor T cell immunity in such models, especially regarding the development of intratumoral T cell exhaustion. Methods: We wanted to develop a Treg-dependent tumor model in humanized mice to study the effect of AUMsilence FOXP3 antisense oligonucleotides (ASO) targeting of intratumoral human CD4+ FOXP3+ regulatory T cells (Tregs) in vivo. The ideal model would support development and function of human Tregs, CD4+ and CD8+ T cells, allow tumor growth without apparent allogeneic reactivity, demonstrate the development of a suppressive tumor microenvironment, including with exhaustion of tumor-infiltrating T cells, and prove to be a Treg dependent tumor model. To do so, we evaluated two novel JAX strains of humanized CD34+ engrafted mice, NSG-SGM3 and NSG-SGM3-IL15. Results: Both strains of mice had high (&amp;gt;80%) reconstitution by human CD45+ cells, no signs of GVHD, and increased proportions of FOXP3+ Tregs in their spleens, blood and livers (23-35% of CD4+ cells). Suppressive function of isolated liver and splenic Tregs were comparable with healthy donor blood Tregs. Both strains of mice supported similar growth of A549 lung tumor cells without rejection, and tumors were infiltrated by human CD45+ cells (8-20%), including 15-35% of FOXP3+ Tregs. Expression of T cell exhaustion markers was observed in tumors, but not in spleens, livers or blood. FOXP3 ASO treatment resulted in a decrease in tumor growth, while scramble treated mice developed multiple lung metastases and larger tumors. FOXP3 expression was also decreased in tumors (2.7 times, p =0.02) but not in the spleens and livers of ASO treated mice. Of note, targeting of intratumoral Tregs led to decreased expression of most T cell exhaustion markers in tumors, confirming our previous report that intratumoral Treg may promote T cell exhaustion. Conclusions: NSG-SGM3 and NSG-SGM3-IL15 mice provide a platform for preclinical drug testing involving an immunosuppressive tumor microenvironment and accumulation of exhausted T cells and fully functional Tregs. AUMsilence FOXP3 ASO therapy has powerful anti-tumoral effects in vivo, decreases metastases and reverses features of T cell exhaustion. Citation Format: Wayne W. Hancock, Tatiana Akimova, Liqing Wang, Zhanna Bartosh, Lanette M. Christensen, Pali Kaur, Veenu Aishwarya. ASO targeting of intratumoral human FOXP3+ Tregs in humanized SGM3-IL15 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 2252.