tbuckley/cabot-search huggingface dataset:
Abstract 67: Deciphering the mechanisms underlying the pathophysiology and chemotherapy resistance in acute myeloid leukemia using intravital imaging and humanized NSGW41IL7 mouse
Authors: Raheleh Niavarani, Xi Lei, Michael Edson, Emily Chen, Shirley Wang, Ralph DaCosta
Journal: Cancer Research (2025)

Introduction: Acute Myeloid Leukemia (AML) is an aggressive &amp; highly heterogeneous malignancy that originates within the bone marrow (BM). A major challenge in treating AML is its resistance to therapy &amp; high relapse rates, driven in part by changes AML induces in the BM microenvironment, promoting immune suppression &amp; creating hypoxic conditions. However, the mechanisms behind therapeutic resistance in AML patients in the presence of hypoxic BM niche, are poorly understood.Innovation &amp; Clinical Impact: To address this knowledge gap, our study employs two pioneering methods: a humanized NSGW41IL7 mouse model engrafted with human AML cells &amp; the femur window chamber (FWC) technique, enabling unprecedented real-time visualization of AML dynamics within BM. Using advanced intravital imaging, we are the first to observe the intricate, continuous interactions between AML cells &amp; immune components, such as human gamma delta T cells, within the BM microenvironment. Furthermore, we are interested in using our new approach to investigate how standard chemotherapies impact AML cell survival &amp; immune responses under hypoxic conditions over time. Ultimately, our findings will provide new insights into treatment resistance mechanisms &amp; pave the way for innovative therapeutic strategies targeting the BM microenvironment, improving outcomes for AML patients. Citation Format: Raheleh Niavarani, Xi Lei, Michael Edson, Emily Chen, Shirley Wang, Ralph DaCosta. Deciphering the mechanisms underlying the pathophysiology and chemotherapy resistance in acute myeloid leukemia using intravital imaging and humanized NSGW41IL7 mouse [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 67.
Abstract 1670: The SHMT inhibitor SHIN1 augments the antitumor efficacy of 5-Fuin preclinical models of gastric cancer
Authors: Huan Deng, Yajie Wang, Lin Xiao, Yisheng Pan
Journal: Cancer Research (2025)

Abstract Advanced gastric cancer (GC) is a malignant tumor with poor prognosis, which requires in-depth exploration of its malignant progression mechanism and the development of efficient therapeutic protocols. Serine hydroxymethyltransferase (SHMT), an important hub in serine-glycine-nucleotide metabolic pathways, plays a crucial role in the occurrence and progression of GC. Bioinformatics analysis and cytological experiments preliminary identified the important role of SHMTs in GC. Drug synergistic screening assays were used to build the therapeutic model in the study. The transcriptomic analysis was performed to clarify the underlying mechanism of combination treatment. Here, we found that the SHMT1 and SHMT2 promoted malignant progression and 5-Fu resistance on GC, and their targeted inhibitor SHIN1 is a promising antitumor drug for GC. The synergistic screening analysis showed that SHIN1 was an efficient synergist for 5-Fu, and combination therapy, alleviated 5-Fu resistance to GC. Mechanistically, The combination treatment induces cell cycle arrest, DNA damage and cellular senescence through the activation of the P53 signaling pathway. These unique characteristics of cell growth inhibition, which are induced via interfering with nucleotide synthesis, were validated by substantial in vitro and in vivo assays. The regimen of SHIN1 combination with 5-Fu may be an efficient preclinical model for the treatment of GC. Citation Format: Huan Deng, Yajie Wang, Lin Xiao, Yisheng Pan. The SHMT inhibitor SHIN1 augments the antitumor efficacy of 5-Fuin preclinical models of 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 1670.
Abstract 237: Species-specific role of RAS in malignant transformation
Authors: Nikhil Gupta, Milla Majaniemi, Otto Kauko, Tero Aittokallio, Vera Gorbunova, Jukka Westermarck
Journal: Cancer Research (2025)

Abstract Malignant transformation is a complex, multi-step process driven by the interplay between oncogene activation and tumor suppressor inhibition. The role of RAS in this process has been shown to exhibit striking species-specific differences. In mouse cells, RAS can effectively induce transformation with the inhibition of a single tumor suppressor. However, in human cells, RAS-driven transformation uniquely requires the inhibition of Protein Phosphatase 2A (PP2A). Despite over 20 years of investigation, the molecular explanation for this radical difference remains elusive. To address this fundamental gap in understanding, we performed a comprehensive phosphoproteogenomics analysis comparing mouse and human cells overexpressing oncogenic RAS.Transcriptomics, proteomics, and phosphoproteomics analyses revealed remarkably significant intra- and interspecies heterogeneity, highlighting the profound species-specific differences in RAS-induced signaling. Strikingly, while mTOR, CDK4-E2F1, and MYC signaling pathways were robustly activated by RAS in mouse cells, these activations were notably absent in human cell models. However, co-inhibition of the tumor suppressor phosphatase PP2A rendered human cells permissive to RAS-induced malignant transformation and restored pathway activities overlapping with RAS-only transformed mouse cells. Intriguingly, our findings suggest that RAS overexpression in human cells opposes phosphosignaling and pathway-targeted therapy responses, a phenomenon absent in mouse cells. This highlights a unique buffering role for RAS against transformation in human cells. Moreover, whereas RAS induced substantial signaling pathway connectivity in mouse cells, similar connectivity in human cells was observed only upon PP2A co-inhibition.Collectively, these findings reveal that, unlike in immortalized mouse cells, RAS signaling in human cells acts as a buffer against transformation unless PP2A is inhibited. This underscores the inadequacy of mouse models in representing RAS-driven signaling and transformation in human cells. Our results highlight the need for human cancer models to revolutionize the cancer therapies. Citation Format: Nikhil Gupta, Milla Majaniemi, Otto Kauko, Tero Aittokallio, Vera Gorbunova, Jukka Westermarck. Species-specific role of RAS in malignant transformation [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 237.
Abstract 368: Unique breast cancer CDX panels for KAT6, ER, and CDK4/6
Authors: Tianyu Pang, Haiting Dai, Ziwei Li, Wenbo Du, Wen-Jen Yu
Journal: Cancer Research (2025)

Abstract Estrogen receptor-positive (ER+) breast cancer accounts for approximately 75% of all breast cancers. Over-expression of lysine acetyltransferase 6A (KAT6A), a histone acetyltransferase (HAT), shared a proportion of 10-15% in breast cancer patients and increased the tumor growth through binding the promoter region to enhance ER expression level. Inhibitors of KAT6A were thought to be anti-tumorigenic by deregulation of ER expression. In addition, the cyclin-dependent kinases 4/6-cyclinD-Rb (CDK4/6-cyclinD-Rb) pathway is very important and crucial for ER downstream signaling in ER+ breast cancers. To accelerate the discovery of anti-ER+ breast cancer drugs through KAT6A and CDK4/6 pathways, we generated four specific CDX models which cover the most popular ER+/KAT6A cell lines (BT-474, ZR-75-1) and ER+/ CDK4/6 cell lines (MCF-7, HCC1428) and revealed the efficacy of KAT6A inhibitor (PF-9363), CDK4/6 inhibitor (Palbociclib), or ER inhibitor (Fulvestrant) on these breast CDX models. The in vivo MOA of these inhibitors were also evaluated by Western Blotting and pathological examination. Citation Format: Tianyu Pang, Haiting Dai, Ziwei Li, Wenbo Du, Wen-Jen Yu. Unique breast cancer CDX panels for KAT6, ER, and CDK4/6 [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 368.
Abstract 800: Safety and efficacy of same-day administration of novel long-acting G-CSF efbemalenograstim α in breast cancer patients undergoing cytotoxic chemotherapy
Authors: Shoubing Zhou, Jing Pan, Qiujun Zhang, Wenyu Li, Dandan Hu, Qianyu Zhang, Shikai Hong, Zhengzhi Zhu, Hu Liu, Xudong Zhang, Hua Xie, Yueyin Pan
Journal: Cancer Research (2025)

Abstract Background: There is controversy over whether Granulocyte colony-stimulating factor (G-CSF) can be used within 24 h after chemotherapy. Efbemalenograstim α is a novel long-acting G-CSF approved by FDA in 2023. Guard-02 trial (ChiCTR2300078792) was to evaluate the efficacy and safety of efbemalenograstim α for prevention of chemotherapy-induced neutropenia (CIN) within 24 h after chemotherapy. Methods: This was a prospective, multicenter, single-arm, two-stage clinical study. Breast cancer patients received chemotherapy with epirubicin (90 mg/m2) and cyclophosphamide (600 mg/m2) for 4 cycles were enrolled. If less than 9 cases of grade 3-4 neutropenia occurred in 16 patients in first stage, the toxicity was acceptable and more patients would be recruited in second stage. Patients received 20 mg efbemalenograstim α at 24±4 h (d2) after chemotherapy in first cycle and at 4±1 h (d1) after chemotherapy in subsequent cycles. The primary endpoint was incidence of grade 3-4 (ANC &amp;lt;1×109/L) neutropenia in cycle 1-2. The safety profile was evaluated. Results: The incidence of grade 3-4 neutropenia in cycle 1-2 and cycle 1-4 of 16 patients (median age at 51 years, r.35-60) were 25.00% (90% CI: 9.03%-48.44%) and 31.25% (95% CI: 11.02%-58.66%), both lower than that in phase III trial using efbemalenograstim α at 48 ± 4 h (d3) after EC chemotherapy (NCT04174599, whose incidence of grade 3-4 neutropenia in cycle 1-2 and cycle 1-4 were 34.16% and 36.67%). Using efbemalenograstim α within 24 h after chemotherapy was safe, the most frequently adverse event (AE) related to study drug was muscle pain (6.25%). The incidences of AEs were low and no serious adverse event was related to study drug. Conclusions: Using long-acting G-CSF on same-day of chemotherapy was as safe and effective as on d3 of chemotherapy in reducing CIN. In patients with daytime chemotherapy, efbemalenograstim α provides oncologists an alternative for simplifying management of CIN. Citation Format: Shoubing Zhou, Jing Pan, Qiujun Zhang, Wenyu Li, Dandan Hu, Qianyu Zhang, Shikai Hong, Zhengzhi Zhu, Hu Liu, Xudong Zhang, Hua Xie, Yueyin Pan. Safety and efficacy of same-day administration of novel long-acting G-CSF efbemalenograstim α in breast cancer patients undergoing cytotoxic chemotherapy [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 800.
Abstract 168: Genomic heterogeneity drives distinct infiltration patterns in glioblastoma
Authors: Dylan Harwood, Sara Blaabjerg Artzi, Vilde Pedersen, Alessio Locallo, Maya Jeje Lü, David Scheie, Anne Dorte Nørøxe, Nadine Margaretha Hammouda, Ulrik Lassen, Joachim Lütken Weischenfeldt, Bjarne Winther Kristensen
Journal: Cancer Research (2025)

Abstract Glioblastoma is the most common and malignant type of primary brain cancer with a median patient survival of only 15 months. Tumors are typically categorized into three molecular subtypes—proneural, classical, and mesenchymal—each linked to specific genomic and microenvironmental factors. However, the functional and clinical implications of these subtypes remain poorly understood. Standard treatment involves surgical resection followed by chemotherapy and radiotherapy. Despite this, malignant cells have already at the time point of diagnosis infiltrated healthy brain tissue, driving tumor recurrence. Infiltrating cells have been found to maintain high proliferative rates while invading the brain (termed “go-and-grow”) but have also been shown be non-proliferative (termed “go-or-grow”). Here, we perform computational analyses on transcriptomic data from over 600 patients, supplemented with genomic data, to investigate infiltration patterns in glioblastoma tumors. We identify a proliferative astrocytic state strongly associated with the classical subtype and EGFR amplification and distinct from a non-proliferative astrocytic state. Further analysis showed subtype-specific infiltrative patterns between the tumor core and adjacent brain tissue. To validate these findings, we performed single-cell spatial transcriptomics on patient samples, revealing that classical tumors exhibit a “go-or-grow” phenotype, where core regions are proliferative and infiltrative regions are dormant. In contrast, proneural tumors maintain consistent malignant states and proliferation rates, reflecting a “go-and-grow” phenotype. These findings indicate a direct relationship between the genomic status of glioblastoma tumors and the transcriptomic profiles of their infiltrating malignant cells. Together, our study provides insights into genomically-driven infiltration patterns in proneural and classical glioblastomas, with potential implications for clinical treatment. Citation Format: Dylan Harwood, Sara Blaabjerg Artzi, Vilde Pedersen, Alessio Locallo, Maya Jeje Lü, David Scheie, Anne Dorte Nørøxe, Nadine Margaretha Hammouda, Ulrik Lassen, Joachim Lütken Weischenfeldt, Bjarne Winther Kristensen. Genomic heterogeneity drives distinct infiltration patterns in glioblastoma [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 168.
Abstract 325: Innovative approach in evaluating gap junction functionality using co-cultured spheroids
Authors: Tomas Lugo, Annelise Nguyen, Stephanie Myers
Journal: Cancer Research (2025)

Abstract In recent years, significant advancements were made in colorectal cancer research, particularly in understanding the role of gap junctions in cancer development and progression. However, challenges persisted in effectively evaluating gap junction functionality within 3D structures without disrupting spheroids or relying on dye-addition methods to the media, which often had limitations. To address these issues, we developed an innovative method for microinjecting dye into a single cell within a multicellular spheroid, enabling real-time analysis of gap junction functionality in living cells. Building on this approach, we aimed to create a more physiologically relevant tumor microenvironment by co-culturing spheroids with fibroblast cells. This setup better replicated the complexity of in-vivo conditions. To further enhance our analysis, we fixed these spheroids at various time points and used immunohistochemistry (IHC) to evaluate dye penetration into the spheroid core. The experimental method involved co-culturing fibroblasts (CCD-112CoN) with colorectal cancer epithelial cells (Caco2, SW620, SW480, or HT-29) in a CelVivo Clinostar reactor to produce spheroids larger than 300 µm in diameter. These spheroids were then microinjected using an Eppendorf FemtoJet 4i Microinjector with a dye mixture containing Texas Red (high molecular weight, 40, 000 Da) and Lucifer Yellow (low molecular weight) to assess gap junction activity using a Leica confocal microscope. Additionally, we examined gap junction proteins using an immunofluorescence assay between co-cultured and single-cell cultured spheroids. The results indicated that microinjection was a reliable method for evaluating gap junction functionality within spheroids. Notably, different stages of colorectal cancer modulated dye absorption and transfer, with SW620 spheroids exhibiting lower transfer through cells, while HT-29 spheroids showed increased dye transfer between cells. Furthermore, co-cultured spheroids demonstrated enhanced dye transfer compared to single-cell-type spheroids of the same type. There was an increase in connexin 43 expression based on immunofluorescence in Caco2 with CCD-112CoN spheroids compared to Caco2 and CCD-112CoN single-cell cultures. In conclusion, to our knowledge, this study introduced a novel approach to measuring gap junction activity for spheroids. Furthermore, it highlighted the significant role fibroblasts may play in influencing gap junction dynamics in colorectal cancer cells within complex 3D structures. Citation Format: Tomas Lugo, Annelise Nguyen, Stephanie Myers. Innovative approach in evaluating gap junction functionality using co-cultured spheroids [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 325.
Abstract 829: <i>ITGAV</i> is a targetable vulnerability in epithelial ovarian cancer
Authors: Gilbert K. Salloum
Journal: Cancer Research (2025)

Abstract Ovarian cancer is a lethal heterogenous disease that is typically diagnosed at late stages. In high-grade serous ovarian carcinoma (HGSOC), the most common subtype, PARP inhibitors and chemotherapy are standard of care. Although HGSOC patients are responsive to these therapies, resistance develops and patients invariably relapse. Alterations in genes within the phosphoinositide 3-kinase (PI3K) and AKT network are highly prevalent. Although specific PI3K and AKT small molecule inhibitors have been developed and clinically evaluated, to date none have been approved for clinical use in ovarian cancer patients. To identify collateral druggable vulnerabilities to AKT hyperactivation and develop novel combination therapies in HGSOC, we have performed a CRISPR-based genome-wide synthetic lethal screen. The goal is to identify genes that upon genetic knockout transform a cytostatic cellular response to PI3Ki/AKTi to a cytotoxic one. Using this platform, we have identified genes that regulate integrin signaling as a major mechanism of synthetic lethality against the PI3Ki pictilisib and the AKTi capivasertib. ITGAV, encoding the integrin subunit αV, was a significant dropout against both kinase inhibitors. Pharmacological targeting of integrin αV synergized with pictilisib and capivasertib to induce apoptotic cell death in multiple cell line models of ovarian cancer, as well as patient-derived organoids. Combined PI3K/AKT and integrin αV inhibition induced DNA damage and cell cycle arrest. The mechanisms underlying induction of DNA damage and cell death in response to combination treatment are currently under investigation. The ultimate goal is to bring this combination treatment approach to HGSOC patients and shed new light on mechanisms of resistance to PI3K/AKT pathway inhibitors in ovarian cancer. Citation Format: Gilbert K. Salloum. ITGAV is a targetable vulnerability in epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 829.
Abstract 197: Effects of three nucleoside reverse transcriptase inhibitor analogs on Stat3, NFκB, and JNK/c-Jun signaling in bone metastatic prostate cancer
Authors: Wishrawana Sarathi Ratnayake, Luke Lajmi, Sloan Breedy, Aaron Todman, Karimeh Hagani, Kirpal Bisht, Mildred Acevedo-Duncan
Journal: Cancer Research (2025)

Abstract Bone metastatic prostate cancer (BMPC) is the primary cause of fatality in patients with prostate cancer, and there is currently no effective treatment available. The role of the bone microenvironment in this process has led to an increased focus on the interactions between cancer cells and the bone microenvironment, particularly with osteoblasts. Our study delved into the mechanisms of interactions between prostate cancer cells (DU-145 and PC-3) and the hFOB 1.19 osteoblast cell line. We are investigating the broader effects of three different nucleoside reverse transcriptase inhibitor (NRTI) analogs, namely KBMD-E, KBMD-G, and KBMD-H, for their potential development as anti-cancer drugs. Our previous findings indicated that aPKC-ι and ζ play a role in the progression and metastasis of prostate cancer and that NRTI analogs were capable of inducing apoptosis and pyroptosis in DU-145 and PC-3 cells while showing less pronounced effects on the hFOB.1.19 cell line. Our findings revealed that osteoblasts play a crucial role in helping prostate cells thrive in the bone microenvironment by producing chemokines that promote metastasis. Current data suggested that all three NRTI analogs negatively affect three oncogenic pathways, Stat3, NFκB, and JNK/c-Jun pathways, thereby inducing apoptosis and diminishing metastatic stimulating signals in DU-145 and PC-3. Transcription factors Stat3, c-Jun, and NFκB seem to be critical in establishing the prostate cancer cells in bones. Also, data suggested that these three pathways work in tandem. Data shows that KBMD-E/G/H upregulated interleukin (IL)-18 while downregulating IL-8 and IL-6. KBMD-E/G/H can be used to disrupt critical steps of these metastatic cascades of prostate cancer cells, which can be targeted to develop customized, tailored therapies for bone metastatic prostate cancer, which merit further research. Citation Format: Wishrawana Sarathi Ratnayake, Luke Lajmi, Sloan Breedy, Aaron Todman, Karimeh Hagani, Kirpal Bisht, Mildred Acevedo-Duncan. Effects of three nucleoside reverse transcriptase inhibitor analogs on Stat3, NFκB, and JNK/c-Jun signaling in bone metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 197.