tbuckley/cabot-search huggingface dataset:
Abstract 4083: Pre-clinical development of IAMA-005, a long-acting cytokine fusion of modified IL-2 and IFN-α
Authors: Liming Liu, Zhen Han, Yang Fan, Qi Pan
Journal: Cancer Research (2024)

Abstract In 1990s, both IL-2 and IFN-α were approved as the first two immunotherapies for metastatic melanoma and renal cell carcinoma; IFN-α was also approved for hairy cell leukemia. Although the response rates are relatively low, along ~25%, those who responded have long term survival benefits. However, the severe toxicity especially in high dose prohibited their broad use in oncology. Recently, there have been tremendous interests in modifying these two cytokines in the efforts to reduce the toxicity and enhance the activity. One such effort is to enhance the binding of IL-2 to the intermediate affinity β/γ receptors, which are expressed and function on CD8 T cells and NK cells. Another effort is to reduce the binding of IL-2 to high affinity α/β/γ receptors which mostly expressed on Treg and stimulate the growth of Treg cells, which suppress immune responses. Recently, whether it’s better to target intermediate affinity or high affinity for cancer therapy has become controversial with some studies showing that high affinity receptor engagements are required for robust anti-tumor activity while others favoring intermediate affinity receptor engagement for better efficacy; However, the clinical comparison is still lacking to be sure which approach is better. Here we have developed a long-acting novel IL-2-Fc-IFN-α fusion molecule termed IAMA-005 that has mutations to reduce the toxicity effects of IL-2 and IFN-α. We have characterized this molecule preclinically both in vitro and in vivo. IAMA-005 has demonstrated a potent tumor cell killing activities in numerous cancer cell lines including BT-474, SK-OV-3, NCI-N87, OE19, HCC-1954, MDA-MB-231, MDA-MB-468. When combined with IAMA-004 (a Her2-CD47-CD16 tri-specific antibody) in vitro, the tumor cell killing activities were dramatically increased. In addition, IAMA-005 was also tested in patient-derived Ex-Vivo fluids (one malignant pleural effusion and one malignant asities) and demonstrated excellent tumor cell killing efficacies. In addition, the killing activities of IAMA-005 could be attributed to the specific part of the fusion molecule because of the TME immune cell compositions. The in vivo assays to demonstrate efficacy and safety are ongoing and will be presented in the poster. These results suggest that this fusion cytokine molecule may be used in monotherapy in certain indications and an excellent complementary therapeutic to antibody targeted therapies or immunotherapies when used in combination. Citation Format: Liming Liu, Zhen Han, Yang Fan, Qi Pan. Pre-clinical development of IAMA-005, a long-acting cytokine fusion of modified IL-2 and IFN-α [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 4083.
Abstract 4132: Low-dose carbon monoxide therapies suppress cancer metastasis
Authors: Tiantian Zhang, Cheryl Zhang, Xiang Chen, Xiaoxiao Yang, Qiyue Mao, George Zhang, Zhengming Chen, Adrian Tan, Jenny Zhaoying Xiang, Erika Hissong, Yao-Tseng Chen, Binghe Wang, Nancy Du
Journal: Cancer Research (2024)

Abstract Metastasis is the primary cause of cancer-related deaths. Novel systemic therapies for metastatic cancer are urgently needed. Carbon monoxide (CO) is an endogenously produced signaling molecule in the human body with demonstrated pharmacological activities, including organ protection and anti-inflammation. We determined the therapeutic effect of low-dose CO and CO prodrugs on cancer progression in this study. We found that low-dose CO inhibits the migration of cancer cell lines including breast, pancreatic, colon, prostate, liver, and lung cancer. We showed that low-dose CO inhibits lung metastasis of breast cancer and liver metastasis of pancreatic cancer in preclinical mouse models. Further, to provide safer and more reliable CO delivery, we developed metal-free, organic CO prodrugs and showed that CO prodrugs inhibit tumor growth and metastasis. We demonstrated that low-dose CO blocks the transcription of heme importers, leading to diminished intracellular heme levels. Altogether, our work lays a strong foundation for the development of CO-based systemic cancer therapies. Citation Format: Tiantian Zhang, Cheryl Zhang, Xiang Chen, Xiaoxiao Yang, Qiyue Mao, George Zhang, Zhengming Chen, Adrian Tan, Jenny Zhaoying Xiang, Erika Hissong, Yao-Tseng Chen, Binghe Wang, Nancy Du. Low-dose carbon monoxide therapies suppress cancer 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 4132.
Abstract 6811: IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages
Authors: Anthony Cannon, Mark H. Kaplan
Journal: Cancer Research (2024)

Abstract A defining characteristic of cancer is its ability to evade detection by immune cells through the generation of a myeloid cell-dependent immunosuppressive tumor microenvironment. Arginine is utilized by Arginase 1 (ARG1) or nitric oxide synthase in tumor-associated macrophages to respectively elicit pro-tumor or anti-tumor activity. The balance between these enzymes is regulated by extracellular cytokines including Interleukin 9 (IL-9), a pleiotropic cytokine that can be a positive or negative regulator of tumor growth. Our lab identified that IL-9 promotes tumor development in the lung by expanding interstitial macrophage populations and inducing ARG1. Lung tumor growth is attenuated in mice with myeloid cell deficiency of Arg1. Similarly, macrophage-targeting nanoparticles containing Arg1 siRNA can therapeutically reduce tumor burden and alter macrophage populations in the lung toward an immunostimulatory phenotype. However, an understanding of the mechanism by which IL-9R/ARG1+ interstitial macrophages drive tumor progression remains incomplete. Here, using a B16F10 lung metastasis model in mixed-bone marrow chimeric mice, we demonstrate that IL-9-responsive interstitial macrophages are intrinsically altered at the transcriptomic level toward an ARG1-dependent immunosuppressive phenotype. Furthermore, our research shows that the absence of IL-9 signaling or ARG1 expression in macrophages has a notable impact on the levels of arginine and its metabolites in the lung tissue and bronchoalveolar lavage fluid of tumor-bearing mice. These alterations subsequently lead to an enhanced anti-tumoral immune response, reflected by changes in Interferon-gamma expression in both lung macrophages and T cells. Thus, our work suggests that the IL-9R/ARG1/interstitial macrophage axis promotes lung tumor development by altering intrinsic arginine metabolism and reprogramming immune cell populations toward an immunosuppressive phenotype. Citation Format: Anthony Cannon, Mark H. Kaplan. IL-9 enhances lung tumor growth through intrinsic and ARG1-dependent transcriptomic changes in interstitial macrophages [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 6811.
Abstract 6807: Cancer suppressive mechanism of IL-6 secreted by cancer-related fibroblasts in biliary tract cancer
Authors: Kenjiro Kimura, Ryota Tanaka, Simpei Eguchi, Kosuke Hatta, Masahiko Kinoshita, Jun Tauchi, HIroji Shinkawa, Kohei Nishio, Go Ohira, Takeaki Ishizawa
Journal: Cancer Research (2024)

Abstract Background and aims: Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment and can exhibit cancer-promoting functions; however, recent studies indicate that CAFs can also inhibit cancer growth and progression. In this study, we identified CAFs that act in an inhibitory manner in biliary tract cancer and elucidated their mechanisms. Methods: Three biliary tract cancer cell lines and CAFs isolated from resected specimens from four types of biliary tract cancer were used to evaluate the proliferative potential of cancer cells. Potential suppressors that inhibited the growth of cancer cells were identified using protein arrays from CAFs. We determined the effects of these suppressors on cancer cells. Results: Among the biliary tract cancer CAFs, we identified CAFs that inhibited cancer growth. Protein arrays of conditioned medium from CAFs revealed that Interleukin-6 (IL-6) was one such growth inhibitor. Treatment of biliary tract cancer cell lines with IL-6 significantly reduced their proliferative potential. SOCS3 expression levels increased and STAT3 expression level decreased, suggesting that SOCS3, a downstream signal of IL-6, may be involved. Conclusion: Inhibitory CAFs are present among biliary tract cancer CAFs and IL-6 production by CAFs may inhibit the growth of biliary tract cancer cells. Citation Format: Kenjiro Kimura, Ryota Tanaka, Simpei Eguchi, Kosuke Hatta, Masahiko Kinoshita, Jun Tauchi, HIroji Shinkawa, Kohei Nishio, Go Ohira, Takeaki Ishizawa. Cancer suppressive mechanism of IL-6 secreted by cancer-related fibroblasts in biliary tract 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 6807.
Abstract 6847: IGF2BP3 promotes esophageal squamous cell carcinoma progressions via Wnt/CTNNB1 pathway
Authors: Zhongxian Tian, Yongjia Zhou, Yi Ding, Zhengwen Wu, Xiaogang Zhao
Journal: Cancer Research (2024)

Abstract The M6A RNA modification plays a crucial role in the progression of tumors. Simultaneously, IGF2BP3 is primarily expressed in the tumor cells of squamous cell carcinoma, rather than in stromal cells, including esophageal squamous cell carcinoma (ESCC), a subtype mainly prevalent in East Asia. However, the mechanism of IGF2BP3 in the progression of esophageal squamous cell carcinoma and its role in the tumor microenvironment (TME) remain unknown and require further exploration. Our research reveals that IGF2BP3 not only plays a significant oncogenic role in tumor cells, including the activation of the Wnt pathway, PI3K-AKT pathway, and MAPK pathway, but also, the high expression of IGF2BP3 is positively correlated with the enrichment of M2 macrophages in ESCC tissues, in the TME, IGF2BP3 promotes the infiltration of M2 macrophages, ultimately facilitating the progression of ESCC. Mechanistically, IGF2BP3 enhances the translation of USP36 mRNA by directly binding to its mRNA, rather than increasing the stability of mRNA. The IGF2BP3-mediated USP36 protein elevation enhances the binding capacity with CTNNB1 protein, reducing its degradation through the ubiquitin-proteasome pathway, and following improved the Wnt/CTNNB1 pathway activating, Ultimate, IGF2BP3 aggravated the malignancy of the tumor. Additionally, the activation of the Wnt pathway promotes TGFB1 transcription and secretion, subsequently activating the polarization of M2 macrophages, infuriating the formation of the tumor immune-suppressive microenvironment, ultimately promoting the progression of esophageal squamous cell carcinoma. Our findings strongly emphasize the oncogenic role of IGF2BP3 in the progression of ESCC both in vitro and in vivo, providing new insights and perspectives for the treatment of esophageal squamous cell carcinoma. Citation Format: Zhongxian Tian, Yongjia Zhou, Yi Ding, Zhengwen Wu, Xiaogang Zhao. IGF2BP3 promotes esophageal squamous cell carcinoma progressions via Wnt/CTNNB1 pathway [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 6847.
Abstract 6809: Tumor-associated macrophages promote bladder cancer cell migration and invasion through activation of CCL20-CCR6 axis
Authors: Ryunosuke Nakagawa, Izumi Kouji, Ren Toriumi, Shuhei Aoyama, Taiki Kamjima, Hiroshi Kano, Tomoyuki Makino, Renato Naito, Hiroshi Yaegashi, Takahiro Nohara, Hiroki Nakata, Atsushi Mizokami
Journal: Cancer Research (2024)

Abstract We focused on Tumor-Associated Macrophages (TAM) and explored its effects on bladder cancer (BC). Co-culturing PMA-treated THP-1 with BC cell lines (UMUC3 and T24) induced THP-1 to develop suppressed CD68 and increased CD206 expression which differentiated into M2-like macrophages. Co-culture of BC with TAM of this M2-like macrophage enhanced the migration and invasive activities of BC, as well as the expression of EMT marker. Human cytokine antibody array of conditioned medium from the co-culture of BC and TAM showed high CCL20, CCL2 and CXCL7. qPCR revealed that these chemokines were mainly derived from TAMs, not BC. Only CCL20 enhanced the migration and invasion of BC and the expression of EMT markers when each of these three recombinant chemokines was administered to BC. Furthermore, inhibiting CCR6, a receptor specific for CCL20, suppressed migration and invasion as expected. In BC, TAMs promote progression and metastasis by secreting CCL20, and inhibition of CCR6 may be one potential therapeutic approach to suppress BC activity. Citation Format: Ryunosuke Nakagawa, Izumi Kouji, Ren Toriumi, Shuhei Aoyama, Taiki Kamjima, Hiroshi Kano, Tomoyuki Makino, Renato Naito, Hiroshi Yaegashi, Takahiro Nohara, Hiroki Nakata, Atsushi Mizokami. Tumor-associated macrophages promote bladder cancer cell migration and invasion through activation of CCL20-CCR6 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 6809.
Abstract 6845: MAGEA3 expression and secretion in MMR-MSH6 and MMR-PMS2 microsatellite-stable colorectal cancer
Authors: Jina Yom, Rachel Gonzalez, Bailey Gilmore, Zhaoying Guo, Andy Han, Eden Zewdu, Dehe Kong, Tianli Qu, Hailey Guo, Alex Strom, Zoe Zhao, Xiaomin Hu, Qi Ren, Yan Ma, Ranran Zhang, Zhaohui Wu, Xuan Liu, Wei Fu
Journal: Cancer Research (2024)

Abstract Despite the breakthrough of PD-1/PD-L1 blockade therapy in the recent years, mixed responses have been shown across multiple tumor types, including in colorectal cancer (CRC), the second leading cause of death worldwide. This immunotherapy has proven to be successful for a subtype of CRC that carries mismatch repair deficiency (dMMR) and high microsatellite instability (MSI-H), despite a lack of response by microsatellite-stable CRC. For these types of non-responsive cancers, new immunotherapy targets are currently being investigated for alternative therapy such as the MAGE-A cancer testis antigen family whose expression is restricted to germline cells in normal tissue but is overexpressed in many cancer cells. In this study, we examine the relationship between MAGEA3 and MMR proteins MSH6 and PMS2. Immunohistochemical staining of CRC tissues demonstrated co-expression between MAGEA3 with both MSH6 and PMS2. Immune cells were observed to express MAGEA3 in CRC as well. To investigate the possibility of secreted MAGEA3 from tumor cells, we performed western blot analysis of CRC cell lines, ELISA, and binding assay on cell lines and the positive results suggest that MAGEA3 protein is secreted. The results suggest that MAGE-A3 may be a promising target for microsatellite-stable colorectal cancer immunotherapy. Citation Format: Jina Yom, Rachel Gonzalez, Bailey Gilmore, Zhaoying Guo, Andy Han, Eden Zewdu, Dehe Kong, Tianli Qu, Hailey Guo, Alex Strom, Zoe Zhao, Xiaomin Hu, Qi Ren, Yan Ma, Ranran Zhang, Zhaohui Wu, Xuan Liu, Wei Fu. MAGEA3 expression and secretion in MMR-MSH6 and MMR-PMS2 microsatellite-stable colorectal 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 6845.
Abstract 7058: NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome
Authors: Amin Sobh, Elena Encinas, Alisha Patel, Greeshma Surapaneni, Charlotte Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphne Dupere-Richer, Alberto Riva, Benjamin Barwick, Daohong Zhou, Lawrence Boise, Constantine Mitsiades, Baek Kim, Richard Bennett, Navdeep Chandel, Jonathan Licht
Journal: Cancer Research (2024)

Abstract Chromosomal translocation (4;14), an adverse prognostic factor in multiple myeloma (MM), drives overexpression of the oncogenic histone methyltransferase NSD2. Genome-wide CRISPR screens in isogenic MM cells with high and low NSD2 expression identified adenylate kinase 2 (AK2), an enzyme critical for transport of ATP from the mitochondria, as an NSD2-driven vulnerability. AK2 suppression in t(4;14) MM cells decreased NADP(H) critical for conversion of ribonucleotides to deoxyribonucleosides by the enzyme ribonucleotide reductase (RNR). Consequently, metabolomic studies revealed depletion of deoxynucleotide triphosphates (dNTPs) in AK2-deficient t(4;14) MM cells, which resulted in replication stress, DNA damage and apoptosis. Exogenous supplementation with deoxynucleosides rescued AK2 depleted MM cells confirming the role of AK2 in dNTP homeostasis. In addition, NSD2 overexpression drives a large genome-wide increase in chromatin methylation, which depletes the methyl donor S-adenosylmethionine (SAM). Accordingly, we found that high NSD2 expression in MM cells disrupts creatine biosynthesis, a process dependent on SAM. The creatine/phosphocreatine system represents an alternative means of transporting high energy phosphate from the mitochondria. Hence, creatine supplementation restored NADP(H) levels and rescued AK2-deficient t(4;14) MM cells indicating that the hypersensitivity of these cells to AK2 depletion is driven by creatine deficiency due to NSD2 overexpression. Furthermore, AK2 inhibition impaired ATP-dependent protein folding increasing sensitivity of t(4;14) MM cells to proteasome inhibition. These findings delineate a novel mechanism in which aberrant transfer of carbon to the epigenome creates a metabolic vulnerability, with direct therapeutic implications for t(4;14) MM. Citation Format: Amin Sobh, Elena Encinas, Alisha Patel, Greeshma Surapaneni, Charlotte Kaestner, Janai Poullard, Monica Clerio, Karthik Vasan, Tzipporah Freeman, Dongwen Lv, Daphne Dupere-Richer, Alberto Riva, Benjamin Barwick, Daohong Zhou, Lawrence Boise, Constantine Mitsiades, Baek Kim, Richard Bennett, Navdeep Chandel, Jonathan Licht. NSD2 overexpression drives multiple myeloma dependence on adenylate kinase 2 by diverting one-carbon metabolism to the epigenome [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 7058.
Abstract 1414: HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile
Authors: Jue Zeng, Dongxu Zhang, Louis Liu, Lingbing Zhang
Journal: Cancer Research (2024)

Abstract Background: Leukemia inhibitory factor (LIF) and cardiotrophin like cytokine factor 1 (CLCF1) are multi-functional cytokines from IL-6 family. They are reported to be highly expressed in a variety of human cancers such as pancreatic carcinoma, cholangiocarcinoma, NSCLC, GBM, head and neck cancer etc. Their expression is associated with poor prognosis and survival. LIFR is the key component of LIF/CLCF1 receptors. Antibody targeting LIFR has the advantage to block both LIF and CLCF1 pathways thus inhibiting tumor growth more effectively than products to block single cytokines. Methods: Fully human Anti-LIFR antibodies were generated from H2L2 Harbour Mice® transgenic platform. In vitro function of the antibodies was tested for their abilities to block LIF/CLCF1 induced downstream signaling pathway and tumor spheroid proliferation. In vivo efficacy was tested in multiple tumor models as monotherapy and in combination with cisplatin. DRF toxicokinetics was evaluated on NHP with a 4-week repeat-dose toxicity study. Results: HBM9014, a fully human anti-LIFR antibody generated by H2L2 Harbour Mice®, specifically binds LIFR thus blocks the interaction between LIF/CLCF1 and their respective receptors, inhibits downstream STAT3 phosphorylation, and reduces exogenous and endogenous LIF induced tumor spheroid proliferation in vitro. Furthermore, HBM9014 shows potent anti-tumor activity in multiple tumor models in vivo. In a GLP NHP 4-week repeat-dose toxicity study, HBM9014 is well tolerated up to 150 mg/kg with no discernable drug-related toxicity. Conclusions: HBM9014 specifically binds to the key component of LIF and CLCF1 receptor, LIFR, thus blocks both LIF and CLCF1 signaling pathways. HBM9014 shows significant cell proliferation inhibition alone or in combo with small molecule inhibitors in 3D culture of multiple cancer cell lines. It also shows significant in vivo antitumor efficacy as monotherapy, and enhanced efficacy in combination with Cisplatin in multiple mouse models. Importantly, despite the benefits of double blocking, HMB9014 has an excellent safety profile. Taken together, HMB9014 is a promising drug candidate for advanced cancer with favorable efficacy and safety profiles that warrant clinical validation. Citation Format: Jue Zeng, Dongxu Zhang, Louis Liu, Lingbing Zhang. HBM9014, a first-in-class fully human anti-LIFR antibody with excellent preclinical efficacy and safety profile [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 1414.