bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6356: Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC
Authors: Wu Jennifer Donglan , Sosman Jeff , Kocherginsky Masha , Serritella Anthony , Hussian Maha , Vanderweele David J.
Published: March 2024

In response to genomic insults and DNA double-strand breaks, the stressed epithelial cells express the MHC I-chain related molecule (MIC) on the surface as a byproduct of activating the ATM pathway. The MIC molecule itself has no known impact on tumor survival or growth. In the context of immune microenvironment, tumor cell surface MIC can activate NK cells and co-stimulate CD8 T cells by engaging in the activating receptor NKG2D to hinder the early tumorigenesis. However, in established malignancies, in particular metastatic diseases, tumor cells shed surface MIC to release the soluble form MIC (sMIC). It has been well demonstrated that, in contrary to cell surface MIC, sMIC is highly immune suppressive by disturbing NK cell homeostasis and repolarizing NK cells function, impairing antigen-specific CD8 T cell function by downmodulating NKG2D expression and CD3z expression, and facilitating immune suppression of MDSCs and TAMs in tumor microenvironment. We have demonstrated that MIC is prevalently expressed by prostate tumor cells and significantly upregulated in mCRPC tumors. We have shown significantly elevated levels of serum sMIC in prostate cancer patients with metastatic diseases. We have developed a novel class of clinical candidate monoclonal antibody huB10G5 that can target both sMIC and surface MIC to re-invigorate both NK and CD8 T cell function and inhibit MDSCs and TAMs in preclinical models. The huB10G5 has an acceptable safety profile and is currently completing CMC for IND enabling. We hypothesize that huB10G5 is a novel immune therapeutic reagent for mCRPC patients. To test our hypothesis, we first conducted serial studies of the clinical candidate huB10G5 in pre-clinical models of prostate cancers. We found that huB10G5 can effectively induce 100% long-term tumor complete regression (CR) as low as 1.0 mg/KG. These animals are fully protected from tumor re-challenge. The anti-tumor effect is mediated by the combined action of NK and CD8 T cells. With the support of our pre-clinical efficacy and safety data, we have planned to initiate Phase I clinical trial with huB10G5 for mCRPC patients in 2024.

Citation Format: Jennifer Donglan Wu, Jeff Sosman, Masha Kocherginsky, Anthony Serritella, Maha Hussian, David J. Vanderweele. Novel antibody targeting tumor NKG2D ligand MIC: Preclinical studies and clinical development plan for mCRPC [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 6356.
Abstract 6380: Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database
Authors: Shen Junyi , Lin Anqi , Cheng Quan , Zhang Jian , Luo Peng
Published: March 2024

Background: With the widespread use of immune checkpoint inhibitors (ICIs) in the treatment of childhood cancers, their associated ICIs-related adverse events (irAEs) have become an important challenge. Our study was conducted to explore the pediatric high-risk ICIs-related AEs (pediatric irAEs) and explore the underlying mechanisms of pediatric irAEs.

Methods: We analyzed ICIs-related adverse reaction reports in VigiBase from 1967 to 2023 and the FDA Adverse Event Reporting System (FAERS) database from 2013 to 2022. Using three methods, the reporting odds ratio (ROR), the proportional reporting ratio (PRR), and the information component (IC), we conducted a disproportionality analysis between pediatric and adult cancer patients using ICIs to discover pediatric irAEs. Furthermore, we explored the impact of clinical factors on the occurrence of pediatric irAEs and their subsequent prognosis through univariate and multivariate logistic regression analyses. Finally, combining these data with pan-cancer transcriptome data from the Gene Expression Omnibus (GEO) database, we explored the potential biological mechanisms related to pediatric irAEs.

Results: We identified 4 categories of pediatric irAEs in the VigiBase and FAERS databases, including cytokine release syndrome (RORVigiBase = 17.05; RORFAERS = 14.17), acute respiratory distress syndrome (RORVigiBase = 10.26; RORFAERS = 12.39), seizure (RORVigiBase = 7.18; RORFAERS = 10.63) and febrile neutropenia (FN) (RORVigiBase = 3.01; RORFAERS = 4.84). The occurrence of pediatric irAEs may be related to mechanisms such as activation of immune cells, imbalance of inflammatory factors, activation of pathogen recognition, downregulation of inhibitory synapses, excitation/inhibition imbalance and central nervous system dysfunction.

Conclusion: This study systematically analyzed the high-risk irAEs that may occur after using ICIs in pediatric cancer patients. Next, we explored the possible biological mechanisms of these pediatric irAEs to provide certain theoretical guidance for the prevention and treatment of adverse reactions in pediatric cancer patients after treatment with ICIs.

Citation Format: Junyi Shen, Anqi Lin, Quan Cheng, Jian Zhang, Peng Luo. Exploring immune checkpoint inhibitor-related adverse events in pediatric cancer patients: A pharmacovigilance analysis of VigiBase and the FDA adverse event reporting system (FAERS) database [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 6380.
Abstract 6509: GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors
Authors: Hou Xiaodan , Yan Honghua , Zhang Xin , Qian Weidong , Chen Dong , Ren Zhihua , Tong Youzhi
Published: March 2024

Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is the central signal molecule in regulating cell growth, metabolism, angiogenesis, and survival. The first generation of mTOR inhibitors specifically inhibit mTORC1 but are insensitive to mTORC2 and cannot eliminate the downstream signaling cascade in cancer. GT0486, a second-generation mTORC1/2 dual inhibitor, can selectively suppress mTOR kinase activity while has no inhibitory effect on other kinase receptors. We investigate the anti-tumor efficacy of GT0486 in a variety of tumor cells and xenograft animal models in vitro and in vivo. The combination effects of GT0486 and BTKi (BTK inhibitor) were also evaluated. Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer). In B-cell lymphoma, compared with the CC-223, GT0486 shows greater inhibitory potency against TMD8, DoHH2 and WSU-DLCL2, with IC50 values of 85nM, 96nM and 83nM, respectively. Moreover, in the U87 and the PC-3 xenograft animal models, GT0486 strongly reduced tumor growth in dose dependent manner. High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells. In BTKi resistant DoHH2 cells, GT0486 also enhanced the drug sensitivity of BTKi. The possible biomarkers on the synergistic mechanism were further studied. GT0486 improves the role of BTKi on cell cycle arrest in phase G1. At the same time, the phosphorylation levels of mTOR downstream effectors AKT, 4EBP1 and S6 were dose-dependently downregulated after GT0486 treatment, and a significant reduction were observed when combined with BTKi. These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials.

Citation Format: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong. GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors [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 6509.
Abstract 6517: ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM patients
Authors: Yang Yi-Fang , Chan Ming-Hsien , Chen Chi-Long , Hsiao Michael , Chang Yu-Chan
Published: March 2024

Aldolase is an enzyme that takes part in glycolysis by catalyzing a six-carbon intermediate to yield two three-carbon products, requiring ATP. The aldolase family comprises three members, namely ALDOA, ALDOB, and brain-specific ALDOC. Low-grade gliomas and glioblastoma (GBM) are characterized by shared genetic events, including chromosome 1p/19q codeletion, EGFR amplification, and ATRX loss of function, in which ALDOC plays a role. Additionally, ALDOC is responsive to IDH1 mutations. If patients display IDH1 mutations, it is expected that ALDOC performance will be relatively higher. This finding suggests a more favorable prognosis. The ALDOC promoter region's function is impeded by hypermethylation, which declines as glioma progresses. The regulatory mechanisms and implications remain unclear. We established a multi-omics profile and identified several crucial mechanisms activated upon the loss of ALDOC expression. Among these mechanisms, we found HMGB1 to have a key role in linking the immune response, tumor microenvironment, and epigenetic modifications. We compared the proteomic and secretomic platforms in an ALDOC overexpression/knockdown model, which showed abundant HMGB1 expression following ALDOC inhibition. Importantly, there is an inverse correlation between ALDOC expression and HMGB1 protein levels. Additionally, our findings reveal that upregulation of ALDOC promotes its translocation to the nucleus, thereby enhancing its binding affinity with HMGB1. This, in turn, enables extracellular release of HMGB1 in GBM, which triggers signaling via receptors for advanced glycation end-products (RAGE) and several cytokines. Moreover, HMGB1 remodels the immune microenvironment and upregulates multiple immune checkpoint molecules, including PD-L1, PD-L2, B7-H3, and MHCs. Not all GBM models exhibited significant effects when combined with immune checkpoint blockade using HMGB1 blockade. However, ALDOC knockout mice demonstrated poorer survival and treatment efficacy, suggesting that ALDOC may be crucial for a personalized immunotherapy strategy.

Citation Format: Yi-Fang Yang, Ming-Hsien Chan, Chi-Long Chen, Michael Hsiao, Yu-Chan Chang. ALDOC as an indicator of HMGB1 blockade combined with checkpoint inhibitor based immunotherapy in GBM patients [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 6517.
Abstract 6574: UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas
Authors: Liu Shiqin , Chai Timothy , Marques Fernando , Yin Qingqing , Hsu En-Chi , Shen Michelle , Toland Angus , Bermudez Abel , Hartono Alifiani B. , Massey Christopher F. , Lee Chung S. , Zheng Liwei , Baron Maya , Denning Caden J. , Aslan Merve , Nguyen Holly , Nolley Rosalie , Zoubeidi Amina , Das Millie , Kunder Christian , Howitt Brooke , Soh H Tom , Weissman Irving L. , Liss Michael A. , Chin Arnold I. , Brooks James D. , Corey Eva , Pitteri Sharon , Huang Jiaoti , Stoyanova Tanya Ivanova
Published: March 2024

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer (NEPC), small cell lung cancer (SCLC), and neuroblastoma, share common histological features, including expression of neuroendocrine markers, rapid relapse after treatment, and poor prognosis. Due to the poor clinical outcome of patients with neuroendocrine carcinomas, there is a critical need to identify new drivers, therapeutic targets, and effective therapeutic strategies for these malignancies. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a protease that has a dual function in regulating protein stability. We demonstrated that UCHL1 is significantly elevated in tissues from patients with NEPC, SCLC, and neuroblastoma. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of key transcriptional factors, E2F1 and c-MYC. Conversely, UCHL1 binds p53 and promotes p53 degradation. Importantly, treatment with UCHL1 inhibitors significantly reduces tumor growth and metastasis of neuroendocrine carcinomas. The combination of UCHL1 inhibitors with cisplatin, the standard of care used for neuroendocrine carcinomas, halts tumor growth in pre-clinical settings. Our study reveals new mechanisms of UCHL1 function in neuroendocrine carcinomas tumorigenesis and identifies UCHL1 as a therapeutic target and potential molecular indicator for diagnosis and monitoring treatment responses in neuroendocrine carcinomas.

Citation Format: Shiqin Liu, Timothy Chai, Fernando Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Toland, Abel Bermudez, Alifiani B. Hartono, Christopher F. Massey, Chung S. Lee, Liwei Zheng, Maya Baron, Caden J. Denning, Merve Aslan, Holly Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian Kunder, Brooke Howitt, H Tom Soh, Irving L. Weissman, Michael A. Liss, Arnold I. Chin, James D. Brooks, Eva Corey, Sharon Pitteri, Jiaoti Huang, Tanya Ivanova Stoyanova. UCHL1 is a molecular indicator and a therapeutic target for neuroendocrine carcinomas [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 6574.
Abstract 6637: The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment
Authors: Giurini Eileena F. , Pappas Sam G. , Gupta Kajal H.
Published: March 2024

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease projected to become the second leading cause of cancer deaths by 2030. First-line chemotherapies gemcitabine and FOLFIRINOX provide little therapeutic benefit and are accompanied by severe adverse toxicities, precluding long-term treatment. In addition, PDAC is notoriously refractory to checkpoint inhibitor immunotherapies, due to poor immunogenicity and a tumor microenvironment dominated by suppressive cell types. Thus, there is an unmet need for innovative, immune-based strategies to combat PDAC. A previous study utilized engineered bacteria to effectively kill PDAC tumor cells by directly delivering immunogenic tetanus toxoid to the tumor. Given the potential toxicity in using live bacteria, our group utilized a less toxic alternative, an FDA-approved Haemophilus influenzae type b vaccine (HibVx) also containing a tetanus toxoid component. To determine the antitumor potential of HibVx, our group used a physiologically relevant murine model, low T cell clone murine PDAC tumor model 641c95 and clinically relevant KPC mice model for PDAC. After tumors were established, animals received three consecutive daily treatments of HibVx via intraperitoneal injection. HibVx-treated animals experienced a dramatic reduction in tumor growth compared to PBS-treated controls (p<0.001). Given that tetanus toxoid is highly immunogenic in nature, changes in intratumoral immune cell populations following HibVx treatments were of great interest. Using flow cytometry analysis, HibVx-treated tumors had a significant increase in natural killer cells compared to control tumors (p<0.05). In addition, HibVx affected myeloid-derived suppressor cell populations (MDSCs), which are heavily implicated in the suppressive nature of PDAC tumors. HibVx also significantly decreased MDSCs within the tumor (p<0.05). In all, these findings position HibVx as an effective immunostimulatory agent that can be used as an alternative to live bacteria-based therapy for the treatment of PDAC.

Citation Format: Eileena F. Giurini, Sam G. Pappas, Kajal H. Gupta. The Haemophilus influenzae vaccine mitigates pancreatic tumor progression and lowers immunoregulatory cell levels in the tumor microenvironment [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 6637.
Abstract 6698: Tumor microbiota associated with immune enrichment in breast tumor
Authors: Yeo Li-Fang , Lim Bernard KB , Islam Tania , Teoh Li-Ying , Jamaris Suniza , See Mee-Hoong , Looi Lai-Meng , Taib Nur Aishah Mohd , Yip Cheng-Har , Rajadurai Pathmanathan , Teo Soo-Hwang , Pan Jia Wern
Published: March 2024

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 < 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 <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 < 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.
Abstract 6739: Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian cancer
Authors: Medina Lorel Y. , Serda Rita E. , Marwedel Benjamin , Jun Melanie S. , Adogola Josh
Published: March 2024

Ovarian cancer is predominately left undetected and untreated until the later stages of the disease where it becomes incredibly difficult to treat. Preclinical studies demonstrate that immunotherapy can be highly effective. Our lab has been working on an immunotherapy approach to treat women with ovarian cancer that utilizes mesoporous silica nanoparticles(MSN). MSN that present pathogen-associated molecular patterns (PAMPS) are able to significantly reduce tumor burden in mouse models of serous epithelial ovarian cancer when administered by intraperitoneal injection. These microbial mimetic particles are decorated with polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA). When in the presence of antigen presenting cells, they bind to Toll-like receptors (TLR) present on the cell surface and within the endosome. To better understand mechanisms underlying their efficacy, we injected fluorescent MSN-PEI-CpG-MPLA (100 or 500 nm) or unmodified MSN into mice with advanced ovarian cancer. The particles, regardless of the presence of TLR-agonists, were rapidly internalized by myeloid cells, with trafficking almost exclusively to immune clusters located in tumor-burdened adipose tissues when administered by intraperitoneal injection. Conversely, intravenous injection of MSN-PEI-CpG-MPLA led to predominate accumulation in liver, with no particles found in tertiary lymphoid clusters 24 hours post injection. Furthermore, unlike intraperitoneal injection, intravenous injection of MSN-PEI-CpG-MPLA was without therapeutic effect. Currently we are studying MSN safety and the impact of administration route and dose on efficacy and cytotoxicity. In summary, MSN, with and without TLR agonists, are trafficked by myeloid cells to tumor-burdened fat-associated lymphoid clusters when administered by intraperitoneal injection. Intraperitoneal injection of TLR-agonist modified MSN effectively reduces tumor burden in mice with ovarian cancer.

Citation Format: Lorel Y. Medina, Rita E. Serda, Benjamin Marwedel, Melanie S. Jun, Josh Adogola. Efficacy and toxicity of microbial mimetic mesoporous silica nanoparticles in a mouse model of ovarian 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 6739.
Abstract 6809: Tumor-associated macrophages promote bladder cancer cell migration and invasion through activation of CCL20-CCR6 axis
Authors: Nakagawa Ryunosuke , Kouji Izumi , Toriumi Ren , Aoyama Shuhei , Kamjima Taiki , Kano Hiroshi , Makino Tomoyuki , Naito Renato , Yaegashi Hiroshi , Nohara Takahiro , Nakata Hiroki , Mizokami Atsushi
Published: March 2024

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 702: Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds
Authors: Alfsen Maria Zeiler , Thaysen Maria , Nielsen Nikoline , Wick Michael , Piggott Luke , Gnosa Sebastian , Nielsen Carsten Haagen
Published: March 2024

Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Several treatment strategies are used including the FDA approved 177Lu-vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment due to tumor intrinsic resistance mechanisms. Therefore, the combination of targeted radionuclide therapy with inhibitors against e.g. DNA damage response, cell cycle progression or cell survival pathways are investigated to enhance the radiosensitivity of the tumor. Current models to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we have developed a radioresistant patient-derived xenograft (PDX) prostate cancer model (ST1273, XenoSTART), that is positive for PSMA. Resistance to radiation was initially established by sequential irradiation of the tumors with external beam radiation. Moreover, the model has proven to be resistant towards treatment with 30 MBq 177Lu-PSMA-617. Utilizing this radioresistant model we are now able to investigate the treatment response of 177Lu-PSMA-617 in combination with different drug inhibitor classes to evaluate their potential radiosensitizing effect. The PARP inhibitor, Olaparib, was administered at 50 mg/kg QDx48 alone or in combination with a single dose of 177Lu-PSMA-617 in radioresistant ST1273 tumor bearing NMRI nude mice. First results showed a prolonging treatment effect of Olaparib given in combination with 177Lu-PSMA-617 compared to 177Lu-PSMA-617 alone. Tumor relapse was observed 29 days after treatment with 177Lu-PSMA-617 alone, whereas it was observed 49 days after combination treatment. Olaparib given alone did not influence tumor growth. To further investigate the mechanism of resistance we are currently investigating the radiosensitizing potential of additional compounds and evaluating the tumors by RNA- and whole-exome- sequencing. Altogether, we successfully established a PSMA positive prostate cancer model resistant to PSMA targeted radionuclide therapy. With this model we are able to investigate the radiosensitizing effect of different drug classes.

Citation Format: Maria Zeiler Alfsen, Maria Thaysen, Nikoline Nielsen, Michael Wick, Luke Piggott, Sebastian Gnosa, Carsten Haagen Nielsen. Development of a radioresistant PDX prostate cancer model to evaluate potential radiosensitizing compounds [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 702.
Abstract 7077: The oncogenic transcription factor ERG has distinct roles and signaling in different prostate cancer cell types
Authors: Rajendran Saranya , Hollenhorst Peter C.
Published: March 2024

ERG is the most common oncogene in prostate cancer, as it is aberrantly expressed in about 50% of cases due to the TMPRSS2/ERG gene rearrangement. ERG is not normally expressed in the adult prostate. The normal function of ERG is confined to hematopoietic stem cells and blood vessels. Aberrant expression of ERG in prostate epithelial cells is oncogenic when combined with mutations that activate the PI3K/AKT signaling pathway. The RAS/MAPK pathway can also regulate ERG function through direct phosphorylation of ERG by ERK. The function of these regulatory events and how they can be exploited to develop therapy for ERG-positive prostate cancer remains unclear. Here we find that ERG expression in prostate epithelial cells with low PI3K/AKT pathway activity drives epithelial to mesenchymal transition and stemness properties. This function requires ERG phosphorylation via a positive feedback loop with the TLR4 signaling pathway, and can be repressed by a TLR4 inhibitor. However, activation of the PI3K/AKT pathway rearranges the ERG cistrome and alters ERG function, where ERG now promotes luminal epithelial differentiation. In the presence of activated AKT, new ERG targets include genes involved in vascular development and ERG phosphorylation is regulated through a positive feedback loop with the VEGF signaling pathway. Despite these differences in cellular differentiation, we find that ERG can promote stemness and tumorigenesis in both AKT-high and AKT-low cellular backgrounds. ERG functions in prostate epithelial cells appear to mirror ERG functions in hematopoietic stem cells and blood vessels. These findings suggest strategies of combinatorial inhibition of ERG function through signaling pathway inhibition.

Citation Format: Saranya Rajendran, Peter C. Hollenhorst. The oncogenic transcription factor ERG has distinct roles and signaling in different prostate cancer cell types [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 7077.
Abstract 7081: Comprehensive investigation of NAT10’s catalytic and non-catalytic functions in cancer cell proliferation
Authors: Raikundalia Sweta Pradeep , Dalhat Mahmood Hassan , Patrasso Emmely A. , Suh Adam , Arango Daniel
Published: March 2024

N-acetyltransferase 10 (NAT10) is emerging as an oncoprotein in multiple cancers including acute myeloid leukemia and liver cancer. In addition, my preliminary studies show that NAT10 is a stress response that promotes the resilience of cancer cells to anti-tumor drugs. However, the underlying mechanisms by which NAT10 promotes cancer growth and drug resistance are unknown. NAT10 is an RNA acetyltransferase, where it acetylates cytidines in rRNA, tRNA, mRNA, and lncRNAs. Our previous work demonstrated that NAT10 promotes translation efficiency and mRNA stability through the acetylation of cytidines in mRNA. However, NAT10 is a multifunctional protein. Besides acetylating RNA, NAT10 also acetylates proteins at lysine residues, has RNA helicase activity, and can serve as a scaffold in ribonucleoprotein complexes. Based on this complexity, it is imperative to elucidate whether NAT10 exerts its oncogenic activity via RNA acetylation, protein acetylation, disruption of RNA structures, or non-catalytic functions. Strikingly, our preliminary results indicate that the acetyltransferase function of NAT10 is dispensable for cell proliferation. To evaluate NAT10’s oncogenic activity unbiasedly, we are now performing a deep mutagenesis scanning (DMS) assay. For this purpose, we generated a library of mutants in hundreds of NAT10 residues. This library was transduced in multiple cell lines from acute myeloid leukemia and liver cancer carrying a PROTAC system, which allow us to deplete NAT10 in a rapid and controlled manner while expressing ectopically thousands of NAT10 mutants. In this conference, I will talk about, my results, how DMS is a powerful tool to delineate the molecular functions of candidate oncoproteins, and the implications of our results for the potential drugging of NAT10 in cancer.

Keywords: Cell proliferation, NAT10, RNA modifications, Deep mutagenesis scanning.

Citation Format: Sweta Pradeep Raikundalia, Mahmood Hassan Dalhat, Emmely A. Patrasso, Adam Suh, Daniel Arango. Comprehensive investigation of NAT10’s catalytic and non-catalytic functions in cancer cell proliferation [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 7081.
Abstract 7151: Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor
Authors: Dheeraj Arpit , Marques Fernando Jose , Tailor Dhanir , Bermudez Abel , Grau Benedikt , Pitteri Sharon , Malhotra Sanjay V.
Published: March 2024

Background: Triple Negative Breast Cancer (TNBC) is the most aggressive type of breast cancer, making up 15-20% of diagnosed cases, and has high rates of metastasis and recurrence. Most women with this disease experience a recurrence after curative-intent therapy for early breast cancer, while a smaller proportions are diagnosed with distant metastases initially. Cancer cells are characterized by their reprogramming of glucose metabolism. Cancer cells show increased proliferation along with higher energy and substrate demands. Through our efforts to find effective therapies for TNBC, we have identified CET019, a new small molecule that effectively suppresses the growth of breast cancer cells.

Methods: Cell viability and clonogenic assays were performed on a range of TNBC cells, including MDA-MB-231, MDA-MB-468, SUM159, HCC1395, HCC1806, EMT6, and 4T1. Cell cycle distribution was assessed through flow cytometry. LC-MS/MS analysis was performed on TMT-labeled samples for global proteome profiling. The efficacy of CET019 (30 mg/kg) was tested using tumor and patient derived xenograft studies.

Results: Our studies show that CET019 suppresses the clonogenic potential and growth of various triple-negative breast cancer cells. The CET019 treatment causes cell cycle arrest in TNBC cells at the G2/M phase. Proteomics analysis suggests that CET019 specifically affects metabolic and proteosomal pathways. In vivo studies with CET019 found an inhibition of tumor growth kinetics in the mouse xenograft study with different TNBC models, as compared to the control group. We also observed that CET019 inhibited metastatic lung nodules. The results were further substantiated in three Patient Derived Xenograft (PDX) models.

Conclusion: In summary, our study has identified a novel small molecule candidate CET019 as a promising lead candidate for TNBC treatment, paving the way for further development.“The complete chemical structures of the compounds used will be disclosed at the time of presentation at the meeting.”

Citation Format: Arpit Dheeraj, Fernando Jose Marques, Dhanir Tailor, Abel Bermudez, Benedikt Grau, Sharon Pitteri, Sanjay V. Malhotra. Targeting metabolic pathway in triple negative breast cancer with a small molecule inhibitor [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 7151.
Abstract 7201: Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models
Authors: Ott Connor A. , Purwin Timothy , Tiago Manoela , Lou Kristine , Chen Pan-Yu , Chowdhury Somaneth , Mersky Glenn , Hacohen Nir , Lamar John , Capparelli Claudia , Bollag Gideon , Aplin Andrew
Published: March 2024

Targeted therapies in cancer are limited by drug tolerance. In melanoma, tolerance to MAPK pathway inhibitors is associated with loss of SOX10 and enhanced YAP1/TAZ-TEAD activity. We show that loss of SOX10 is sufficient to up-regulate a TEAD transcriptional program with a strong dependence on TAZ. We developed a unique gene signature based on the transcriptomic changes following TAZ or YAP1 depletion. Expression of active TAZ was sufficient to mediate tolerance to BRAF inhibitors and MEK inhibitors. In WM983B cells, depletion of TAZ significantly reduced cell growth, whereas YAP1 knockdown resulted in little to no effect. These studies demonstrate that TAZ-TEAD activity plays an important role in melanoma drug tolerance and the development of acquired resistance.

Citation Format: Connor A. Ott, Timothy Purwin, Manoela Tiago, Kristine Lou, Pan-Yu Chen, Somaneth Chowdhury, Glenn Mersky, Nir Hacohen, John Lamar, Claudia Capparelli, Gideon Bollag, Andrew Aplin. Targeting TAZ-TEAD in minimal residual disease enhances the duration of targeted therapy in melanoma models [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 7201.
Abstract 7354: Proteogenomic and metabolomic characterization of acute myeloid leukemia
Authors: Chu Alec , Hsiao Yi , Deng Yamei , Wang Chenwei , Kyle Jennifer , Dou Yongchao , Pino James C. , Posso Camilo , Henry Leanne , Chen Lijun , Li Ginny Xiaohe , Lih Tung-Shing Mamie , Geffen Yifat , Yu Fengchao , Ding Li , Omenn Gil , Kumar Chandan , Dhanasekaran Saravana M. , Traer Elie , Tyner Jeffrey W. , Zhang Hui , Liu Tao , Gosline Sara , Zhang Bing , Chinnaiyan Arul , Nesvizhskii Alexey I. , Cieslik Marcin ,   The CPTAC Consortium
Published: March 2024

Acute myeloid leukemia (AML) is a blood malignancy of poor prognosis with marked heterogeneity. To elucidate the underlying mechanisms that drive AML as part of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) effort, we performed comprehensive genomics, transcriptomics, proteomics including multiple post-translational modifications (phosphorylation, acetylation, and glycosylation), metabolomics, and lipidomics characterization of 173 treatment-naïve AML patients. Applying the similarity network fusion method on both transcriptomics and proteomics data, we identified 8 proteogenomic clusters. These clusters recapitulate specific recurrent mutations and established clinical subtypes available within the cohort. We used single-cell RNAseq data as a reference to perform immune component analysis for collected bulk samples. The result reveals that our proteogenomic clustering also captures the variations of AML differentiation hierarchies including CD14+ monocyte-like and GMP-like AML. To assess the complex disease nature of AML, we performed functional analysis for each cluster to reveal interplay between multiple genomic aberrations such as NPM1, FLT3-ITD, DNMT3A mutations, complex chromosomal alterations, and the leukemia cell differentiation. Importantly, the multi-omics analysis performed not only connects previously identified molecular drivers and cell differentiation variations within AML, but also links them with observed cancer metabolomic reprogramming with their drug response implications. Moreover, our study also identified site-specific post-translational modifications previously not known in AML, highlighting the valuable insights and clinical relevance of these newly identified clusters.

Citation Format: Alec Chu, Yi Hsiao, Yamei Deng, Chenwei Wang, Jennifer Kyle, Yongchao Dou, James C. Pino, Camilo Posso, Leanne Henry, Lijun Chen, Ginny Xiaohe Li, Tung-Shing Mamie Lih, Yifat Geffen, Fengchao Yu, Li Ding, Gil Omenn, Chandan Kumar, Saravana M. Dhanasekaran, Elie Traer, Jeffrey W. Tyner, Hui Zhang, Tao Liu, Sara Gosline, Bing Zhang, Arul Chinnaiyan, Alexey I. Nesvizhskii, Marcin Cieslik, The CPTAC Consortium. Proteogenomic and metabolomic characterization of acute myeloid leukemia [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 7354.
Abstract 7423: BATCH-FLEX: Feature-level equalization of x-batch in heterogeneous cancer data
Authors: Davis Joshua , Obermayer Alyssa , Duong Thac , Hesterberg Rebecca , Wang Xuefeng , Teng Mingxiang , Grass G. Daniel , Shaw Timothy
Published: March 2024

Purpose: Develop a shiny application to help integrate cancer datasets and guide researchers in selecting an appropriate method of correction for their technical artifacts.

Description: Integrative analysis of heterogeneous expression data remains challenging due to variations in platform, RNA quality, sample processing, and other unknown technical effects. As the field performs omics profiling of samples from cancer patients and murine models, there is the need for harmonizing, identifying, and correcting these technical effects to ensure robust analysis on the treatment and conditional effects of the underlying genetics or biological events. However, selecting and implementing different approaches for removing unwanted batch effects can be a time-consuming and tedious process, especially for more biologically focused investigators. In this project, we present Shiny BATCH-FLEX, a Shiny app to rapidly visualize batch correction by established batch correction methods such as ComBat, Mean Centering, ComBatSeq, and Limma RemoveBatchEffect. With BATCH-FLEX, users can visualize the contribution of variance of a factor before and after correction using principal component analysis, relative log expression plots, heatmaps, and explanatory variables. Users can also save all plots and matrices as a single ZIP file for further downstream analysis.

Results: As a proof of concept, we assessed BATCH-FLEX using simulated data generated from a linear model framework introduced by Gagnon-Bartsch and Speed, which assumes that gene expression measurements can be distilled to a combination of the biological signal, systemic nose, and random noise. BATCH-FLEX was able to successfully identify and remove the introduced effect using each of the batch correction methods listed above. Next, we evaluated BATCH-FLEX using a comprehensive collection of bladder cancer data consisting of microarray data from 13 studies spanning 1452 samples. Following the cleaning of study-dependent noise, BATCH-FLEX was successful in revealing the heterogeneity among bladder cancer based on known sample type annotations.

Conclusion: We have developed BATCH-FLEX, a tool for oncologic researchers to rapidly assess, select, and implement commonly used batch correction methods. This tool is available at https://github.com/shawlab-moffitt/BATCH-FLEX. Our integrative web portal of a Bladder Cancer Resource for Translational Science (BEACON) will also be shared at the meeting.

Citation Format: Joshua Davis, Alyssa Obermayer, Thac Duong, Rebecca Hesterberg, Xuefeng Wang, Mingxiang Teng, G. Daniel Grass, Timothy Shaw. BATCH-FLEX: Feature-level equalization of x-batch in heterogeneous cancer data [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 7423.
Abstract 7567: In-depth mass cytometry analysis reveals different immune cell composition of unique molecular subtypes in extensive stage small-cell lung cancer
Authors: Li Yuekang , Qu Jingjing , Wu Binggen , Shen Qian , Sun Wenjia , Chen Lijun , Wang Bo , Ying Lixiong , Zhou Jianya , Zhou Jianying
Published: March 2024

Background: A novel molecular subtype classification was fashionable for small cell lung cancer (SCLC). However, the distribution of SCLC molecular subtype classification in Chinese patients were unknown, especially extensive stage (ES)-SCLC. It should validate and define their associated microenvironments across subtypes in ES-SCLC.

Method: We used immunohistochemical (IHC) to evaluate SCLC markers of the subtypes including ASCL1, NEUROD1, POU2F3, SCLC-A/N/P in 135 ES-SCLC tumors. Peripheral blood of 24 ES-SCLC patients was test by mass cytometry using time-of-flight (CyTOF) to evaluate the differences in immune subsets regard to the subtype tumor microenvironment (TME). Validation was performed using flow cytometry and multiplex IF.

Results: ASCL1, NEUROD1, POU2F3, and Inflamed were account for 60.7%, 28.9%, 7.4%, and 18.5% of SCLC tumors, respectively. Significant intratumoral heterogeneity was observed with 15.6% of the tumors being both positive for SCLC-A and -N subtype markers, respectively. The SCLC-I type possessed more CD8+ T-cells infiltration and had higher frequency an ‘inflamed’ immunophenotyped. CyTOF data showed greater CD161+CD127+CD8+T cells proportion in SCLC-I than SCLC-N subtypes before and after anti-immunotherapy. Furthermore, we validated that lung tissue of SCLC-I were infiltrated more CD161+CD127+CD8+T cells compared to SCLC-N subpopulation(P=0.0281). Flow cytometry further showed the stronger immune activation of CD161+CD127+CD8+T cells in SCLC-I types induced higher expression of GZMB and GNLY and lower-expression of T-cell exhaustion markers PD-1,TIGIT and LAG3 in comparison with SCLC-N types. We further confirmed that the high level of CD161+CD127+CD8+T associated with a favorable treatment response and prolonged overall survival.

Conclusion: The present study validated the molecular subtypes in ES-SCLC patients. Furthermore, SCLC-I subtype has longer PFS and OS than SCLC-A, -N and -P patients. Our research not only provides an insight into the immune landscape of ES-SCLC but also sheds light on a special subset of CD161+CD127+CD8+T cells with prognostic and therapeutic significance.

Citation Format: Yuekang Li, Jingjing Qu, Binggen Wu, Qian Shen, Wenjia Sun, Lijun Chen, Bo Wang, Lixiong Ying, Jianya Zhou, Jianying Zhou. In-depth mass cytometry analysis reveals different immune cell composition of unique molecular subtypes in extensive stage small-cell lung 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 7567.