tbuckley/cabot-search huggingface dataset:
Abstract 4748: Aronia berry overcomes gemcitabine resistance by regulating the MYD88/NF-kB/P-glycoprotein pathway in pancreatic ductal adenocarcinoma
Authors: Yuan Li, Caiming Xu, Haiyong Han, Ajay Goel
Journal: Cancer Research (2024)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is lethal, which is partly due to the limited efficacy of Gemcitabine (Gem)-based chemotherapy, resulting from the development of acquired resistance to this regimen. Aronia berry extract (ABE) is a natural source of phenolic compounds known for its anti-cancer properties. Previous research has highlighted the ability of ABE to help overcome chemoresistance to conventional chemotherapies in various cancers. In this study, we interrogated the ability of ABE to overcome Gem-resistance (Gem-R) in PDAC and identify specific pathway(s) responsible for this anti-cancer efficacy. Methods: We performed a series of in-vitro experiments in Gem-R cells to evaluate the synergistic effect of combined treatment with Gem and ABE. Furthermore, we conducted a genomewide transcriptomic analysis to identify the critical regulatory pathways associated with chemoresistance and potential therapeutic targets of ABE in Gem-R PDAC cells. The cell culture findings were validated in patient-derived 3D organoids. Results: The combined treatment with ABE and Gem in Gem-R cells exhibited significant synergistic anticancer effects on cell viability, proliferation, migration, and invasion. The transcriptomic analysis revealed that the NF-κB signaling pathway was associated with Gem-R (p&amp;lt;0.05), with a significant upregulation of MYD88. Additionally, MYD88 was significantly associated with overall survival in PDAC patients in the TCGA cohort (HR=1.58, P=0.045). The MYD88/NF-κB signaling is associated with chemoresistance as it can upregulate the efflux transporters like P-glycoprotein (P-gp). Our results confirmed that combined treatment inhibited the NF-κB signaling pathway by suppressing MYD88 and downregulating P-gp expression to overcome Gem-R. Finally, the combined treatment demonstrated superior anti-cancer activity in 3D organoids by reducing both their number and size (P&amp;lt;0.05). Conclusion: We provide novel insights into the potential of ABE in overcoming Gem-R in PDAC cells by targeting the MYD88/NF-κb/P-gp axis, which offers a safe and inexpensive approach for improving therapeutic outcomes in this fatal malignancy. Citation Format: Yuan Li, Caiming Xu, Haiyong Han, Ajay Goel. Aronia berry overcomes gemcitabine resistance by regulating the MYD88/NF-kB/P-glycoprotein pathway in pancreatic ductal adenocarcinoma [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 4748.
Abstract 731: pHLIP targeted intracellular delivery of calicheamicin
Authors: Michael DuPont, Craig Klumpp, Marissa Iraca, Dana Allababidi, Hannah Visca, Donald Engelman, Oleg Andreev, Anna Moshnikova, Yana Reshetnyak
Journal: Cancer Research (2024)

Abstract Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its approved use in a targeted form as antibody-drug conjugates (ADC) for the treatment of liquid tumors. Mylotarg, one of the first such ADCs, was voluntarily withdrawn from the market due to safety concerns. However, Mylotarg was recently reapproved for acute myeloid leukemia based on new data that demonstrated efficacy with an acceptable safety profile. Besponsa, a related ADC, was approved for acute lymphocytic leukemia in 2017. In both agents, Mylotag and Besponsa, calicheamicin is conjugated to antibodies via an acid-labile hydrazone linker. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) via a disulfide bond to generate a linkerless cytoplasmic release. The cytoplasmic reduction of the disulfide releases the calicheamicin, which leads to its activation, DNA binding, and strand scission. pHLIP is a tumor-targeting agent now in clinical trials with imaging and therapeutic payloads. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In mice, treatment led to the growth inhibition of immuno-suppressive CT26 tumors with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The fluorescent version of the agent was observed within the tumor mass and tumor-stroma interface, where CD206+ M2 tumor-associated macrophages (M2-TAMs) reside. Treatment of tumors led to the depletion of M2-TAMs within the tumor core. Thus, pHLIP-calicheamicin could be developed into an effective therapeutic for the treatment of solid tumors with abundant immuno-suppressive M2-TAMs. Citation Format: Michael DuPont, Craig Klumpp, Marissa Iraca, Dana Allababidi, Hannah Visca, Donald Engelman, Oleg Andreev, Anna Moshnikova, Yana Reshetnyak. pHLIP targeted intracellular delivery of calicheamicin [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 731.
Abstract 4137: Feasibility of a novel image guided injection tool for non-surgical implantation of orthotopic tumors
Authors: Thomas M. Kierski, Juan D. Rojas, Nathan Beaumont, Theresa Charity, Robert D. Marek, Kenneth H. Young, Gregory M. Palmer, Ryan C. Gessner, Tomek J. Czernuszewicz
Journal: Cancer Research (2024)

Abstract The purpose of this study was to evaluate a novel device for non-surgical implantation of tumor cells using ultrasonic (US) image guidance. There are a variety of mouse model cancer types (e.g. sub-cu, orthotopic, genetically engineered). Orthotopic tumors are increasingly prevalent but usually require surgery, which reduces throughput and injures the surrounding anatomy. Injections are an alternative to surgery, but usually require image guidance or extensive training. US guided injection systems exist, but are suboptimal because they require significant training, as the US beam is not necessarily coplanar with needle location or trajectory, reducing accuracy and throughput. We tested a new approach to image guided injection which ensures that the US beam is coplanar with the needle. To test the efficacy of the image guided injection device across a variety of common orthotopic tumors, we delivered luc-tagged cells to the prostate (2.5e5 cells in 40 µL, PC3, N=8), liver (2e6 cells in 100 µL, Hep G2, N=5), and brain (1.75e5 cells in 100 µL, U87-MG, N=3). The brain tumor model was introduced via intracardiac injection to simulate metastases. Between 3 and 8 mice were injected for each tumor model. For injection, animals were anesthetized and positioned on motion stage. A 1 mL syringe was mounted to the adjustable injection gantry with the needle co-planar with the US beam, and the target organ was visualized with US. Cells were delivered to the targets using the US live stream as a guide. Between 1 to 3 weeks after the injections, tumors were confirmed via BLI with an IVIS (Revvity, Waltham, MA, USA). For each of the three tumor cell lines, animal preparation and injections could be performed in 10 mins by recently-trained novice users. All three cell lines could be effectively delivered to the orthotopic host tissues, and this was confirmed by using BLI of the cells. This study represents the first time a co-planar US beam and needle delivery mechanism was used for the purpose of non-surgical implantation of orthotopic tumors. Future developments of this platform could include improvements to automation of needle placement and trajectory to ensure successful payload delivery by novice users. Citation Format: Thomas M. Kierski, Juan D. Rojas, Nathan Beaumont, Theresa Charity, Robert D. Marek, Kenneth H. Young, Gregory M. Palmer, Ryan C. Gessner, Tomek J. Czernuszewicz. Feasibility of a novel image guided injection tool for non-surgical implantation of orthotopic tumors [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 4137.
Abstract 4084: Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status
Authors: Hee Geon Park, Sung Hun Cho, Ha Yeon Park, Mi Gyoung Jo, Ji Hyun Park, Myeung Ryun Seo, Ji Hyun Kim, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin
Journal: Cancer Research (2024)

Abstract Epidermal growth factor receptor (EGFR) is overexpressed or mutated in many patients with non-small cell lung cancer (NSCLC). Targeting EGFR mutation by tyrosine kinase inhibitors (TKIs) has significantly improved overall survival (OS) in patients with EGFR mutations. However, many patients experience tumor recurrence due to various resistance mechanisms. Therefore, there is an unmet medical need for new treatment strategies for patients with EGFR-positive NSCLC, regardless of EGFR mutation status. ABN202 is an antibody-cytokine fusion protein (ACFP) that serves as a platform technology compromising the IFN-β mutein (ABN102) fused to various antibodies for specific tumor targeting. In a previous study, we designed ABN202 (αEGFR) to comprise an EGFR targeting antibody (Cetuximab) and IFN-β mutein (ABN102) and we confirmed anti-cancer activities of ABN202 against EGFR-positive NSCLC. In this study, the direct cytotoxicity of ABN202 (αEGFR) was evaluated in human NSCLC cell lines with various driving mutations and EGFR expression levels. The indirect immune activation was tested in human peripheral blood mononuclear cells (PBMCs) and human IFNAR1/2 knock-in (KI) mice. The in vivo efficacy was evaluated in human NSCLC xenograft mouse models and human IFNAR1/2 KI mouse models. ABN202 (αEGFR) demonstrates potent anti-tumor activity through direct cytotoxicity and indirect immune activation in NSCLC, regardless of EGFR mutation status. Taken together, we suggest that ABN202 (αEGFR) is a promising drug candidate against NSCLC, regardless of EGFR mutation status. Citation Format: Hee Geon Park, Sung Hun Cho, Ha Yeon Park, Mi Gyoung Jo, Ji Hyun Park, Myeung Ryun Seo, Ji Hyun Kim, Sung Youl Hong, Kyoung Song, Chan Gyu Lee, Hae Min Jeong, Sae Hyung Lee, Na Young Kim, Jun Young Choi, Young Kee Shin. Potent anti-tumor activity of ABN202 (anti-EGFR antibody-interferon-beta mutein) through direct cytotoxicity and indirect immune activation against non-small cell lung cancer, regardless of EGFR mutation status [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 4084.
Abstract 6963: Cysteinyl leukotriene receptors promote melanoma progression and metastasis
Authors: Emma Elizabeth Sabu Kattuman, Lakshminarayan Reddy Teegala, Somayeh Darzi, Sailaja Paruchuri
Journal: Cancer Research (2024)

Abstract Background: Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, LTE4) are pro-inflammatory mediators mainly produced by hematopoietic cells, which enhance inflammation through their receptors, CysLT1R and CysLT2R. They play a pivotal role in the development of chronic asthma in humans. Recent association of inflammation with cancer has led to immense interest on the role of cysteinyl leukotrienes in cancer progression and metastasis. However, the exact molecular mechanisms regarding how these inflammatory mediators regulate the tumor proliferation and metastasis remain unexplored. A thorough investigation of these precise molecular mechanisms and identification of the specific receptor/s responsible can aid in understanding the therapeutic potential of these receptors in various cancers like melanoma. Since the inhibitors of these receptors are already FDA approved for the treatment of asthma, our goal is to repurpose these drugs to treat melanoma progression. Objective: To determine the mechanistic aspects of how CysLTRs regulate melanoma tumor initiation, progression, and metastasis. Methods: Protein expression by western blotting and ELISA, transcript expression by qPCR, viability, and proliferation by XTT and BrDU, migration using trans-well assay, tumor growth and metastasis were confirmed through in vivo experiments. Results &amp; Conclusion: B16F10 melanoma cells express high CysLT1R compared to CysLT2R and produce endogenous cys-LTs that function in an autocrine signaling pattern. Further, cys-LTs mediated the activation of several signaling proteins such as ERK, p38, AKT, and CREB that are important for melanoma survival and proliferation. Moreover, treatment with CysLTR antagonists significantly reduced melanoma cell proliferation, survival, and migration. Accordingly, we observed a significant reduction in the melanoma tumor volume in vivo in both Cysltr1−/- and Cysltr2−/− mice compared to the WT mice. Interestingly, angiogenesis was significantly reduced in Cysltr2−/- mice but not in Cysltr1−/−.Therefore, we speculate that while both receptors play a crucial role in tumor proliferation in vivo, CysLT2R is the main driver of angiogenesis and metastasis. Therefore, targeting both these receptors using their specific antagonists can offer potential therapy for melanoma progression and metastasis. Citation Format: Emma Elizabeth Sabu Kattuman, Lakshminarayan Reddy Teegala, Somayeh Darzi, Sailaja Paruchuri. Cysteinyl leukotriene receptors promote melanoma progression and metastasis [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 6963.
Abstract 2675: A new dual-targeting anti-immune checkpoint therapeutic approach for the treatment of “hot” and “cold” tumors
Authors: Moutuaata M. Moutuou, Nora DeLuce, Elodie Creton, Honorine Lucchi, Julien Accolas, Alexandra Savatier, Michel Léonetti
Journal: Cancer Research (2024)

Abstract Anti-Immune Checkpoint (ICP) antibody approaches provided a major breakthrough in the field of cancer therapy. However, their efficiency is mainly restricted to patients with “hot” tumors characteristics, which limits the breadth of their use. To tackle this limit, we developed a new strategy aimed at amplifying anti-ICP antibody ability to activate immune cells. This approach is based on antibodies engineered to make them able to target both an ICP receptor and a co-receptor often involved in receptor-mediated activation, namely Heparan Sulfate Proteoglycan. The dually-targeting engineered anti-ICP antibodies were produced in eukaryotic cells. They were purified to homogeneity using two chromatographic steps and remain stable for months in frozen conditions. A first engineered antibody-derived construct was assessed for its ability to impact immune cell activation and tumor-growth. It is able to stimulate subsets of immune cells from mouse splenocytes as well as from human peripheral mononuclear cells, in vitro. In addition, its injection in healthy mice triggers activation of T-cells. Last, in mice previously implanted with different types of cancer cells it impacts growth of “hot” as well as “cold” tumors. Immune profiling in a “cold” cancer model shows that the treatment decreases the proportion of MDSCs and increase that of CD8+ T-cells and NK-cells in tumor microenvironment making it close of that found in “hot” tumors. Altogether, our data indicate that our first engineered antibody-derived construct presents an attractive immunotherapeutic potential for a large variety of cancers paving the way for its evaluation in clinical phases. Citation Format: Moutuaata M. Moutuou, Nora DeLuce, Elodie Creton, Honorine Lucchi, Julien Accolas, Alexandra Savatier, Michel Léonetti. A new dual-targeting anti-immune checkpoint therapeutic approach for the treatment of “hot” and “cold” tumors [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 2675.
Abstract 1571: Upregulation of phosphoglyceric acid mutase (PGAM)-1 is related to lymph node metastasis in gastric cancer
Authors: Helei Wang, Zhicheng Liu, Lei Wang, Zitian Wang, Christina Jamieson, Nicholas A. Cacalano
Journal: Cancer Research (2024)

Abstract Gastric cancer (GC) is the most common malignancy of the digestive system, causing over 750,000 deaths worldwide. Gastric cancer mortality is largely due to its high level of invasiveness and metastasis to distal organs. Thus, it is an urgent priority to identify mechanisms underlying GC metastasis to improve cancer diagnosis develop of effective biological targeting agents. In this study, we demonstrate that phosphoglyceric acid mutase-1 (PGAM1) was preferentially over-expressed in lymph node metastasis (LNM) tissues of GC patients and correlated with poor prognosis. PGAM1 knock down in two human GC cell lines resulted in impaired cell proliferation and increased cell cycle arrest. Further, PGAM knockdown inhibited migration of both GC cell lines, which correlated with decreased expression of MMP2, MMP9 and ICAM-1. In a murine xenograft model, GC cells with a PGAM1 knockdown displayed decreased growth capacity in vivo. Western blot analysis showed that PGAM1 knockdown in SGC7901 and BGC823 decreased the phosphorylation of Src, FAK and Paxillin relative to the parental cell lines. These results indicate that PGAM1 may play an important role in promoting GC lymph node metastasis by driving cell proliferation and activating cytoskeletal reorganization and cell migration through the regulating Src/FAK/Paxillin pathway. Citation Format: Helei Wang, Zhicheng Liu, Lei Wang, Zitian Wang, Christina Jamieson, Nicholas A. Cacalano. Upregulation of phosphoglyceric acid mutase (PGAM)-1 is related to lymph node metastasis in gastric 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 1571.
Abstract 5097: Effectiveness and safety of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: A multicenter, retrospective real-world study in China
Authors: Hui Zhang, Minghua Shao, Binbin Tan, Yin Fu, None Yuan, Hailei Chen
Journal: Cancer Research (2024)

Abstract Background: Atezolizumab plus bevacizumab (Atezo+Bev) has shown better benefits than sorafenib as the first-line treatment for unresectable hepatocellular carcinoma (uHCC) in IMbrave 150. However, the real-world evidence of Atezo+Bev in uHCC is limited, especially in China. We aimed to investigate the real-world effectiveness and safety of Atezo+Bev in Chinese patients with uHCC. Methods: Patients with uHCC treated with Atezo+Bev were included at 5 centers in China from Jan. 2021 to Jan. 2023. Overall response (ORR), organ-specific response rate (OSRR), disease control rates (DCR), time to disease progression (TPP), progression-free survival (PFS), metastasis-specific PFS and overall survival (OS) were calculated. Results: Among 48 patients, the median age was 58.4 years with 85.4% being male. A total of 35 and 13 patients received Atezo+Bev as 1st and 2nd line treatment, respectively. The median number of treatment cycles were 8, and 27 (56.3%) patients received locoregional therapies. Detailed treatment response is in the Table. The overall ORR and DCR assessed by mRECIST were 60.4% and 75.0%, while the intra- and extrahepatic OSRR were 59.4% and 62.5%, respectively. With a median follow-up of 14.5 months, the median PFS was 8.5 months (95%CI: 4.4, 11.2) in 1st line setting and 5.1 months (95%CI: 2.1, 7.9) in 2nd line setting. Median intra- and extrahepatic metastasis-specific PFS were 7.9 and 7.6 months, respectively. Median overall TTP was 7.6 months. The median OS was not reached. A total of 36 patients (75%) experienced any grade adverse events, most commonly being thrombocytopenia (27.1%, n=13), lymphopenia (25%, n=12) and abnormal liver function (14.6%, n=7). Conclusion: This study confirmed effectiveness and safety of Atezo+Bev in the 1st line treatment of uHCC, and observed its potential in 2nd line in a real-world setting. Further studies are warranted to confirm these observations and refine treatment strategies. Table. Treatment response N (%) Response Evaluation Criteria in Solid Tumors (RECIST) 1.1(N=48) Modified RECIST(N=48) Complete response (CR) 7 (14.6) 9 (18.8) Partial response (PR) 12 (25.0) 20 (41.7) Stable disease (SD) 15 (31.2) 7 (14.6) Progressive disease 11 (22.9) 12 (25.0) Not evaluated 3 (6.2) 0 ORR (CR+PR) 19 (39.6) 29 (60.4) DCR (CR+PR+SD) 34 (70.8) 36 (75.0) Citation Format: Hui Zhang, Minghua Shao, Binbin Tan, Yin Fu, Yuan, Hailei Chen. Effectiveness and safety of atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: A multicenter, retrospective real-world study in China [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 5097.