tbuckley/cabot-search huggingface dataset:
Abstract 3852: Comprehensive genomic profiling of recurrent or metastatic head and neck cancer presenting with combined positive score 90 or more
Authors: Yuki Saito, Kage Hidenori, Kenya Kobayashi, Osamu Fukuoka, Koji Yamamura, Aya Shinozaki-Ushiku, Katsutoshi Oda, Kenji Kondo
Journal: Cancer Research (2024)

Abstract Background. Biomarkers that predict response to immune checkpoint inhibitor (ICI) in recurrent metastatic squamous cell carcinoma of the head and neck (RMHNSCC) are not well known. Previously, we have found that Combined positive score (CPS) ≥90 and albumin &amp;gt;3.5 respond well to ICI treatment in patients with RMHNSCC treated with ICI irrespective of addition of chemotherapy. In the present study, we investigated whether RMHNSCC with CPS ≥90 has a characteristic genomic mutational profile. Methods. CPS measurements were performed on a single tumor specimen at the time of diagnosis of RMHNSCC, as approved by Japanese health insurance. Tumor specimens were obtained from the primary tumor as much as possible, and sections that best reflected anti-tumor immunity were decided by a pathologist. We retrospectively reviewed the results obtained from comprehensive genomic profiling (CGP) testing of RMHNSCC cases with CPS ≥90 who were treated by ICI experienced at our institution. Results. There were 117 eligible RMHNSCC cases. The number of primary lesions were oral cavity in 28 cases (23.9%), nasopharynx in 10 cases (8.5%), oropharynx in 21 cases (17.9%), hypopharynx in 33 cases (28.2%), and others in 18 cases (15.4%). Of 117 patients, 28 patients (23.9%) had a CPS ≥90. Of the 28 cases, the number of primary lesions were oral cavity in 12 cases (42.9%), nasopharynx in 4 cases (14.3%), oropharynx in 0 cases (0%), hypopharynx in 8 cases (28.6%), and others in 3 cases (10.7%). When ICI was administered, CPS ≥90 had a statistically significantly better prognosis than CPS &amp;lt;90 for OS and PFS. Of the 28 cases with CPS ≥90, CGP test was performed in 6 cases. The primary lesions in the 6 cases consisted of 3 oral cavity, 2 nasopharynx, 1 hypopharynx, and 1 maxillary sinus. All three oral primary cases had co-mutations in the TERT promoter and HRAS. Two of the nasopharyngeal primary cases had mutations in JAK3 and STAT, respectively. One of the hypopharyngeal primary cases had mutations in FGFR3. Conclusion. RMHNSCC with CPS ≥90 had unique mutations that could account the enhanced PD-L1 expression, such as TERT/HRAS co-mutation, JAK-STAT pathway mutation, and FGFR pathway mutation. The above findings may be useful for predicting the efficacy of ICI for RMHNSCC. Citation Format: Yuki Saito, Kage Hidenori, Kenya Kobayashi, Osamu Fukuoka, Koji Yamamura, Aya Shinozaki-Ushiku, Katsutoshi Oda, Kenji Kondo. Comprehensive genomic profiling of recurrent or metastatic head and neck cancer presenting with combined positive score 90 or more [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 3852.
Abstract 1770: Right oncogene, wrong tumor - CBL mutations in pediatric CNS and solid tumors
Authors: Lauren M. Brown, Chelsea Mayoh, Pablo Acera Mateos, Antoine De Weck, Robert Salomon, Teresa Sadras, Neevika Manoharan, Marie Wong, Mark J. Cowley, Paul G. Ekert
Journal: Cancer Research (2024)

Abstract The molecular analysis of individual patient tumors by personalized medicine programs like the Zero Childhood Cancer Program (ZERO) enables the detection of potentially targetable lesions, unlocking new therapeutic opportunities for patients. Somatic mutations in the E3-ubiquitin ligase, CBL, are known to activate receptor tyrosine kinases (RTKs) in cancer and have been exclusively characterized in hematological malignancies. This includes acute myeloid leukemia, where CBL mutations lead to FLT3 activation. Using molecular data from ZERO we have identified known and novel CBL variants in novel tumor contexts. Our findings raise the possibility that CBL mutation may be a marker of RTK activation in a range of paediatric cancer types and may represent a group of patients who could benefit from tyrosine kinase inhibitor (TKI) therapy. We analyzed whole genome and RNA sequencing data from the ZERO cohort and identified 26 somatic CBL variants in 22 individual patients, the majority of which were in CNS tumors (14 patients). In 8 patients with CNS tumors, we identified missense and splicing variants, which were either novel or not previously seen in this tumor type, that are predicted to have a functional impact on CBL E3 ligase activity due to their location in the linker region or RING finger domain of CBL. Interestingly, most of these patients did not fall into a pre-defined DNA methylation-based subtype classification of CNS tumors and had no significant upregulation of RTK genes. In addition to the novel variants, we identified an established oncogenic CBL deletion variant, CBL exon 8/9 deletion (CBL ex8/9Δ), in novel tumor types - neuroblastoma and a germ cell tumor. Functionally, we show that overexpression of CBL ex8/9Δ enhances cell proliferation and maintains EGFR signaling by blocking CBL mediated degradation of phosphorylated EGFR in neuroblastoma cells. In this study, we demonstrate that CBL is mutated in a range of pediatric cancer types beyond hematological malignancies and may represent a marker of RTK activation and a new target for high-risk patients with limited therapeutic options. Citation Format: Lauren M. Brown, Chelsea Mayoh, Pablo Acera Mateos, Antoine De Weck, Robert Salomon, Teresa Sadras, Neevika Manoharan, Marie Wong, Mark J. Cowley, Paul G. Ekert. Right oncogene, wrong tumor - CBL mutations in pediatric CNS and solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1770.
Abstract 5780: Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity
Authors: Bingbing X. Li, Jian Wang, Bo Chao, Jake Piesner, Felice Kelly, Stefanie Kaech Petrie, Xiangshu Xiao
Journal: Cancer Research (2024)

Abstract Protein synthesis and subsequent delivery to the target locations in cells are essential for their proper functions. Newly synthesized proteins and existing protein have differential properties that can potentially be exploited for targeting to maximize therapeutic potentials. Methods to label and distinguish newly synthesized proteins from existing ones are critical to assess their differential properties, but such methods are lacking. We describe the first chemical genetics-based approach for selective labeling of existing and newly synthesized proteins that we termed as CG-SLENP. Using HaloTag in-frame fusion with lamin A (LA), we demonstrate that the two pools of proteins can be selectively labeled using CG-SLENP in living cells (https://doi.org/10.1101/2023.11.02.565346). We further employ our recently developed selective small molecule ligand LBL1 for LA to probe the potential differences between newly synthesized and existing LA. Our results show that LBL1 can differentially modulate these two pools of LA. We further extend our CG-SLENP strategy to evaluate the differences of the two pools for BRD4 (bromodomain containing 4). These observed differences motivated us to investigate the synergistic anticancer properties of BRD4 degraders and inhibitors in triple negative breast cancer. Our results show that simultaneous targeting newly synthesized proteins and existing proteins display strong synergistic anticancer activities. Citation Format: Bingbing X. Li, Jian Wang, Bo Chao, Jake Piesner, Felice Kelly, Stefanie Kaech Petrie, Xiangshu Xiao. Simultaneous targeting existing proteins and nascent proteins for synergistic anticancer activity [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 5780.
Abstract 7400: AI-driven multimodal 3D tumor modeling with spatial molecular insights for predicting ICI response in gastric cancer
Authors: Yoon Ho Choi, Minji Kim, Katya Redekop, Inyeop Jang, Jean R. Clemenceau, Isabel Barnfather, Sumanth Reddy Nakkireddy, Changjin Hong, Sunho Park, Ji-Youn Sung, Jeong Hwan Park, Shitara Kohei, Aoki Yu, Sung Hak Lee, Sam Wang, Jaeho Cheong, Tae Hyun Hwang
Journal: Cancer Research (2024)

Abstract Traditional cancer research methodologies predominantly focus on 2D tumor modeling, including spatial profiling and AI-driven analysis at the 2D level. To advance beyond these limitations, we implemented Holotomography (HT), a 3D, label-free optical imaging method. This technique, leveraging refractive index contrasts, allows for enhanced visualization of tumor tissues, organoids, and cells in three dimensions. Using serial H&amp;E sections and unstained slides, we created detailed 3D tumor models in gastric cancer, providing insights into tumor, immune, and stromal composition, as well as cell-cell interactions and extracellular matrix characteristics. AI algorithms further enhanced our 3D tumor modeling, offering novel perspectives on the initiation and progression of tumor, immune, and stromal components at the subcellular level. Analyzing gastric tumors treated with immune checkpoint inhibitors before, during, and after treatment revealed dynamic changes in spatial composition over time, offering unique insights into the evolution of the 3D tumor ecosystem. Additionally, by integrating spatial transcriptomic and in situ molecular imaging data, we developed a novel Multimodal 3D Tumor Model. This model not only uncovers subcellular-level molecular characteristics but also elucidates cellular interactions during treatment, suggesting potential biomarkers and therapeutic approaches. Lastly, by constructing 3D cellular interaction networks incorporating true 3D interactions, we provided an in-depth view of cellular communication within the tumor microenvironment. This pioneering approach, representing the first Multimodal 3D Tumor Model at the subcellular level, offers novel insights into gastric cancer's spatial evolution, potentially revolutionizing our understanding and treatment of gastric cancer. Citation Format: Yoon Ho Choi, Minji Kim, Katya Redekop, Inyeop Jang, Jean R. Clemenceau, Isabel Barnfather, Sumanth Reddy Nakkireddy, Changjin Hong, Sunho Park, Ji-Youn Sung, Jeong Hwan Park, Shitara Kohei, Aoki Yu, Sung Hak Lee, Sam Wang, Jaeho Cheong, Tae Hyun Hwang. AI-driven multimodal 3D tumor modeling with spatial molecular insights for predicting ICI response in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7400.
Abstract 5794: DX2206, a humanized monoclonal antibody that targets IL1RAP, exhibits potent inhibition of IL-1 pathways and activities against tumors <i>in vitro</i> and <i>in vivo</i>
Authors: Qinghao Liu, Yaqi Ru, Yan Jiang, Huimin Li, Wenbo Li, Lan Yang, Qian Shi
Journal: Cancer Research (2024)

Abstract Background: The Interleukin-1 Receptor Accessory Protein (IL1RAP) is found on cancer cells, stromal cells, and infiltrating immune cells within the tumor microenvironment (TME) of various cancers. It plays an important role in tumor development at various stages by activating IL-1 superfamily pathway, thus become an interesting target in cancer treatment. Methods: We investigated the correlation between IL1RAP and tumor prognosis through the analysis of the public dataset. An antibody discovery campaign was performed and DX2206 was identified as the top clone against IL1RAP. Epitope of DX2206 was determined by examining the binding of DX2206 with different IL1RAP structural domains and in silico analysis. The activities of DX2206 against IL-1, IL-33, and IL-36 were examined using multiple assays with HEK293-Luc reporter cells, primary HUVEC cells, and A431 human skin squamous carcinoma cells. In vivo efficacy was evaluated in a CDX model. Results: Based on public data, IL1RAP is overexpressed in various types of cancer patients compared to healthy individuals, and high expression of IL1RAP is associated with poor prognosis in multiple cancer types. Furthermore, high expression of the members of the IL-1 superfamily, such as IL1RAP, IL-1, and IL-36, are negatively correlated with pan-Cancer OS. Our epitope analysis indicated that DX2206 binds to a unique epitope within IL1RAP domain 2. In vitro assays demonstrated that DX2206 inhibited the activities of all three pathways, IL-1, IL-33, and IL-36, with sub-nanomolar IC50s. Simultaneously, it induced a potent ADCC effect in the tumor killing assay. Finally, in a CDX model, DX2206 significantly inhibited tumor growth in vivo. Conclusions: We discovered a potent antagonist antibody, DX2206, that binds to a unique epitope of IL1RAP, inhibits all three pathways of signaling, and demonstrates in vitro and in vivo activities against tumors. Considering these characteristics, DX2206 emerges as an outstanding preclinical candidate for cancer therapy. IND enabling study was ongoing to expedite the candidate into clinic. Citation Format: Qinghao Liu, Yaqi Ru, Yan Jiang, Huimin Li, Wenbo Li, Lan Yang, Qian Shi. DX2206, a humanized monoclonal antibody that targets IL1RAP, exhibits potent inhibition of IL-1 pathways and activities against tumors in vitro and in vivo [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 5794.
Abstract 3115: Systematic analysis of gene mutations and therapeutic efficacy via <i>ex vivo</i> hematological vitroscreen platform
Authors: Fu-Ju Chou, Stefano Cairo, Mara Gilardi, Abhay Andar, Karin Abarca-Heidemann, Maria Mancini
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is a common hematological malignancy found in adult patients, and FMS-like tyrosine kinase 3 gene (FLT3) mutation occurs in about 30% of patients. In 2019, a phase 3 clinical trial suggested that gilteritinib treatment resulted in significantly longer survival than salvage chemotherapy in relapsed or refractory FLT3-mutated AML patients. Targeting FLT3-mutants in AML has become one of the important therapeutic strategies in this decade. The ex vivo hematological VitroScreen platform provides a powerful tool to evaluate the performance of FLT3 inhibitors and other test articles. With Champions Oncology’s primary hematological repository (https://www.championsoncology.com/hematological-vitroscreen) and proprietary LUMIN Bioinformatics platform, we classified models based on patient responses, clinical annotation, NGS data, and cell surface markers. In this Ex vivo study, we tested gilteritinib in 30 AML patients, and 8 of models were identified as FLT-3 mutants’ carrier. Fold changes of cell viability after gilteritinib treatment were assessed based on quantitation of the ATP present. FLT3-mutants models showed significantly higher sensitivity to gilteritinib than FLT3-WT models (IC50, 132.56 nM vs. 234.16nM) in a 6-day assay. Only 25% of models in the FLT3-mutants group had higher IC50 than the average of all AML models (n=28, IC50 = 204.05 nM), compared to 53% in the FLT3-WT group. Our preclinical data highly match the observations in previous clinical trials, which suggest that VitroScreen is a reliable high throughput tool for drug development of drug resistant cancers. Citation Format: Fu-Ju Chou, Stefano Cairo, Mara Gilardi, Abhay Andar, Karin Abarca-Heidemann, Maria Mancini. Systematic analysis of gene mutations and therapeutic efficacy via ex vivo hematological vitroscreen platform [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 3115.
Abstract 7415: Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment
Authors: Raviteja Vangara, Marcos Diaz-Gay, Mark D. Barnes, Xi Wang, S M Ashiqul Islam, Ian Vermes, Stephen Duke, Nithish Bharadhwaj Narasimman, Ting Yang, Zichen Jiang, Sarah Moody, Sergey Senkin, Paul Brennan, Michael R. Stratton, Ludmil B. Alexandrov
Journal: Cancer Research (2024)

Abstract Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. To evaluate the mutational signatures operative in a cancer genome, one first needs to quantify their activities by estimating the number of mutations imprinted by each signature, a process known as refitting of mutational signatures. Although multiple tools for refitting known signatures were developed in the past decade, most provide support almost exclusively for single base substitution signatures and lack an online interface. Further, these tools have never been compared, and no existing tool supports probabilistically assigning signatures to a single somatic mutation. Here, we present SigProfilerAssignment, a desktop and online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. The analysis of 2,700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures, with consistent top performance across cancer types and most signatures. SigProfilerAssignment stands out as the most precise and sensitive tool while maintaining high computational performance and bringing novel capabilities. SigProfilerAssignment is distributed as an open-source Python/R package available at https://github.com/AlexandrovLab/SigProfilerAssignment, with an online interface available as part of the COSMIC Mutational Signatures website at https://cancer.sanger.ac.uk/signatures/assignment/. Citation Format: Raviteja Vangara, Marcos Diaz-Gay, Mark D. Barnes, Xi Wang, S M Ashiqul Islam, Ian Vermes, Stephen Duke, Nithish Bharadhwaj Narasimman, Ting Yang, Zichen Jiang, Sarah Moody, Sergey Senkin, Paul Brennan, Michael R. Stratton, Ludmil B. Alexandrov. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment [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 7415.
Abstract 1669: KRAS G12X mutants display differential preferences in downstream effector binding
Authors: Leonard J. Ash, Ottavia Bourdain, Dennis Lam, Shlomo S. Pallas, Andrew L. Wolfe
Journal: Cancer Research (2024)

Abstract KRAS is among the most frequently mutated oncogenic driver proteins in human cancers including lung, colorectal, and pancreatic cancers. Activating KRAS mutants cause increased cell proliferation through direct binding and overactivation of effector proteins. Effector activation preference is driver mutation specific, as KRAS G12D and G12C purportedly bind both RAF and PI3K, whereas G12R has been reported to bind RAF but not PI3K. The mechanisms of effector binding of G12S action are under-investigated. Furthermore, most KRAS mutations remain clinically untreatable, as clinically approved KRAS inhibitors (KRASi) are currently limited to specifically targeting G12C. While experimental non-G12C inhibitors are being developed, resistance mechanisms to non-G12C mutations—including G12D/R/S/V—remain relatively understudied. We set out to characterize the binding efficiency of KRAS to RAF1 and the PI3K subunit p110α, and to understand how isoforms differ in inhibitor resistance strategies. Our findings suggest that significant variances in KRAS mutation-specific effector binding preference exist and are cell line dependent. We performed proximity ligation based immunofluorescence assays (PLA) on an isogenic panel of human colorectal SW48 KRAS cells with G12C/D/R/S/V or wildtype. SW48 cells with G12S significantly prefer the KRAS-RAF1 mode of binding over otherwise isogenic WT cells, and G12V homologs prefer PI3K. Our findings suggest that in this model, G12R cells have no specific preference of one binding mode over the other. We hypothesize that G12 chemistry drives effector binding preference and that G12X inhibitor resistant cell cultures will demonstrate variant mechanisms of resistance in line with their preferred binding partner. Ongoing studies will further characterize understudied RAS isoform biology and evaluate the links between isoform chemistry and mechanisms of inhibitor resistance. These studies will expand our mechanistic knowledge of the interplay between G12X chemistry and adaptive resistance in human cancer. Citation Format: Leonard J. Ash, Ottavia Bourdain, Dennis Lam, Shlomo S. Pallas, Andrew L. Wolfe. KRAS G12X mutants display differential preferences in downstream effector binding [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 1669.