tbuckley/cabot-search huggingface dataset:
Abstract 6640: Zap! Irreversible electroporation in pancreatic cancer cells induces proinflammatory cell death and improves progression free survival
Authors: Manali Powar, Khan Mohammad Imran, Irving C. Allen, Rafael V. Davalos, Zaid Salamah, Kenneth Aycock, Rebecca M. Brock, Sheryl Coutermarsh-Ott, Katie Orr
Journal: Cancer Research (2024)

Abstract Pancreatic cancer is the third leading cause of cancer-related death due to its late diagnosis, few treatment options, and extremely low survival rates due to its immunosuppressive microenvironment. Irreversible electroporation (IRE),is a tumor non-thermal ablation technique that applies high-voltage electrical pulses to permeabilize the cell membrane that is irreversible and leads to necrotic cell death. IRE has had strong success in clinical trials nevertheless, little is known about the effect of IRE beyond the initiation of cell death in the tumor tissue. We hypothesize that IRE can not only induce cell death by membrane disruption to facilitate a proinflammatory microenvironment but also causes death via cell cycle arrest. We utilized in-vitro, and immunocompetent in-vivo murine models to investigate changes to pancreatic cancer and the tumor microenvironment. Our findings show that treating the cells with an increasing voltage of IRE induces more cell death. We observed cell cycle arrest in the G1 phase which may have been caused by DNA damage. There was upregulation of DNA damage repair machinery in the treated samples. Our histopathology data suggests increased necrosis on the tumor treated with IRE, as also PCR array analysis showed more proinflammatory cell death caused by pyroptosis. Finally, we demonstrated a reduction in the tumor size and a better survival rate aftertreatment. Our data suggest that Irreversible electroporation has a promising future in inducing proinflammatory type of cell death in the tumor and benefits increased patient survival. More investigation is needed to define ideal parameters for the electrical pulses and device development for tumor ablation in larger animals like porcine models. Citation Format: Manali Powar, Khan Mohammad Imran, Irving C. Allen, Rafael V. Davalos, Zaid Salamah, Kenneth Aycock, Rebecca M. Brock, Sheryl Coutermarsh-Ott, Katie Orr. Zap! Irreversible electroporation in pancreatic cancer cells induces proinflammatory cell death and improves progression free survival [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 6640.
Abstract 5815: Next-generation RNAi therapeutics: siRNA-loaded exosomes targeting KRAS G12C in non-small cell lung cancer (NSCLC)
Authors: Hyo Kyeong Kim, Yujeong Choi, Kyoung Hwa Kim, Yeongju Byun, Tae Hee Kim, Jae Hwan Kim, Shung Hyun An, DaeHo Bae, MyeongKwan Choi, Jihwa Chung, Kihwan Kwon
Journal: Cancer Research (2024)

Abstract Background: NSCLC represents the predominant subtype of lung cancer, boasting an overall 5-year survival rate of 26%, a figure that fluctuates based on the disease stage. Within NSCLC, certain cancer gene mutations, notably KRAS G12C, are currently classified as 'undruggable targets,' creating hurdles in achieving effective treatment. The development of innovative anticancer drugs aimed at these challenging targets is expected to present a viable solution to these difficulties. Methods: Exosomes have garnered attention as an inventive drug delivery system for in vivo gene delivery through systemic injection. We used a new post-loading approach by actively loading KRAS G12C siRNA into exosomes using the shock waves (SWEET: shock wave exosome engineering technology ) in this study. The effect of in vitro and in vivo were tested in NCI-H358 (KRAS G12C mt NSCLC) cells and its xenograft mouse model. The tumor size and weight were measured twice a week. Results: We developed an exosome-based therapeutic using siRNA to effectively inhibit KRAS G12C, targeting NSCLC. The SWEET platform's post-loading method showed a high efficiency in loading KRAS G12C siRNA into exosomes. The KRAS G12C siRNA-loaded exosomes effectively silenced oncogenic KRAS G12C expression in cancer cells; they inhibited tumor growth when administered intravenously in a NSCLC xenograft mouse model. Remarkably, the anticancer effect of KRAS G12C-loaded exosome was similar to that of Sotorasib, a KRAS G12C mutation targeting anti-cancer drug. Conclusion: Our study showed KRAS G12C siRNA loaded exosomes were effectively delivered to NSCLC tumor tissue via intravenous (IV) administration. And its anti-cancer effects were very similar to sotorasib, showing potential as a treatment for KRAS G12C mutation-expressing cancer. The effective delivery of siRNA to tumor tissues through exosomes highlights the potential of this technology as a promising approach for developing new RNAi therapeutics for cancer. Citation Format: Hyo Kyeong Kim, Yujeong Choi, Kyoung Hwa Kim, Yeongju Byun, Tae Hee Kim, Jae Hwan Kim, Shung Hyun An, DaeHo Bae, MyeongKwan Choi, Jihwa Chung, Kihwan Kwon. Next-generation RNAi therapeutics: siRNA-loaded exosomes targeting KRAS G12C in non-small cell lung cancer (NSCLC) [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 5815.
Abstract 3795: Possible role of miR-375-3p in cervical lymph node metastasis of oral squamous cell carcinoma
Authors: Masato Saika, Koh-ichi Nakashiro, Norihiko Tokuzen, Hiroyuki Shirai, Daisuke Uchida
Journal: Cancer Research (2024)

Abstract Latent cervical lymph node metastasis (LNM) is the most important prognostic factor in early oral squamous cell carcinoma (OSCC). However, no clinically useful predictors of LNM in early OSCC are available. In this study, we focused on the microRNAs (miRNAs) involved in the expression of numerous genes and explored those associated with latent cervical LNM in OSCC. Microarray analysis of miRNA expression showed that the expression levels of miR-375-3p were significantly reduced in primary OSCC tissues with latent cervical LNM. Subsequently, we quantified the expression of miR-375-3p by RT-qPCR and digital PCR. Similar to the results of miRNA microarray analysis, miR-375-3p was significantly downregulated in primary OSCC tissues with latent cervical LNM. The results of digital PCR showed a more significant difference than those of RT-qPCR. When the reference value for predicting latent cervical LNM was set to less than 57.85 copies based on the receiver operating characteristic curve, the sensitivity, specificity, accuracy, and area under the curve were 80%, 100%, 90%, and 0.942, respectively. Next, we examined the effects of miR-375-3p mimics on the growth and migration of four human OSCC cell lines (SAS-L1, HSC2, HSC3, and Ca9-22) that do not express miR-375-3p. When an miR-375-3p mimic was introduced into these cells, cell proliferation and migration were significantly suppressed. Total RNA was extracted from these cells reverse-transfected with miR-375-3p mimic for 48 hours. Microarray analysis and Ingenuity Pathway Analysis (IPA) miRNA target filter showed that miR-375-3p overexpression reduced the expression of 266 genes, of which 37 genes had the target sequences of miR-375-3p in their 3’-untranslated region. Among these target genes, CEPT1 and TIMM8A knockdown significantly inhibited the migration of all human OSCC cells, similar to miR-375-3p mimics. Furthermore, IPA core analysis revealed a decrease in expression of genes involved in the activation of PI3K-AKT pathways by miR-375-3p overexpression. These results indicated that downregulating miR-375-3p expression could promote cervical LNM by enhancing cell proliferation and migration in OSCC. We also found that CEPT1 and TIMM8A as novel target genes of miR-375-3p regulated the migration of human OSCC cells. The expression levels of miR-375-3p in primary OSCC tissues appear to be a useful biomarker for predicting latent cervical LNM. Citation Format: Masato Saika, Koh-ichi Nakashiro, Norihiko Tokuzen, Hiroyuki Shirai, Daisuke Uchida. Possible role of miR-375-3p in cervical lymph node metastasis of oral squamous cell carcinoma [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 3795.
Abstract 5226: A 3D ECM embedded tumoroid platform for testing antibody drugs and engineered TCRs for immune oncology
Authors: Erik H. J. Danen
Journal: Cancer Research (2024)

Abstract We developed a screening platform for immune oncology using an assay based on automated image guided injection of tumoroids in wells of multi-well plates preloaded with a collagen-rich ECM. The identical x-y-z position and size of the ECM-embedded tumoroids in each well facilitates automated real time confocal microscopy and quantitative image analysis algorithms. The model is used to generate quantitative data for T cell recruitment to tumoroids and killing of tumoroids by T cells. We have applied this to screening a panel of CD3:Her2 bispecific antibodies (BsAb) binding with different affinities to CD3 or Her2 or displaying high affinity interactions with different epitopes on Her2. Exposure to fresh, non-activated peripheral blood mononuclear cell (PBMC) derived T cells shows an initial phase of random T cell movement throughout the ECM followed by a BsAb-dependent phase of active T cell recruitment to tumoroids (day 2-4) and a subsequent phase of tumoroid killing (day 4-6). We show that the wave of T cell recruitment following initial T cell-tumoroid contact involves chemotactic signaling. Decreased affinity at the Her2 or CD3 arm can be compensated for by increasing BsAb concentrations. However, we detect major differences in efficacy for different high affinity epitopes. I.e., of two BsAbs interacting with high affinity with distinct Her2 epitopes and each causing effective tumor cell killing in 2D co-culture, only one was able to trigger a wave of T cell recruitment and subsequent tumoroid killing in 3D. We have applied the same setup to testing the efficacy of T cells expressing engineered TCRs aimed at application in adoptive T-cell therapy. Kinetics of experiments using these activated engineered T cells are considerably shorter (24 hours instead of ~6 days) but show a similar pattern of T cell recruitment and subsequent tumoroid killing. We demonstrate successful generation of quantitative data for T cell recruitment and tumoroid killing for engineered T cells targeting tumor antigens expressed on TNBC and uveal melanoma tumoroids. Citation Format: Erik H. J. Danen. A 3D ECM embedded tumoroid platform for testing antibody drugs and engineered TCRs for immune oncology [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 5226.
Abstract 6632: Adipocyte death drives dormant breast cancer cell reactivation
Authors: Xiaoyu Yuan, Qihao Ren, Sheila A. Stewart
Journal: Cancer Research (2024)

Abstract Despite significant responses to initial treatments, upwards of 30% of breast cancer patients will experience a recurrence of their disease. Unfortunately, there are few clinical features that predict which patients will recur, relegating patients and their doctors to a wait-and-see approach where they must remain vigilant. Recent studies have reported that the presence of disseminated tumor cells (DTCs) in the bone marrow of early-stage breast cancer patients predicts a higher chance of recurrence and that obese patients experience 35%-40% higher rates of recurrence than lean patients. Interestingly, in addition to increased adipocyte size, obese patients experience higher rates of adipocyte apoptosis, macrophage recruitment to adipocyte tissue, and increased inflammation, shown as the formation of crown-like structures (CLSs). Given the rising prevalence of obesity, the need for mechanistic studies to elucidate its contribution to breast cancer dormancy and recurrence is urgent. To investigate how microenvironmental changes associated with obesity affect breast cancer dormancy, we utilized a well-established syngeneic mouse model of ER+ breast cancer dormancy (D2.0R). We found that D2.0R cells remained dormant in the visceral fat of wildtype mice but were reactivated upon adipocyte death due to obesity or genetic manipulation, and this reactivation required the recruitment of macrophages. To understand why macrophages were recruited to the adipose tissue and how they led to dormant tumor cell reactivation, we profiled the microenvironmental changes in visceral fat using single-cell RNA-sequencing and found that the infiltrating macrophages exhibited unique pro-inflammatory and lipid regulatory phenotypes. Further investigation revealed that macrophages activated the integrin-focal adhesion kinase (FAK) pathway in dormant D2.0R cells and the inhibition of integrin and FAK inhibited this activation. Given tumor cells can metastasize to visceral fat depots in breast cancer patients, our findings provide an important model to determine what drives dormant tumor cell growth in adipose tissue. Our study provides novel insights into how tumor microenvironment (TME) impacts breast cancer dormancy and also highlights the importance of adipose tissue as a unique reservoir that potentiates cancer relapse. Citation Format: Xiaoyu Yuan, Qihao Ren, Sheila A. Stewart. Adipocyte death drives dormant breast cancer cell reactivation [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 6632.
Abstract 5333: NeoMab: A novel platform for fully human therapeutic antibody development
Authors: Mingkun Zhang, Cunxiang Ju, Song Li, Junchao Peng, Jing Zhao, Xiang Gao
Journal: Cancer Research (2024)

Abstract Antibodies and antibody containing therapeutics, such as multivalent antibodies, chimeric antigen receptors (CARs), and antibody directed conjugates (ADCs), have been proven to be highly prominent in cancer treatment. However, challenges such as immunogenicity stemming from non-human or unnatural sequences and limitations in preclinical animal study systems still impede the rapid development of antibody drugs. To overcome these hurdles, GemPharmatech has created a novel antibody gene humanized model, the NeoMab mouse, to develop fully human antibodies. The NeoMab model was established via large genomic fragment knock-in technology, retaining native mouse constant region encoding genes and regulatory elements, while incorporating human variable gene repertoires into the endogenous loci. Developed in the BALB/c background, the NeoMab mouse carries fully functional MHC molecules, potentially enhancing antigen presentation. These mice sustain a competent immune system with a B cell development and maturation pattern, immune cell profile, and serum immunoglobulin levels comparable to those of BALB/c mice. NeoMab mice exhibit a robust humoral immune response, with a rapid increase in antigen-specific serum titers upon immunization using different antigens, such as recombined protein, plasmids, and overexpressing cell lines. Utilizing human V(D)J genes to encode immunoglobulins at a human-like frequency and diversity, antibodies derived from NeoMab mice demonstrate affinity and functional activity comparable to, or even surpassing, FDA-approved drugs. In conclusion, the NeoMab mouse model in the BALB/c background has been rigorously validated to elicit a robust response to specific antigen immunization, producing antibodies with high affinity, diversity, and functional activity. GemPharmatech's extensive drug-target gene humanized mouse library (comprising over 800 targets) and diverse disease models in oncology and other fields facilitate a seamless connection between in vitro antibody screening and in vivo animal studies. The integration of NeoMab, target humanization animals, and disease models enables GemPharmatech to provide an integrated solution, reducing time and costs while elevating the quality of antibody discovery in the field. Citation Format: Mingkun Zhang, Cunxiang Ju, Song Li, Junchao Peng, Jing Zhao, Xiang Gao. NeoMab: A novel platform for fully human therapeutic antibody development [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 5333.
Abstract 1386: CD1d-restricted iNKT cells promote liver metastasis from colon cancer
Authors: Marc Nater, Giulia Lucchiari, Michael Brügger, Tomas Valenta, Virginia Cecconi, Geo Forni, Stephan Benke, Maries van den Broek
Journal: Cancer Research (2024)

Abstract The liver is a prominent site for metastasis, yet little is known about the role of liver immunity in antimetastatic defense. Compared to other organs, the liver harbors a unique immune environment characterized by the abundance of innate cell lineages, including CD1d-restricted invariant natural killer T (iNKT) cells. To investigate the influence of iNKT cells on metastasis, we established an orthotopic model of colorectal cancer (CRC) with spontaneous dissemination to the liver. We induce the primary tumor by implanting CRC organoids into the colon mucosa of syngeneic C57BL/6 mice, resulting in hepatic macrometastases within 5 weeks. We observed that liver metastasis hardly occurred in mouse strains lacking iNKT cells (Cd1d−/− and Traj18−/− mice), while the growth of the primary tumor was comparable to that in wild-type mice. These results indicate a tumor-promoting function for hepatic iNKT cells. We uncovered that hepatic iNKT cells respond to disseminating cancer by producing IL-4 and IL-13, two cytokines known to activate hepatic stellate cells (HSCs) into fibrogenic myofibroblasts. Indeed, we saw rapid activation of HSCs and deposition of extracellular matrix upon arrival of cancer cells in the liver of wild-type but not iNKT cell-deficient mice. We propose that hepatic iNKT cells contribute to the formation of a supportive niche for disseminated tumor cells by activating HSCs early in the development of hepatic metastasis. Taken together, our findings highlight an essential tumor-promoting role for iNKT cells during the development of liver metastasis and contribute to our understanding of immune regulation of metastasis. Citation Format: Marc Nater, Giulia Lucchiari, Michael Brügger, Tomas Valenta, Virginia Cecconi, Geo Forni, Stephan Benke, Maries van den Broek. CD1d-restricted iNKT cells promote liver metastasis from colon 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 1386.
Abstract 386: BACH1 is a key regulator of the tumor hypoxia response
Authors: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Madeline Henn, Emily Shi, Thomas Li, Letícia Stock, Wenchao Liu, Margarite Matossian, Andrea Valdespino, Yoo Jane Han, Jing Zhang, Geetha Priyanka Yerradoddi, Yan Li, Mitsuyo Matsumoto, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner
Journal: Cancer Research (2024)

Abstract Hypoxia is an important hallmark of aggressive solid tumors and a key driver of metastasis and resistance to therapy. Hypoxic stress induces the activation of various factors, such as hypoxia-inducible factors (HIFs), which facilitate cellular adaptation and promote tumorigenesis. Given the complexity of this mechanism, identifying novel targets that sensitize hypoxic tumors to therapy could have significant clinical impact. Here we show that the pro-metastatic BTB and CNC homology 1 (BACH1) transcription factor is prolyl-hydroxylated by the HIF Prolyl Hydroxylase (PHD), similar to HIFs, in an oxygen-dependent manner. We describe two major prolyl hydroxylation sites in BACH1 and demonstrate that prolyl hydroxylation increases protein turnover and decreases DNA binding in normoxia. We further demonstrate HIF-independent induction of BACH1 within multiple TNBC (Triple-Negative Breast Cancer) cell lines and patient-derived organoids under hypoxic conditions. Utilizing ChIP-seq, bulk, single-cell and spatial transcriptomics across diverse BACH1 knockout tumor models, our study revealed that BACH1 selectively and directly modulates the transcriptional response associated with hypoxia and stress in TNBC. Our findings identify BACH1 as a clinically relevant target for attenuating hypoxia induced, pro-metastatic signaling and therapeutic resistance in cancers. Citation Format: Long Chi Nguyen, Christopher Dann, Dongbo Yang, Madeline Henn, Emily Shi, Thomas Li, Letícia Stock, Wenchao Liu, Margarite Matossian, Andrea Valdespino, Yoo Jane Han, Jing Zhang, Geetha Priyanka Yerradoddi, Yan Li, Mitsuyo Matsumoto, Olufunmilayo I. Olopade, Kazuhiko Igarashi, Marsha R. Rosner. BACH1 is a key regulator of the tumor hypoxia response [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 386.
Abstract 6281: Context dependent role of glucocorticoids in breast cancer
Authors: Wendy Effah, Suriyan Ponnusamy, Sarah Asemota, Yekta Khosrosereski, Ramesh Narayanan
Journal: Cancer Research (2024)

Abstract Glucocorticoids bind to the transcription factor glucocorticoid receptor (GR) and regulate genes in response to cellular metabolism, inflammation, and stress. Although GR has been extensively evaluated in inflammation and metabolic diseases, its role as a therapeutic target in cancer has not been thoroughly studied. Results from studies with another member of the steroid receptor family, androgen receptor (AR), demonstrated that the AR is an oncogene in estrogen receptor (ER)-negative breast cancer, but a tumor suppressor in ER-positive breast cancer. We expected a comparable mechanism with GR in different breast cancer subtypes. In this study, we evaluated the role of GR in various breast cancer subtypes and discerned the mechanism of action. Six breast cancer cell lines and seven patient-derived xenografts (PDXs) were characterized by Western blot for their expression of GR, ER and AR. Proliferation assays were performed in cell lines with a dose-response of a synthetic glucocorticoid, dexamethasone. Subsequently, we performed xenograft studies in cell line xenografts (CDXs) and PDXs. GR was ubiquitously expressed in various cell lines and PDX models. Dexamethasone reduced cell proliferation in ER-positive models, while it increased the proliferation in ER-negative cell lines, suggesting that the GR might have a mechanism of action that is similar to AR. GR antagonist, mifepristone, reversed the effects of dexamethasone. CDX studies in an ER-positive cell line, MCF7 suggested that dexamethasone (10 mpk) inhibited the tumor growth significantly that was better than the standard of care fulvestrant. This result was confirmed in an ER positive PDX model HCI013. Study by Obradović et al, indicates that glucocorticoids have an oncogenic role and furthermore promote breast cancer metastasis in TNBC model thereby validating the subtype and context dependent role of the glucocorticoid receptor. We are currently exploring the mechanism of GR’s context-dependent tumor suppressor and oncogenic role in distinct breast cancer subtypes. Citation Format: Wendy Effah, Suriyan Ponnusamy, Sarah Asemota, Yekta Khosrosereski, Ramesh Narayanan. Context dependent role of glucocorticoids in 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 6281.