tbuckley/cabot-search huggingface dataset:
Abstract 3740: Tusamitamab ravtansine induces immunogenic cell death and synergizes with anti-PD-1 or anti-PD-L1 antibody combination in solid tumor
Authors: Celine Nicolazzi, Anne-Marie Lefebvre, Nicolas Moindrot, Christelle Larois, Marion Classe, Sukhvinder Sidhu
Journal: Cancer Research (2024)

Abstract Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC) targeted to carcino-embryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivering DM4, a maytansinoid cytotoxic. CEACAM5 is highly expressed in several tumor types, including non-squamous non-small cell lung cancer (NSQ NSCLC). It is currently being evaluated in patients with advanced CEACAM5-positive NSQ NSCLC, in a phase II study in combination with pembrolizumab, and a phase III trial as single agent in comparison with docetaxel. Preclinical investigations were performed to determine whether SAR408701 could be beneficially combined with immune checkpoint inhibitors. We, first, demonstrated that the tusamitamab ravtansine payload, DM4, is able to induce robust immunogenic cell death (ICD) using an in vivo vaccination assay. In this assay, immunocompetent mice were “vaccinated” by DM4-treated CT26 cells and then later rechallenged with CT26 tumor cells. Tumor rejection was observed in more than 50% of “vaccinated” mice. The ICD was characterized by the expression or release of danger-associated molecular patterns (DAMPs), and we observed DAMP modulation such as calreticulin (CRT) exposure at the cell surface of dying tumor cells, and the release of the High-Mobility Group Box 1 (HMGB1) in the extracellular space by CT26 cells in response to DM4 treatment. We also showed that DM4-treated CT26 tumor cells implanted into mice or SAR408701 treatment of MC38 tumor-bearing mice induced an elevation of plasmatic level of murine IL-6 and INFγ, revealing potential antitumor immunity modulation by the ADC and its payload. Immunohistochemistry analysis of MC38 tumors also revealed that tusamitamab ravtansine treatment induced a dose-dependent increase of CD8 T-cell infiltration in tumors correlating to dose-dependent efficacy. Finally, tusamitamab ravtansine was combined with immune checkpoint inhibitors (ICIs) in immunocompetent mice bearing MC38 tumor model. In this model, the combination of tusamitamab ravtansine with anti-PD-1 or anti-PD-L1 antibody led to complete response and, even, tumor-free survivors at 120 days post tumor implantation while single agents were inactive or transiently active. In summary, these preclinical data show that tusamitamab ravtansine could be beneficially combined with immune checkpoint and strongly support their evaluation in clinical development. Citation Format: Celine Nicolazzi, Anne-Marie Lefebvre, Nicolas Moindrot, Christelle Larois, Marion Classe, Sukhvinder Sidhu. Tusamitamab ravtansine induces immunogenic cell death and synergizes with anti-PD-1 or anti-PD-L1 antibody combination in solid tumor [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 3740.
Abstract 2175: Multiple exposures to antibiotics and increased risk of colorectal cancer
Authors: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena
Journal: Cancer Research (2024)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and worldwide. In 2023, approximately 153,020 individuals will be diagnosed with CRC and 52,550 will die, including 19,550 cases and 3750 deaths in patients under 50 years of age. CRC in younger patients (less than 55 years) is known as early onset colorectal cancer (EOCRC). It is a growing global phenomenon whose incidence and mortality has incidence from 11% to 20% between 1995 to 2019 and is expected to increase by 140% by 2030. While it has been linked to known and established risks for CRC, the underlying causes and mechanisms are poorly understood. Based on our current knowledge of the disease, we propose that EOCRC results from exposure of children and young adults to exposome factors that have been increasing globally in the last four decades that may impact the microbiome causing dysbiosis and inflammation in the distal colon and rectum, the anatomical site of EOCRC. Among the likely factors is the use of antibiotics, particularly in infants and children. In this study we hypothesized that early life exposure to antibiotics causes dysbiosis and inflammation in the distal colon and rectum leading to increased mutations and epigenetic events that promote EOCRC development. Specifically, we examined the effect of the most commonly prescribed pediatric antibiotics on the gut microbiota and inflammatory environment in the colon, and their impact on tumor development upon exposure to a carcinogen. We treated A/J mice with multiples rounds of antibiotics and then exposed them to azoxymethane, a carcinogen to determine the effect on tumor development in the colon. The results showed that antibiotic exposure caused dysbiosis and inflammation in the colon of antibiotic treated mice as well as systemic inflammation in mice treated with antibiotics. Treatment with azoxymethane, a carcinogen in the presence of antibiotic-induced dysbiosis led to increased tumor burden in the distal colon. These results suggest a possible involvement of antibiotics on increased risk of EOCRC. Citation Format: Niti Jani, Maredith Richardson, Kristen Hogan, Maria M. Pena. Multiple exposures to antibiotics and increased risk of 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 2175.
Abstract 5422: Identification of ZEB1-regulated circular RNAs in lung cancer cells
Authors: Seongran Cho, Jin-A Choi, Young-Ho Ahn
Journal: Cancer Research (2024)

Abstract ZEB1 is a master transcription factor playing a crucial role in promoting epithelial-mesenchymal transition (EMT), as well as the progression and metastasis of lung cancer. The progression of lung cancer is regulated by non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs). In this study, we aimed to identify circRNAs under the regulation of ZEB1 and elucidate their functions within lung cancer cells. Through RNA sequencing and subsequent CIRI-full analysis in ZEB1-overexpressing lung cancer cells, we identified 25 circRNAs displaying differential expression compared to control cells. Among these circRNAs, we targeted circDennd1b, which showed down-regulation in ZEB1-overexpressing cells. We used siRNAs to target the back-splicing junction of circDennd1b, resulting in its knockdown and consequently promoting the invasion of lung cancer cells. Now, we are studying how circDennd1b affects the progression and metastasis of lung cancer. In summary, the circRNAs modulated by ZEB1 are anticipated to play a key role in the invasion, progression, and metastasis of lung cancer. Citation Format: Seongran Cho, Jin-A Choi, Young-Ho Ahn. Identification of ZEB1-regulated circular RNAs in lung cancer cells [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 5422.
Abstract 5902: Targeting MAPK-driven tumors via inhibition of MAP2K4
Authors: Mark Wade, Emiliano Tamanini, Mathieu Unbekandt, Nicola Wallis, John Lyons, Joanne Munck, Andrew Woodhead, Patrick Schopf, Jessie Stow, Charlotte East, Mellissa Clark, Jeffrey St. Denis, Puja Pathuri
Journal: Cancer Research (2024)

Abstract MAPK pathway activation is a feature of multiple tumor types. Drugging KRAS and BRAF, the two main oncogenic drivers in the MAPK pathway, has proven successful in the clinic. Inhibition of the downstream effectors, MEK and ERK, can also induce tumor regression. Despite this, many tumors are intrinsically resistant to MAPK pathway inhibitors, or acquire resistance under selective pressure to drug treatment. This creates a need for combination treatments to improve clinical responses. A synthetic lethal (SL) interaction between inhibition of the MAPK pathway and blockade of JNK-JUN signaling has recently been described1. Specifically, data from yeast genetics and CRISPR knockout experiments in human cells have identified MAP2K4 as a potential therapeutic target that could be combined with MAPK inhibitors. To date, however, no potent MAP2K4 inhibitors with in vitro and cellular selectivity against key anti-targets have been reported. Here, we describe the development of potent covalent inhibitors of MAP2K4 kinase activity. Biochemical and cell-based assays show that the compound(s) are selective for MAP2K4 versus anti-targets including MAP2K7 and ERK kinases. The combination of MAP2K4 and MEK/ERK inhibitors was effective in cell lines driven by MAPK signaling. These data provide the rationale for further development of MAP2K4 inhibitors to advance our understanding of this novel drug combination. References: 1. Xue Z, Vis DJ, Bruna A, Sustic T, van Wageningen S, Batra AS, et al. MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell Res. 2018; 28:719-29. Citation Format: Mark Wade, Emiliano Tamanini, Mathieu Unbekandt, Nicola Wallis, John Lyons, Joanne Munck, Andrew Woodhead, Patrick Schopf, Jessie Stow, Charlotte East, Mellissa Clark, Jeffrey St. Denis, Puja Pathuri. Targeting MAPK-driven tumors via inhibition of MAP2K4 [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 5902.
Abstract 6758: Eradication of tumors and development of immunity from pHLIP-targeted intracellular delivery of STINGa
Authors: Michael DuPont, Anna Moshnikova, Marissa Iraca, Craig Klumpp, Hannah Visca, Dana Allababidi, Phoebe Pelzer, Donald Engelman, Oleg Andreev, Yana Reshetnyak
Journal: Cancer Research (2024)

Abstract Activation of the stimulator of interferon genes (STING) pathway causes the release of factors that trigger the immune response in the tumor microenvironment (TME). Transient strong activation leads to immune activation and tumor suppression, while prolonged weak activation leads to immuno-suppression promoting tumor development. Reprogramming of M2-type tumor-associated macrophages (M2-TAMs) toward an M1 phenotype, suppression of cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (mMDSCs), as well as activation of dendritic cells (DCs) to train T-cells are advantageous, while the activation of STING pathway in T-cells is leads to their apoptosis. Thus, targeted delivery of STINGa to specific cells with TME to induce strong transient activation may be a key to therapy. We have developed a delivery approach that uses one or two pH Low Insertion Peptides (pHLIPs) that collaborate in the targeted intracellular delivery of a STINGa. STINGa were conjugated with pHLIPs via S-S cleavable self-immolating linkers. Biophysical studies were performed to ensure proper interactions of pHLIP-STINGa agents with membrane lipid bilayers. pHLIPs extend the lifetime of STINGa in the blood and target them to acidic cancer and stromal cells (CAFs), as well as M2-TAMs, mMDSCs and DCs within TME. The targeting results in selective cytokine activation in tumors with no systemic activation, which triggers the eradication of small (100 mm3) and large (400-700 mm3) CT26 tumors in mice after one or two doses of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the level of acidity within the TME was reduced. No tumors developed in mice re-challenged by an additional injection of cancer cells in a 90-day experiment. Thus, targeted delivery of STINGa to cancer cells, tumor stroma and TAMs induces activation of signaling, potentially resulting in the recruitment and infiltration of T- and NK-cells, which gain access to the tumor core. The cytotoxic activity of T- and NK-cells is not impaired by the acidic environment and immune memory is developed. The pHLIP technology may allow transformation of immuno-activating agents into more potent therapeutics, since pHLIP can target and deliver these agents to cancer cells, tumor stroma and myeloid cells. Citation Format: Michael DuPont, Anna Moshnikova, Marissa Iraca, Craig Klumpp, Hannah Visca, Dana Allababidi, Phoebe Pelzer, Donald Engelman, Oleg Andreev, Yana Reshetnyak. Eradication of tumors and development of immunity from pHLIP-targeted intracellular delivery of STINGa [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 6758.
Abstract 482: Advancing treatment for metastatic triple negative breast cancer: Liposomal oncolytic adenovirus as a novel neoadjuvant therapy
Authors: Jaimin R. Shah, Tao Dong, Abraham Phung, Sarah L. Blair, Omonigho Aisagbonhi, William C. Trogler, Andrew C. Kummel
Journal: Cancer Research (2024)

Abstract Introduction: Adenovirus type-5 (Ad) is considered a prominent viral vector in cancer therapy due to its modifiability for the selective lysis of cancer cells. However, challenges are posed in Ad delivery to cancers lacking coxsackievirus and adenovirus receptors (CARs). In response to this limitation, Ad-encapsulated DOTAP-folate liposomes were developed, which improved Ad delivery and heightened therapeutic efficacy through membrane fusion and folate receptor-mediated endocytosis. Methods: The 4T1 mammary carcinoma model, a CAR-negative triple-negative breast cancer (TNBC) cell line (ER-, PR-, HER2-), resistant to adenoviral infection, was utilized for studying the comparative in vitro transduction of green fluorescent protein (GFP)-expressing Ad (Ad-GFP). The study assessed Ad-GFP with and without DOTAP-folate liposomal encapsulation at a multiplicity of infection (MOI) of 50. Additionally, an oncolytic adenovirus, Ad-hTERT, with a human telomerase promoter, underwent liposomal encapsulation. CAR-negative 4T1 GFP-expressing cells and CAR-positive MDA-MB-231-GFP human breast adenocarcinoma TNBC cells were transduced in vitro at MOI 100 with Ad-hTERT, both with and without DOTAP-folate liposomal encapsulation. Results: CAR-negative 4T1 cells exhibited superior Ad-GFP transduction when encapsulated in DOTAP-folate liposomes, compared to the unencapsulated form (p &amp;lt; 0.001). For oncolytic adenovirus Ad-hTERT, encapsulation resulted in 100% cell lysis within 24 hours in 4T1-GFP cells, contrasting with 13% with unencapsulated Ad-hTERT (P &amp;lt; 0.0001). In CAR-positive MDA-MB-231-GFP TNBC cells, encapsulated Ad-hTERT showed enhanced efficacy, resulting in 100% cell lysis within 24 hours compared to 75% with unencapsulated Ad-hTERT (P &amp;lt; 0.001). Discussion: DOTAP-folate liposomal encapsulation enhances the efficacy of oncolytic Ad-hTERT in both CAR-negative and CAR-positive TNBC cells, establishing it as an optimal therapy for tumors with CAR heterogeneity. Ongoing in vivo studies with Balb/C immune-competent mice and the 4T1 tumor model will assess the effectiveness of encapsulation through intratumoral administration. This approach may extend the recurrence-free period post-surgical tumor removal. Citation Format: Jaimin R. Shah, Tao Dong, Abraham Phung, Sarah L. Blair, Omonigho Aisagbonhi, William C. Trogler, Andrew C. Kummel. Advancing treatment for metastatic triple negative breast cancer: Liposomal oncolytic adenovirus as a novel neoadjuvant therapy [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 482.
Abstract 5321: Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation
Authors: Samson Mugisha, Shahnawaz Baba, Shreyas Labhsetwar, Richard Klemke, Jay Desgrosellier
Journal: Cancer Research (2024)

Abstract Tobacco-use is associated with an increased risk of developing aggressive breast cancer, however the cause remains unclear. While there is a dose-dependent decrease of patients’ overall survival due to tobacco-use, the risk persists even after cessation. Here we show that chronic treatment with of breast cancer cells with low-dose nicotine significantly increases tumorsphere formation, self-renewal and tumor growth, while the acute treatment has little effect. Interestingly, these outcomes were noted even weeks after nicotine treatment was stopped. Mechanistically, this was attributed to α7 nAChR, previously described as an essential regulator of inflammation. In fact, α7 nAChR knock-out prevented activation of the STING antiviral pathway by reducing the nicotine-induced mRNA expression of STING, CCL5, CXCL10 and STAT3. Overall, these findings highlight long-term impact of nicotine on cancer progression through α7 nAChR/STING pathway. This may inform new biomarkers for diagnosis and potential new treatment strategies to combat tobacco-related breast cancers. Citation Format: Samson Mugisha, Shahnawaz Baba, Shreyas Labhsetwar, Richard Klemke, Jay Desgrosellier. Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation [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 5321.
Abstract 7270: Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling
Authors: LaKendria K. Brown, Thanigaivelan Kanagasabai, Guoliang Li, Sherly I. Celada, Zhenbang Chen
Journal: Cancer Research (2024)

Abstract Prostate cancer (PCa) is the second-leading cause of cancer mortalities and morbidities in the United States and is the most commonly diagnosed malignancy in men. Despite the fact that androgen deprivation therapy is the first-line option to initial responses, most PCa patients invariably develop castration-resistant prostate cancer (CRPC). CRPC is a lethal type of malignancy, therefore, novel and effective treatment strategies are needed. The goal of this study was to evaluate the combination treatment of small molecule inhibitors, SZL-P1-41, a SKP2 target and PBIT, a KDM5B target on PCa growth and progression; as well as to delineate the underlying mechanisms of suppressing CRPC. Literature reports that S-Phase Kinase Associated Protein 2 (SKP2) is upregulated in PCa and Lysine-specific demethylase 5B (KDM5B) serves as a histone demethylase with a crucial role in cancers. Studies showed that KDM5B is increased in human PCa and KDM5B knockout decreases carcinogenic properties of PCa cells. We previously reported that SKP2 loss partially decreases the growth of prostate tumors and that KDM5B levels are reversely regulated by SKP2 in PCa cells. However, the mechanisms of KDM5B and SKP2 interplay on PCa malignancy is unknown. We hypothesize that combination of PBIT and SZL-P1-41 treatment will enhance anti-cancer effects on PCa progression by inducing cellular senescence. Here, we showed that inhibition of KDM5B and SKP2 decreased the proliferation of PCa cells, and KDM5B KO cells were more vulnerable to SKP2 inhibition. More importantly, a combined inhibition of KDM5B and SKP2 significantly blocked malignant progression and migration of PCa cells. Mechanistically, combined inhibition of KDM5B and SKP2 in PCa cells abrogated AKT activation, resulting in an induction of cellular senescence, which was measured via Western blot analysis and senescence-associated β-galactosidase (SA-β-Gal) staining. Taken together, our results show that combined inhibition of KDM5B and SKP2 is more efficacious in inhibiting proliferation and migration in CRPC cells, and this regimen would be an ideal therapeutic approach for treating CRPC. Citation Format: LaKendria K. Brown, Thanigaivelan Kanagasabai, Guoliang Li, Sherly I. Celada, Zhenbang Chen. Combination targeting of SKP2 and KDM5B induces senescence in castration-resistant prostate cancer cells via AKT signaling [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 7270.
Abstract 6698: Tumor microbiota associated with immune enrichment in breast tumor
Authors: Li-Fang Yeo, Bernard KB Lim, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Lai-Meng Looi, Nur Aishah Mohd Taib, Cheng-Har Yip, Pathmanathan Rajadurai, Soo-Hwang Teo, Jia Wern Pan
Journal: Cancer Research (2024)

Abstract Asian cancer patients have enriched immune profiles when compared to Caucasians. This is associated with improved overall survival and potentially better response to immunotherapy. Yet the reason behind enriched Asian immune profiles is unclear. This study investigated microbes found in Malaysian breast tumors in association with immune profiles. We used an existing dataset of RNA-seq data from fresh frozen breast tumor tissue (n=978). Sequencing reads were trimmed and filtered to remove human reads. Non-human reads were mapped to Kraken2 and relative abundance was estimated using Bracken. Microbiome analysis was conducted on R following Microbiome OMA guidebook. The top five genera found in the Malaysian Breast Cancer (MyBrCa) cohort were Pseudomonas, Siphoviridae, Bacillus, Escherichia and Klebsiella. Alpha diversity of basal subtype microbiota was significantly higher than Her2 subtype (Shannon index, p=0.027) whilst the other subtypes were more homogenous. MyBrCa patients with low immune scores were significantly different from high immune scores while controlling for age, stage, grade, ethnicity and PAM50 subtype (PERMANOVA, F-statistic = 1.656, p=0.05). Differential abundance analysis revealed Sulfidibacter and Priestia to be significantly different in abundance between high vs low IFNg groups (FDR-adjusted p-value &amp;lt; 0.05) using ALDEx2, ANCOM-BC2 and ZicoSeq and LinDA algorithms. Sulfidibacter was significantly different between high vs low immune group for Bindea combined immune score and ESTIMATE score groups (FDR-adjusted p-value &amp;lt;0.05). An independent breast cancer cohort (n=419) was used as validation where Sulfidibacter and Priestia were also significantly different in abundance for immune high vs low groups. Machine learning using Random Forest model predicted immune group with an AUC of 0.79 (CI = 0.74, 0.83; p-value &amp;lt; 0.01). The top five most important features contributing to the random forest model were Sulfidibacter, Prestia, Cutibacterium, Acinetobacter and Rhizobium. This study is the largest to date that characterize the tumor microbiota of an Asian cohort of breast cancers, where Sulfidibacter and Priestia, both relatively new and uncharacterized bacteria, were differentially abundant among patients with high vs low immune scores. Citation Format: Li-Fang Yeo, Bernard KB Lim, Tania Islam, Li-Ying Teoh, Suniza Jamaris, Mee-Hoong See, Lai-Meng Looi, Nur Aishah Mohd Taib, Cheng-Har Yip, Pathmanathan Rajadurai, Soo-Hwang Teo, Jia Wern Pan. Tumor microbiota associated with immune enrichment in breast tumor [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 6698.