tbuckley/cabot-search huggingface dataset:
Abstract LB447: Drug delivery and efficacy testing using vascularized tumor-on-a-chip
Authors: Da-Hyun Kim
Journal: Cancer Research (2024)

Abstract The inhibition of tumor angiogenesis is considered a promising strategy to impede cancer progression, as the vasculature associated with tumors plays a crucial role in supplying blood and facilitating metastasis. Therefore, the in vitro replication of vascularized tumors is essential for comprehending cancer pathology and discerning the mechanisms governing tumor cell proliferation, metastasis, and response to pharmaceutical interventions. In this study, we fabricated vascularized tumor-on-a-chip to recapitulate the pathological features of solid tumors. We first developed hybrid spheroids consisting of tumor and endothelial cells, resulting in self-assembled intratumoral vessels. This approach enhanced the uniformity of the spheroids and peritumoral angiogenic capacity compared to spheroids composed of only cancer cells. RNA sequencing analysis revealed that the tumor-EC hybrid spheroids exhibited expression profiles associated with aggressive behaviors, such as cancer progression, invasion and metastasis. The blood vessels sprouting around the hybrid spheroids on the chip displayed the distinctive characteristics of leaky tumor vessels. We further validated the suppressive effects of axitinib on tumor growth and angiogenesis, depending on exposure dose and time. Notably, we successfully induced both lymphangiogenesis and angiogenesis around the tumor hybrid spheroids by promoting interstitial flow. In summary, our findings demonstrated that vascularized tumor-on-a-chip reproduces various characteristics of vascularized tumors. Consequently, our model stands as a valuable platform for investigating interactions between within tumor microenvironments and exploring therapeutic strategies in cancer. Citation Format: Da-Hyun Kim. Drug delivery and efficacy testing using vascularized tumor-on-a-chip [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB447.
Abstract CT266: Initial efficacy of surufatinib plus sintilimab and IBI310 for patients with high-grade advanced-neuroendocrine neoplasm: A multicenter, single arm phase 2 stud
Authors: Panpan Zhang, Yakun Wang, Jie Li, Lin Shen, Ming Lu
Journal: Cancer Research (2024)

Abstract Background: High-grade advanced-neuroendocrine neoplasm (HG-NEN) are more aggressive and have worse prognosis. Surufatinib (SUR, a selective VEGFRs; FGFR1; and CSF-1R inhibitor). Ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) has been recommended for extrapulmonary and non-pancreatic NEC if the disease progresses following chemotherapy by the NCCN guidelines for neuroendocrine tumors. Preclinical and clinical studies have shown that SUR is a good partner of immune checkpoint inhibitors (ICIs). In this study, we present findings of SUR combined with Sintilimab (SIN, anti-PD-1) and IBI310 (IBI, anti-CTLA-4) for HG-NEN patients (pts). Methods: Pts with histologically confirmed HG-NENs who resistant or intolerant to standard treatment were included in the study. Enrolled pts received SUR (250 mg, qd, po, q3w) combined with SIN (200 mg, d1, i.v.gtt, q3w) and IBI (1 mg/kg, d1, i.v.gtt, q6w). The primary endpoint was ORR per RECIST 1.1. The second endpoints were PFS, DCR, safety and OS. Results: By Dec 29, 2023, 14 pts were enrolled and available for efficacy assessment. Median age, 53 yrs (range 22- 66); male, 71.4%; ECOG PS 1, 50%; GEP-NEN, 57.1%; NEC, 71.4%; Median ki-67 index, 65% (range 25%-90%); liver metastases, 57.1%. 85.7% pts received prior systemic therapy (50% 1L and 35.7% ≥2L). Confirmed ORR was 28.6% and DCR 76.8%. Median PFS was 4.15 months. Among 9 pts with ≤1 prior systemic regimens, confirmed ORR and DCR were 44.4% and 88.9%, respectively, with a median PFS of 4.5 months. Out of 14 pts, all experienced some form of treatment- emergent events (TEAEs), with only 3 participants (21.4%) reporting grade 3 TEAEs. These included manageable events like increased bilirubin, immune pancreatitis, gastric retention, and increased amylase, each with a 7.1% incidence. No grade 4 TEAEs or new safety signals occurred. Conclusion: Surufatinib combined with Sintilimab and IBI310 showed a potential antitumor activity and a tolerable safety profile, providing an additional treatment option for pts with high-grade NEN. Citation Format: Panpan Zhang, Yakun Wang, Jie Li, Lin Shen, Ming Lu. Initial efficacy of surufatinib plus sintilimab and IBI310 for patients with high-grade advanced-neuroendocrine neoplasm: A multicenter, single arm phase 2 stud [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT266.
Abstract LB446: Decoding the mechanism of metastasis: A novel CAF-therapy that blocks the tumor microenvironment and reverses metastatic traits in all solid tumors
Authors: Benjamin Prieto, Muriel Núñez, Valentina I. Cerdfa, Javier Cerda-Infante
Journal: Cancer Research (2024)

Abstract Progression and metastatic spreading of cancer cells are modulated by the carcinoma-associated fibroblasts (CAFs) within the primary tumor microenvironment in solid tumors. However, the mechanisms through which CAFs exert their pro-metastatic effects on cancer cells remain unknown. In this study, we have developed a small molecule that blocks Neuropilin-1 signaling in metastatic CAFs (mCAFs), reversing the mechanisms that promote metastasis in prostate, breast, colorectal and pancreatic cancer. To address these critical needs, in this study, we sought to assess the potential role of proteoglican neuropilin 1 (PG-NRP1) signaling in the maintenance of the activated CAF phenotype. Our results by gene expression profile, qPCR, WB, and ELISA indicate that CAFs isolated from primary tumors of metastatic patients (mCAFs) are functionally different from CAFs isolated from primary tumors of non-metastatic patients, promoting metastasis traits of cancer cells. Among the most prominent differences is an increased PG-NRP1 expression. siRNA studies demonstrated that the knockdown of NRP-1 in mCAFs showed the reversion of the activated phenotype, evaluated by the activation markers a-SMA, Tenascin C, and Fibronectin. Furthermore, conditioned media from PG-NRP1-siRNA-mCAFs failed to increase cancer cells' metastasis traits (migration and invasion) in vitro and tumor progression in vivo. Furthermore, we engineered a small molecule designed to bind PG-NRP1 in mCAFs. Our findings, demonstrate in vitro and in vivo models that the inhibition of PG-NRP1 impedes tumor growth and metastatic dissemination of cancer cells in spontaneous metastasis assay. We designed and validated, using in vivo models, an inhibitor that blocks NRP1-mCAF. Our research demonstrates that blocking PG-NRP1 in mCAF, with a small molecule, is a transversal therapeutic strategy to prevent progression and metastatic spread in solid cancer tumors. Citation Format: Benjamin Prieto, Muriel Núñez, Valentina I. Cerdfa, Javier Cerda-Infante. Decoding the mechanism of metastasis: A novel CAF-therapy that blocks the tumor microenvironment and reverses metastatic traits in all solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB446.
Abstract LB434: Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine
Authors: Wen-Hung Kuo, Yen-Jang Huang, Jia-Yang Chen, Yi-Chun Wu, Chia-Chun Chen, Mark D. Pegram, Ying-Chih Chang
Journal: Cancer Research (2024)

Abstract We have developed a novel single-cell derived 3D organoid culture platform, Rapid, Reproducible, Rare Cell 3D Expansion (R3CE), capable of generating 3D organoids from solid tumors and normal tissues obtained via surgical tissues and needle biopsies within one week. This method demonstrates over 90% success in banking for at least two passages with over 106 cells across various cancer types, including breast cancer, colorectal cancer, hepatoma cancer, and ovarian cancer. The organoids maintain high fidelity to original tissues, as evidenced by H&amp;E staining, WES, and protein marker analysis across generations. Notably, the R3CE platform can also cultivate circulating tumor cells (CTCs) from peripheral blood. The drug sensitivity profiles of RCE-cultured CTCs closely mirrored clinical outcomes in breast cancer patients. For a patient with stage IV HER2-positive breast cancer, our real-time assay results led to an adjustment in treatment from lapatinib/5-FU to lapatinib/Trastuzumab emtansine (TDM-1), which resulted in substantial clinical improvement. To our knowledge, the R3CE platform is the first 3D organoid system that does not require aggregation or 3D scaffold such as matrigel system. These advancements position the R3CE platform as a promising tool for personalized medicine, offering a rapid and accurate method for drug screening and therapeutic response prediction to guide clinical decision-making in cancer treatment. Citation Format: Wen-Hung Kuo, Yen-Jang Huang, Jia-Yang Chen, Yi-Chun Wu, Chia-Chun Chen, Mark D. Pegram, Ying-Chih Chang. Rapid and reproducible expansion of rare tumor cells: The R3CE platform for personalized medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB434.
Abstract LB055: IBI3001: A potentially first-in-class site-specifically conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors
Authors: Jian Guan, Xiao Zhang, Weiwei Wu, Lei Cao, Zhengguang Liao, Tianyu Zhu, Chentao Liu, Shuaixiang Zhou, Jia Lu, Ninghuan Li, Nana Luo, Ying Zhang, Kang Dian, Tiong Sun Chia, Bingliang Chen, Kaijie He
Journal: Cancer Research (2024)

Abstract B7-H3 and EGFR are both clinically validated TAAs in solid tumors. We previously demonstrated in IBI334 (B7-H3/EGFR bsAb) study that (1) B7-H3 and EGFR are co-expressed in multiple solid tumors; (2) B7-H3-aided EGFR signaling inhibition was significantly more potent than Zalutumumab (EGFR mAb) and Amivantamab (c-met/EGFR bsAb); and (3) IBI334 has favorable safety profile in cynomolgus monkey at 120 mg/kg/week. Building on this optimized bispecific antibody, we site-specifically conjugated IBI334 with Exatecan (drug-antibody-ratio = 4) using the clinically validated SyntecanE platform. The resulting bispecific ADC, IBI3001, has multiple mechanism of actions: (1) enhanced EGFR signaling blockage; (2) EGFR- and B7-H3-aided payload internalization and cytotoxicity; and (3) bystander killing effects of ADC. More importantly, the optimized B7-H3 arm not only enhances the EGFR signaling blockage but also reduces EGFR on-target toxicities. IBI3001 demonstrated potent in vitro cytotoxicity in all B7-H3LowEGFRLow, B7-H3HighEGFRLow, B7-H3LowEGFRHigh and B7-H3HighEGFRHigh cancer cells across multiple solid tumors, including lung cancer, colorectal cancer, pancreatic cancer, breast cancer, head and neck cancer, and stomach cancer. In addition, it had strong bystander effects, killing both EGFR+ B7-H3+ cancer cells and EGFR- B7-H3- cancer cells. All in vitro studies were further validated in vivo with robust tumor growth inhibition in NCI-H508 (colorectal cancer), JIMT-1 (breast cancer), BxPC3 (pancreatic cancer) and NCI-1975 (lung cancer) xenograft models. IBI3001 has a favorable PK profile in BALB/c mice with the half-life at 282 hours, and is well-tolerated in cynomolgus monkeys up to 90 mg/kg/week. In conclusion, IBI3001 is a novel bispecific ADC that demonstrated strong anti-tumor efficacy cross multiple solid tumors, and has excellent PK and safety profile. Citation Format: Jian Guan, Xiao Zhang, Weiwei Wu, Lei Cao, Zhengguang Liao, Tianyu Zhu, Chentao Liu, Shuaixiang Zhou, Jia Lu, Ninghuan Li, Nana Luo, Ying Zhang, Kang Dian, Tiong Sun Chia, Bingliang Chen, Kaijie He. IBI3001: A potentially first-in-class site-specifically conjugated B7-H3/EGFR bispecific ADC for multiple solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB055.
Abstract SY07-03: Cell competition shapes metastatic latency and relapse
Authors: Srinivas Malladi
Journal: Cancer Research (2024)

Abstract Cell competition, a fitness-sensing process, is essential for tissue homeostasis. Using cancer metastatic latency models, we show that cell competition results in the displacement of latent metastatic (Lat-M) cells from the primary tumor. Lat-M cells resist anoikis and survive as residual metastatic disease. A remodeled extracellular matrix facilitates Lat-M cell displacement and survival in circulation. Disrupting cell competition dynamics by depleting secreted protein and rich in cysteine (SPARC) reduced displacement from orthotopic tumors and attenuated metastases. In contrast, depletion of SPARC after extravasation in lung-resident Lat-M cells increased metastatic outgrowth. Furthermore, multiregional transcriptomic analyses of matched primary tumors and metachronous metastases from patients with kidney cancer identified tumor subclones with Lat-M traits. Kidney cancer enriched for these Lat-M traits had a rapid onset of metachronous metastases and significantly reduced disease-free survival. Thus, an unexpected consequence of cell competition is the displacement of cells with Lat-M potential, thereby shaping metastatic latency and relapse. Overall, we demonstrate that cell competition within the primary tumor results in the displacement of Lat-M cells. We are investigating the impact of altering cell competition dynamics on metastatic incidence that may guide strategies to limit metastatic recurrences. Citation Format: Srinivas Malladi. Cell competition shapes metastatic latency and relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY07-03.
Abstract LB084: Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node
Authors: Yang Shen, Erin Connolly, Meili Aiello, Chengjing Zhou, Haorui Song, Tarralyn Clark, Patan Tippitak, Gregory B. Lesinski, Chrystal Paulos, Nikki Schmitt, Zachary S. Buchwald
Journal: Cancer Research (2024)

Abstract Radiotherapy (RT) and anti-PD-L1 synergize to enhance local and distant (abscopal) tumor control. However, clinical results in humans have been variable. With the goal of improving clinical outcomes, we investigated the underlying synergistic mechanism focusing on a TCF-1+ PD-1+ CD8+ stem-like T cell subset in the tumor-draining lymph node (TdLN). We found that RT + anti-PD-L1 induces a novel differentiation program in the TdLN stem-like population which leads to their expansion and differentiation into effector cells within the tumor. We also found that optimal synergy between RT + anti-PD-L1 is dependent on the TdLN stem-like T cell population as either blockade of TdLN egress or specific stem-like T cell depletion reduced tumor control. Together, these data demonstrate a multistep stimulation of stem-like T cells following combination therapy which is initiated in the TdLN and completed in the tumor. Citation Format: Yang Shen, Erin Connolly, Meili Aiello, Chengjing Zhou, Haorui Song, Tarralyn Clark, Patan Tippitak, Gregory B. Lesinski, Chrystal Paulos, Nikki Schmitt, Zachary S. Buchwald. Radiation and anti-PD-L1 synergize by stimulating a stem-like T cell population in the tumor-draining lymph node [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB084.
Abstract LB109: Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay
Authors: Youming Wu, Yongqin Tong Tong, Haitao Zhang, Yun Li, Ming Li, Lili Qiu, Wenlan Liu, Siqing Mei, Yu Mao, Yanhua Cao, Caiyan Su, Wentao Yu, Junli Wang, Taizhong Wang, Zhongyuan Zhu, Dehua Derek Yu
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the third most common cancer worldwide, and regular screening is effective in reducing its mortality. Epi proColon was the first blood-based Septin9 gene methylation assay approved by the US FDA for CRC screening. However, the broader application of this assay has been hindered by its relatively lower sensitivity in detecting early-stage CRC and precancerous lesions. In this study, we developed a new multiplex Septin9 methylation assay, named ColonUSK, which simultaneously detects two CpG-rich subregions in the promoter of the Septin9 gene and an internal control in a single reaction. In comparison with the Sepin9 assay targeting only one CpG-rich subregion, this new assay demonstrated improved sensitivity, with a detection limit as low as 12pg of the positive DNA. To assess its value in CRC screening, we conducted an opportunistic screening study involving a total of 1366 subjects. Blind testing was performed to evaluate ColonUSK in comparison with clinical diagnosis using colonoscopy and pathological examination (the clinical gold standard). The clinical sensitivities of ColonUSK for detecting CRC and advanced adenoma were 77.34% (95% CI: 72.89%-81.26%) and 25.26% (95% CI: 17.16%-35.41%), respectively. The clinical specificity of the assay for non-CRC cases was 95.95% (95% CI: 94.36%-97.13%). Notably, ColonUSK was able to detect 54.29% of cases with high-grade intraepithelial neoplasia. The Kappa test value for this experiment was 0.76, indicating a high degree of consistency between ColonUSK and pathological diagnosis. Our results suggest that ColonUSK holds potential as a non-invasive screening tool for colorectal cancer. Citation Format: Youming Wu, Yongqin Tong Tong, Haitao Zhang, Yun Li, Ming Li, Lili Qiu, Wenlan Liu, Siqing Mei, Yu Mao, Yanhua Cao, Caiyan Su, Wentao Yu, Junli Wang, Taizhong Wang, Zhongyuan Zhu, Dehua Derek Yu. Detection of high grade intraepithelial neoplasia in colorectal cancer using a new blood-based multiplex septin9 methylation assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB109.
Abstract LB433: Targeting of ABI1 via DNA-based PROTACs
Authors: Kevin M. Lin, Xiang Li, Leszek Kotula
Journal: Cancer Research (2024)

Abstract Breast cancer is the most commonly diagnosed non-cutaneous cancer in American women. Although current therapies reduce initial tumor burden, patients often relapse with aggressive tumors which can metastasize. Abelson Interactor 1 (ABI1) is an adaptor protein which is traditionally seen as a WAVE complex component- regulating actin polymerization, cell migration and adhesion. In this role, ABI1 serves as a driver of breast cancer metastasis. Recent studies have discovered that ABI1 contains a homeobox homology region (HHR) which is able to bind DNA and regulate transcription. In order to specifically target and degrade ABI1, we designed a novel PROteolysis-TArgeting Chimera (PROTAC) system using DNA as the bait for ABI1. We hypothesized that by linking ABI1 DNA targets to the ubiquitin system, we would be able to effectively target ABI1 for degradation. Lenalidomide, an E3 ubiquitin ligase ligand, was attached to an oligonucleotide via click chemistry. Cells were then treated with PROTAC systems via direct addition to media or via lipofection reagents, and levels of ABI1 were detected using western blotting. Using this DNA-based PROTAC system in cell-culture models of both breast and ABI1-elevated prostate cancer suggested that the system is able to target and degrade ABI1. Usage of lipofection reagents were able to improve drug delivery and effectiveness. Further research is needed to identify off-target effects and effectiveness in vivo models of disease to reduce metastasis. In conclusion, PROTACs targeting ABI1 may prove to be an effective and novel method to reduce metastasis and improve outcomes for cancer treatment. Citation Format: Kevin M. Lin, Xiang Li, Leszek Kotula. Targeting of ABI1 via DNA-based PROTACs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB433.
Therapeutic inhibition of monocyte recruitment prevents checkpoint inhibitor-induced hepatitis
Authors: Cathrin L C Gudd, Eoin Mitchell, Stephen R Atkinson, Marie-Anne Mawhin, Samra Turajlic, James Larkin, Mark R Thursz, Robert D Goldin, Nick Powell, Charalambos G Antoniades, Kevin J Woollard, Lucia A Possamai, Evangelos Triantafyllou
Journal: Journal for ImmunoTherapy of Cancer (2024)

Background Checkpoint inhibitor-induced hepatitis (CPI-hepatitis) is an emerging problem with the widening use of CPIs in cancer immunotherapy. Here, we developed a mouse model to characterize the mechanism of CPI-hepatitis and to therapeutically target key pathways driving this pathology. Methods C57BL/6 wild-type (WT) mice were dosed with toll-like receptor (TLR)9 agonist (TLR9-L) for hepatic priming combined with anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) plus anti-programmed cell death 1 (PD-1) (“CPI”) or phosphate buffered saline (PBS) control for up to 7 days. Flow cytometry, histology/immunofluorescence and messenger RNA sequencing were used to characterize liver myeloid/lymphoid subsets and inflammation. Hepatocyte damage was assessed by plasma alanine transaminase (ALT) and cytokeratin-18 (CK-18) measurements . In vivo investigations of CPI-hepatitis were carried out in Rag2 −/− and Ccr2 rfp/rfp transgenic mice, as well as following anti-CD4, anti-CD8 or cenicriviroc (CVC; CCR2/CCR5 antagonist) treatment. Results Co-administration of combination CPIs with TLR9-L induced liver pathology closely resembling human disease, with increased infiltration and clustering of granzyme B + perforin + CD8 + T cells and CCR2 + monocytes, 7 days post treatment. This was accompanied by apoptotic hepatocytes surrounding these clusters and elevated ALT and CK-18 plasma levels. Liver RNA sequencing identified key signaling pathways (JAK-STAT, NF- Κ B) and cytokine/chemokine networks ( Ifnγ, Cxcl9, Ccl2/Ccr2 ) as drivers of CPI-hepatitis. Using this model, we show that CD8 + T cells mediate hepatocyte damage in experimental CPI-hepatitis. However, their liver recruitment, clustering, and cytotoxic activity is dependent on the presence of CCR2 + monocytes. The absence of hepatic monocyte recruitment in Ccr2 rfp/rfp mice and CCR2 inhibition by CVC treatment in WT mice was able to prevent the development and reverse established experimental CPI-hepatitis. Conclusion This newly established mouse model provides a platform for in vivo mechanistic studies of CPI-hepatitis. Using this model, we demonstrate the central role of liver infiltrating CCR2 + monocyte interaction with tissue-destructive CD8 + T cells in the pathogenesis of CPI-hepatitis and highlight CCR2 inhibition as a novel therapeutic target.