tbuckley/cabot-search huggingface dataset:
Abstract 7323: Tissue resident memory T cell abundances impact non-small-cell lung cancer immune microenvironment and patient prognosis
Authors: Aidan Shen, Aliesha Garrett, Junhua Mai, Yangzhi Zhu, Chongming Jiang
Journal: Cancer Research (2024)

Abstract Tissue resident memory T cells (TRM) are a specialized subset of long-lived memory T cells that reside in peripheral tissues. However, whether TRM exerts any immunosurveillance role in the tumor immune microenvironment (TIME) and progression of non-small-cell lung cancer (NSCLC), which accounts for 85% of all lung cancers, remains unclear. Our comprehensive analysis of multiple independent single-cell and bulk RNA-seq datasets of patient NSCLC samples generated reliable, unique TRM signatures, through which we could infer the abundance of TRM in NSCLC. We discovered that TRM abundance is consistently positively correlated with CD4+ T helper 1 cells, M1 macrophages, and resting dendritic cells in TIME and significantly impacts the prognosis of NSCLC patients. In addition, TRM signatures are strongly associated with immune checkpoint genes and the prognosis of NSCLC patients, suggesting that TRM signatures are promising prognostic markers for immunotherapy in NSCLC. We then built a machine learning model to predict patient survival based on the TRM signatures and immune related genes. The accuracy of the model was validated by Kaplan-Meyer survival analysis, receiver operating characteristic curves, principal component analysis, and t-distributed random neighbor embedding. We developed a 4-gene risk score that effectively stratified patients into low-risk and high-risk categories. The patients with high-risk scores had significantly lower overall survival than patients with low-risk. The prognostic value of the risk score was independently validated by the Cancer Genome Atlas Program (TCGA) dataset and multiple independent NSCLC patient datasets. Notably, low-risk NSCLC patients with higher TRM infiltration exhibited enhanced T-cell activation, macrophage regulation, and other TIME immune responses related pathways, indicating a more active immune profile benefitting from immunotherapy. Altogether, this study provides valuable insights into the complex interactions between NSCLC TRM and TIME and their impact on patient prognosis, highlighting the importance of TRM in shaping the NSCLC microenvironment. The development of a simplified 4-gene risk score provides a practical prognostic marker for risk stratification. Keywords: Tissue resident memory T cell, non-small-cell lung cancer, prognosis, tumor immune microenvironment, machine learning Citation Format: Aidan Shen, Aliesha Garrett, Junhua Mai, Yangzhi Zhu, Chongming Jiang. Tissue resident memory T cell abundances impact non-small-cell lung cancer immune microenvironment and patient prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7323.
Abstract 2431: Identification of highly expressed exosomal RNAs derived from pancreatic cancer cell lines and exploration of their potential as biomarkers
Authors: Yuhan Rong, Naoki Okubo, Noritoshi Kobayashi, Eriko Katsuta, Yasushi Ichikawa
Journal: Cancer Research (2024)

Abstract Background: Not all exosomes in the blood of cancer patients originate from cancer cells. This study evaluated the relationships between mRNAs and miRNAs in pancreatic cancer (PC) cell lines and those in exosomes secreted into the supernatant. We aimed to identify candidates for PC biomarkers from cancer-specific exosomal mRNAs and miRNAs. Materials and Methods: Three PC cell lines were utilized. Exosomes were isolated from the supernatant, and cellular and exosomal mRNAs and miRNAs were extracted. Subsequently, RNA sequencing (RNA-seq) was performed, and the data were analyzed using R software. Results: In the MIAPaCa-2 cell line, the expression of cellular mRNAs and corresponding exosomal mRNAs showed a strong correlation. In the other two cell lines, a moderate correlation was observed. Across all three cell lines, cellular miRNAs and corresponding exosomal miRNAs exhibited moderate correlation. We focused on RNAs that were lowly expressed in cells but highly expressed in exosomes and conducted differential expression analysis using R. Compared with healthy volunteers in the GEO database, some RNAs showed high expression in the supernatant and low expression in the plasma of healthy volunteers. Conclusion: We identified three mRNAs and three miRNAs that may serve as promising biomarker candidates for PC. Citation Format: Yuhan Rong, Naoki Okubo, Noritoshi Kobayashi, Eriko Katsuta, Yasushi Ichikawa. Identification of highly expressed exosomal RNAs derived from pancreatic cancer cell lines and exploration of their potential as biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2431.
Abstract 4466: Omega-3 fatty acid-induced ferroptosis in 4T1 breast cancer through CD36/FABP5 axis
Authors: Anthony Avellino, Jiaqing Hao, Matthew Yorek, Jian yu, Bing Li
Journal: Cancer Research (2024)

Abstract Mammalian cells utilize energy from many different sources, and fatty acids are one of these sources. Dietary fats contain various structures of fatty acids, each impacting cell lipid metabolism in unique ways. Omega-3 fatty acids are known to induce breast cancer cell death through ferroptosis. However, the specific molecular mechanisms by which omega-3 fatty acids trigger ferroptosis have yet to be fully elucidated. Fatty acid binding proteins (FABPs) constitute a family of evolutionarily conserved lipid chaperones, facilitating the transport and utilization of fatty acids within cells. Notably, FABP5 is highly expressed in breast cancer, especially in the most aggressive form, triple-negative breast cancer. We hypothesized that FABP5 acts as a lipid sensor, mediating the ferroptosis induced by omega-3 fatty acids in triple-negative breast cancer cells. To test this, we created Fabp5 stable knockout cell lines in 4T1 and MDA-MB-231, two commonly used triple-negative breast cancer cell lines, using CRISPR/Cas9 technology. When treated with docosapentaenoic acid (DPA), these Fabp5-knockout cells exhibited reduced ferroptosis compared to their wild-type counterparts. Interestingly, blocking the surface protein CD36, either with inhibitors or antibodies, also reduced DPA-induced ferroptosis. Furthermore, mutations in Fabp5 decreased maximal mitochondrial respiration in both 4T1 and MDA-MB-231 cells, suggesting a crucial role for FABP5 in mediating oxygen consumption and reactive oxygen species (ROS) production during DPA-induced ferroptosis. Additionally, mice fed a high-fat diet rich in omega-3 fatty acids showed reduced tumor size and lung metastasis. Collectively, our data indicate that FABP5 is a key molecular sensor mediating oxygen consumption and ROS production, thus contributing to ferroptosis induced by omega-3 fatty acids in triple-negative breast cancer. Citation Format: Anthony Avellino, Jiaqing Hao, Matthew Yorek, Jian yu, Bing Li. Omega-3 fatty acid-induced ferroptosis in 4T1 breast cancer through CD36/FABP5 axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4466.
Abstract 1843: Integrating machine learning with microfluidic technologies for proteomic profiling of extracellular vesicles in triple-negative breast cancer
Authors: Min Woo Kim, Jee Ye Kim, Young Kim, Suji Lee, Sol Moon, Ju-yong Hyon, Kyung-A Hyun, Yeji Yang, Seongmin Ha, Sunyoung Park, Hogyeong Gawk, Haeji Lee, Eun Hee Han, Jin Young Kim, Hyo-Il Jung, Young-Ho Chung, Seung Il Kim
Journal: Cancer Research (2024)

Abstract Accurate diagnosis of breast cancer using circulating biomarkers present in plasma remains an important challenge. In particular, protein changes in tumor-derived extracellular vesicles (tdEVs) have emerged as potential biomarkers for breast cancer diagnosis because they accurately reflect dynamic changes in tumors. In this study, we compared the proteomes of extracellular vesicle (EV) isolated from the plasma of 100 breast cancer patients and 30 healthy individuals who visited Severance Hospital between Mar 2010 and Dec 2015. Microfluidic chip-based protocol that facilitates the removal of contaminants such as albumin and immunoglobulins was used for the extraction of enriched tdEVs with small amounts of plasma. Comparative analysis of the proteomes identified 26 significant biomarkers that could indicate differences between breast cancer patients and healthy individuals. Using the LsBoost-CNN-SVM hybrid machine learning algorithm, we especially identified key EV protein biomarkers for detecting triple-negative breast cancer (TNBC), a breast cancer subtype with a poor prognosis and a high recurrence rate, as well as lacking therapeutic and diagnostic targets. Remarkably, a signature consisting of three EV proteins, specifically extracellular matrix protein 1 (ECM1), mannose-binding lectin 2 (MBL2), and biotinidase (BTD), effectively distinguished TNBC patients from healthy individuals. In our proteomic analysis set (n=73), this signature exhibited impressive performance, achieving a sensitivity of 93.3% and specificity of 93% in the accurate discrimination of TNBC from the control group. The validation set (n=40) confirmed these findings, with 100% sensitivity and 80% specificity. This signature not only served as a diagnostic tool but also provided valuable insights into the risk of recurrence and patient prognosis. We found a novel diagnostic approach that holds the potential to revolutionize breast cancer diagnostics by enhancing the reliability of tumor-related information obtained from blood samples. Citation Format: Min Woo Kim, Jee Ye Kim, Young Kim, Suji Lee, Sol Moon, Ju-yong Hyon, Kyung-A Hyun, Yeji Yang, Seongmin Ha, Sunyoung Park, Hogyeong Gawk, Haeji Lee, Eun Hee Han, Jin Young Kim, Hyo-Il Jung, Young-Ho Chung, Seung Il Kim. Integrating machine learning with microfluidic technologies for proteomic profiling of extracellular vesicles in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1843.
Abstract 7315: Collaboration between NIDCR and NCI promotes innovative research in head and neck cancers
Authors: Zhong Chen, Wendy Wang
Journal: Cancer Research (2024)

Abstract The Oral and Salivary Cancer Biology Program at National Institute of Dental and Craniofacial Research (NIDCR) supports research activities that improve early detection and treatment of cancers of the oral cavity, pharynx, and salivary glands. We promote basic science research on the regulatory pathways and transformation process of pre-cancerous lesions to primary and metastatic tumors, as well as translational science activities to develop novel technologies and therapeutics for the diagnosis, prognosis, and treatment of cancers. NIDCR and National Cancer Institute (NCI) have established long-term collaborations to promote and co-manage awards funded through The Immuno-Oncology Translational Network (IOTN) of the Cancer Moonshot program, Specialized Programs of Research Excellence (SPOREs), and Early Detection Research Network (EDRN) program. NIDCR and NCI have co-developed Notice of Special Interest (NOSI) and Request for Application (RFA) on Advancing Head and Neck Cancer Early Detection Research (AHEAD), which co-funded seven research projects to discover and develop molecular signatures of early detection and diagnosis of HPV positive and negative head and neck cancer (HNC). To further strengthen NIDCR and NCI collaboration, we jointly organized the symposium to promote HNC early detection and biomarker identification at the American Head and Neck Society (AHNS) 11th International Conference on Head and Neck Cancer in July 2023. In addition, NIDCR has organized a symposium to promote HNC research at the 2024 annual meeting of American Association for Dental, Oral, and Craniofacial Research (AADOCR) to celebrate the 75th anniversary of NIDCR. This AADOCR symposium will feature the collaboration between NIDCR with NCI in the Cancer Moonshot program focusing on immunoprevention and immunotherapy, HNC early detection and biomarker research in AHEAD and EDRN, and investigation of HPV positive and negative HNC and clinical translational research under SPORE. At this 2024 AACR annual meeting, NIDCR and NCI program directors will present the collaborations and funding opportunities between NIDCR and NCI, focusing on early cancer detections and biomarker discovery and validation. Collaboration between NIDCR with NCI provides a unique opportunity to promote basic, translational, and clinical research in advancing HNC early detection to benefit cancer patients. Citation Format: Zhong Chen, Wendy Wang. Collaboration between NIDCR and NCI promotes innovative research in head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7315.
Abstract 7629: Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate cancer
Authors: Shigekatsu Maekawa, Ryo Takata, Ei Shiomi, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Jun Sugimura, Wataru Obara
Journal: Cancer Research (2024)

Abstract Background: The enzyme of catechol-O-methyltransferase (COMT) inhibits the proliferation of prostate cancer (PCa). There has been no obvious biomarker that contributes to the selection of a therapeutic agent among new-generation androgen receptor-axis targeted (ARAT) therapy, such as abiraterone (ABI) or enzalutamide (ENZ). We aimed to assess the possibility of using COMT expression as a biomarker for PCa progression and the criteria for selecting ABI or ENZ. Methods: We retrospectively evaluated 60 patients with PCa treated with ABI or ENZ via needle biopsy or radical prostatectomy. Immunostaining of COMT was performed using formalin-fixed, paraffin-embedded blocks obtained from the initial prostate biopsy for diagnosis or prostatectomy. Immunostaining evaluations were scored by immunostaining intensity (0-3) and staining area (0-3), and the total score ≥4 was defined as "high expression" and the total score &amp;lt;4 was defined as "low expression.” The associations between COMT expression levels and clinical outcomes, including the duration of ENZ or ABI response, were also assessed. Results: Of the 60 cases, nine (15%) showed low expression of COMT. Overall survival was significantly shorter in patients with lower COMT expression (hazard ratio [HR] = 0.24, 95% confidence interval [CI] 0.07-0.83, P= 0.024). When ENZ was administered as the first ARAT, progression-free survival (PFS) was significantly different between patients with COMT expression scores &amp;lt;4 and ≥4 (median 5.9 and 23.3 months, respectively). However, when ABI was administered as the first ARAT, there was no significant difference in the PFS of ARAT between COMT expression scores &amp;lt;4 and ≥4. Conclusion: Patients with lower COMT expression have a significantly poorer prognosis for PCa. In addition, PFS after ENZ administration, as the first ARAT, correlated with COMT expression levels. To our knowledge, this is the first report of an association between COMT expression and the duration of ARAT. Citation Format: Shigekatsu Maekawa, Ryo Takata, Ei Shiomi, Daiki Ikarashi, Tomohiko Matsuura, Renpei Kato, Mitsugu Kanehira, Jun Sugimura, Wataru Obara. Association between COMT expression and therapeutic efficacy of androgen receptor-axis targeted in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7629.
Abstract 5079: Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models
Authors: Eunsil Park, Marlene Hinton, Mingmei Cai, Malgorzata A. Gil, Gustave Hebert, Long Cui, Doug Linn, Brian J. Long, Evan R. Barry
Journal: Cancer Research (2024)

Abstract The development of immune checkpoint inhibitors (ICIs) and combinations of immuno-oncology therapies with standard-of-care (SoC) chemotherapeutic agents has shifted therapeutic paradigms for patients with multiple cancer indications. For many patients, these combinations have shown a beneficial effect on clinical outcomes and disease management. However, additional combination therapies are still needed. Preclinically, a comparison of responses from SoC chemotherapies and ICI combinations in multiple disease models may be helpful in identifying optimal treatment combinations in the clinic. Here we report the results of multiple SoC/ICI in vivo combination efficacy studies in a large panel of mouse syngeneic models spanning seven tissue origins: 1) Colon: CT26, MC38; 2) Breast: EMT6, 4T1; 3) Kidney: Renca; 4) Bladder: MB49, MBT2; 5) Skin: B16F10, CM3; 6) Lung: TC1, LL/2, M109; 7) Brain: GL261. The advantage of using syngeneic models is not limited to the rapid and reproducible tumor growth, but importantly that the animals also have an intact immune system and clinically relevant tumor microenvironment, which are required for ICI combination studies. We tested &amp;gt; 10 chemo SoC combinations with a murinized anti-PD-1 antibody (DX400) in 14 syngeneic mouse models. We found that multiple SoC regimens combined well with DX400 treatment, including FOLFIRI, FOLFOX (colon), Carboplatin/Paclitaxel, Carboplatin/Pemetrexed (lung), Capecitabine/Docetaxel, Cisplatin/Gemcitabine (bladder), Cisplatin/5-FU/or capecitabine, and Oxaliplatin/5-FU/or capecitabine (gastric). Specifically, we observed that the SOC/ICI combinations resulted in enhanced antitumor activities compared to single-agent treatments in many of the models. These data, particularly specific SoC combination regimens that combine well with ICIs in each disease, are useful for optimizing promising combination approaches for clinical development and will be presented here. Citation Format: Eunsil Park, Marlene Hinton, Mingmei Cai, Malgorzata A. Gil, Gustave Hebert, Long Cui, Doug Linn, Brian J. Long, Evan R. Barry. Comparative studies of chemotherapy and immuno-oncology combinations in multiple mouse syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5079.
Abstract 6049: Cell-based PROTAC screening for cancer drug discovery
Authors: Yong Wan, Haiqing Ma, Jianghong Wu
Journal: Cancer Research (2024)

Abstract Proteolysis-Targeting Chimeras (PROTACs) have emerged as a promising strategy for selectively degrading specific target proteins, thereby offering a novel approach to precision cancer therapy. Among the most notable oncogenes, KRAS with the G12C mutation is responsible for 45%-50% of KRAS mutations in non-small cell lung carcinomas. Additionally, BRD4, a well-studied member of the Bromo- and Extra-Terminal (BET) protein family, is implicated in various hematological and solid tumors. The implementation of cell-based screening for PROTACs targeting either KRAS(G12C) or BRD4 represents a highly valuable platform for advancing cancer drug discovery. We utilized the NanoBRETTM Ternary Complex Assay, NanoBiTTM Assay, and Western Blot assay to evaluate the efficacy of PROTACs. The NanoBRETTM Ternary Complex Assay revealed that KRAS G12C degrader-1 and LC-2 effectively degrade KRAS(G12C), while dBET6 and MZ-1 demonstrated the ability to degrade BRD4. Notably, the NanoBiTTM assay showed that LC-2 dose-dependently degrades KRAS(G12C) in HEK293 cells co-transfected with KRAS(G12C)-LgBiT and KRAS(G12C)-SmBiT. Moreover, BET6 exhibited a dose-dependent degradation of endogenous BRD4 in HepG2 cells, and LC-2 demonstrated the degradation of endogenous KRAS(G12C) in MiaPaCa2 cells. In summary, the development of a robust cell-based assay platform for high-throughput screening of PROTACs marks a substantial advancement in cancer drug discovery. This approach not only enables the identification of promising PROTACs but also holds the potential for more effective and targeted interventions in the ongoing battle against cancer. Citation Format: Yong Wan, Haiqing Ma, Jianghong Wu. Cell-based PROTAC screening for cancer drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6049.
Abstract 5470: ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma
Authors: Theophilos Tzaridis, Jingbo Liu, Varun Prabhu, Robert Wechsler-Reya, Tobey MacDonald
Journal: Cancer Research (2024)

Abstract Medulloblastoma is the most common malignant pediatric brain tumor with a for certain molecular subgroups very low overall survival and therefore an urgent need for novel treatment approaches. Dordaviprone (ONC201) and its chemical derivative with nanomolar potency ONC206 are inhibitors of the dopamine receptor 2 (DRD2) and more importantly induce apoptosis of cancer cells by activation of the mitochondrial caseinolytic protease P (ClpP). ONC201 has shown objective responses in patients with diffuse midline gliomas and is currently being evaluated in the Phase 3 ACTION study. ONC206 is currently in Phase I clinical trials for pediatric and adult patients with primary brain tumors. In this study, we evaluated the preclinical therapeutic effects of ONC206 in medulloblastoma in vitro and in vivo and investigated the molecular mode of action for this imipridone. We found evidence for high expression of ClpP at both the RNA and protein level in medulloblastoma tumours, compared to very low expression in normal brain and normal cerebellum. In addition, we saw a pronounced reduction in cell viability of human Group 3 and Group 4 and murine medulloblastoma cells treated with ONC206 with extremely low IC-50s (range: 14nM - 2μM).After treatment with ONC206, we observed a significant downregulation of mitochondrial electron transport chain complexes I and III and mitochondrial hyperpolarization, as well as an induction of the ATF4 pathway, thereby implying that ONC206 induces an integrated stress response and mitochondrial damage. In order to test the efficacy of ONC206 in vivo, we used murine models of SHH-driven and Group 3 medulloblastoma as well as Group 3 patient-derived xenografts (PDXs). ONC206 led to a significant prolongation of survival in both murine models, with the SHH mice demonstrating a remarkable survival benefit. Mice from both Group 3 PDXs also responded to ONC206, with 25% of ONC206 treated animals exhibiting long-term tumor-free survival. Our results highlight ONC206 as a novel attractive therapeutic option for patients with relapsed medulloblastoma and importantly pave the way for a clinical trial testing the efficacy of ONC206 in the treatment of these patients. Citation Format: Theophilos Tzaridis, Jingbo Liu, Varun Prabhu, Robert Wechsler-Reya, Tobey MacDonald. ONC206 inhibits tumour growth and is a potential novel therapeutic strategy for refractory medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5470.