tbuckley/cabot-search huggingface dataset:
Abstract 7361: The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma
Authors: Yahia E. Salem, Bayan O. Abu Alragheb
Journal: Cancer Research (2024)

Abstract Background: Temozolomide has been extensively utilized in the treatment of gliomas across various grades, offering significant therapeutic benefits. However, the impact of concurrent mutations in TP53 and other tumor suppressor genes (TSG) on treatment outcomes in patients with IDH1 mutant low-grade glioma (LGG) treated with temozolomide remains to be fully understood. This study aims to explore the influence of these genetic factors on the response to temozolomide therapy, focusing on identifying potential genetic markers that can predict therapeutic outcomes. Methods: Our study exclusively analyzed The Cancer Genome Atlas (TCGA) LGG PanCancer dataset from cBioPortal, focusing on IDH1 mutant cases treated with temozolomide. Data analysis was carried out using Python 3.11. The cohort was categorized based on genetic alterations: TP53 mutation with additional TSGs (ATRX, CIC, FUBP1, NOTCH1) mutations (TP53mut/TSGmut), TP53 mutation without additional TSG mutations (TP53mut/TSGwt), and no TP53 mutations (TP53wt). Results: In our study, 178 LGG samples with IDH-1 mutation treated with temozolomide were selected. Of these, 113 samples had a mutation in TP53, and 88 had an additional mutation in a TSG. For TP53mut/TSGmut compared to TP53wt, the analysis revealed significant differences in clinical outcomes (PFS: HR 1.95, CI: 1.17-3.26, p=0.011; OS: HR 1.6, CI: 1.13-2.26, p=0.008). When comparing TP53mut/TSGwt with TP53mut/TSGmut, the findings were (PFS: HR 1.36, CI: 0.63-2.92, p=0.432; OS: HR 0.93, CI: 0.31-2.79, p=0.896). Finally, the comparison between TP53wt and TP53mut/TSGwt showed (PFS: HR 1.45, CI: 0.62-3.39, p=0.397; OS: HR 2.31, CI: 0.64-8.3, p=0.200). Conclusion: The presence of concurrent mutations in TP53 and other TSGs in IDH1 mutant LGG patients (TP53mut/TSGmut) is indicative of a more aggressive disease course and reduced response to temozolomide treatment, as evidenced by significantly worse clinical outcomes. In contrast, the TP53mut/TSGwt group did not exhibit significant differences in treatment outcomes. These findings underscore the importance of detailed genetic profiling in developing personalized treatment strategies for this patient population. Citation Format: Yahia E. Salem, Bayan O. Abu Alragheb. The prognostic value of TP53 and tumor suppressor gene mutations in temozolomide-treated IDH1 mutant low-grade glioma [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 7361.
Abstract 2829: Strategies to overcome challenges in randomization and grouping methodologies in <i>in vivo</i> studies using the power of animal study workflow software
Authors: Raghu Ramachandra
Journal: Cancer Research (2024)

Abstract Preclinical research in Oncology requires using a wide variety of animal models. Robust, clinically relevant distribution methods including randomized and non-random methods appropriate to the model are essential to ensure unbiased group assignments and reliable experimental outcomes. This presentation will explore flaws and inconveniences in prevalent randomization methods and strategies to overcome them using animal study workflow software and demonstrate the power of each with unique examples. Strategies for randomizing individual animals into groups and randomizing mouse cages into groups will be explored. Strategies for exclusion criteria, robust documentation, multi-parameter randomization, re-randomization, and clinical relevance of these strategies will be discussed. Standardization and automation of distribution methods help improve process integrity, research quality, and reproducibility. Citation Format: Raghu Ramachandra. Strategies to overcome challenges in randomization and grouping methodologies in in vivo studies using the power of animal study workflow software [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 2829.
Abstract 2156: Exploring barriers to colorectal cancer screening among adult male immigrants in Salt Lake City
Authors: Olanrewaju Olusola Onigbogi, Kebba Kah, Kolawole Okuyemi
Journal: Cancer Research (2024)

Abstract Background: The United States (U.S) foreign-born population aged 65+ increased substantially between 1990 and 2010 with migrants from Africa and the Middle East being a part of these new refugee admissions. According to 2010 data, socioeconomic disparities and reduced access to health care is common in this population with 16 percent of foreign-born elderly living below the poverty threshold in comparison with 8 percent of U.S.-born elderly. Colorectal Cancer (CRC) is the second leading cause of cancer related deaths in the U.S despite being easily preventable and treatable. Studies among male African Americans reveal a CRC incidence &amp;gt;20% higher than what obtains among whites. Since, genetic factors are believed to contribute as much as 35% to the overall risk of CRC, male adult immigrants aged 45 years and above from Africa and the Middle East may be at increased risk of developing the disease. Determining CRC screening uptake in this population will be critical in planning interventions which may ultimately reduce disparities in CRC-related morbidity and mortality in the future. Methods: We conducted a mixed methods study comprising administration of questionnaires and organizing four Focus Group Discussion (FGD) sessions among adult males in Salt Lake City who identified as refugees from Africa or the Middle East. The sessions were audio-taped, transcribed and coded using the Dedoose software. Results: We had thirty-one participants who were between 45 and 64 years of age. Twenty-five of them (83%) reported awareness of the existence of CRC screening tests. Ten participants (33%) had undergone a CRC test in the past. However, only nine participants (30%) indicated that they will be willing to participate (WTP) in CRC screening if offered for free. Increased WTP was associated with younger age (OR=1.45, 95% CI: 1.23-1.81), length of stay in the United States (OR=1.41, 95% CI: 1.13-1.78) and higher education (OR= 1.26, 95% CI 1.13-1.37). Three major themes identified in the FGDs include: (1) Mistrust - distrust of the US health system (2) Fear - fear of cancer and nature of test and (3) Fatalism - the belief that screening cannot lead to cancer cure. Conclusion: The low level of WTP in CRC screening tests among the respondents may be associated with past experiences. There may be a need to consider the correlates of increased WTP and explore culture-specific CRC prevention measures in planning interventions designed to improve screening uptake in this population. Citation Format: Olanrewaju Olusola Onigbogi, Kebba Kah, Kolawole Okuyemi. Exploring barriers to colorectal cancer screening among adult male immigrants in Salt Lake City [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 2156.
Abstract 282: <i>SFRP4+</i> cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach cancer
Authors: Seungho Lee, Austin Cho, Hyoung-Il Kim, Hoon Hur, Jae-Ho Cheong, Tae-Min Kim
Journal: Cancer Research (2024)

Abstract Cancer-associated fibroblasts (CAFs), a pivotal component in the tumor microenvironment (TME) of gastric cancer (GC), play a crucial role in tumor progression and resistance to treatment. In this study, we performed analyses to build a comprehensive cellular landscape of fibroblasts in GC EMT using three single-cell RNA cohorts including ours (GSE183904, GSE134520 and GSE167297). We observed distinct fibroblast subtypes (CXCL14+/POSTN+, CXCL14+/APOE+, SFRP4+, and SFRP2+ fibroblasts). Among the subtypes, we observed that SFRP4+ fibroblasts sharing cellular origins with normal tissue-residing SFRP2+ myofibroblasts. Notably, SFRP4+ fibroblasts showed a regional prediction for tumor and deep tumor layers compared to normal and superficial tumor layers, respectively. To further understand the role of these fibroblasts, we employed spatial transcriptome data. Spatially resolving the cellular interactions within the TME, the adjacency of SFRP4+ CAFs to malignant cells undergoing epithelial-to-mesenchymal transition (EMT), was observed. Ligand-receptor analyses demonstrated SFRP4+CAFs regulate key genes of EMT in malignant cells (TGFBI, COL1A1, SPARC, COL3A1, COL1A2, and BGN). The regulatory roles of SFRP4+ CAFs in driving the epithelial-mesenchymal transition (EMT) of malignant cells were further validated in vitro. Clinical relevance was also demonstrated with the correlation between the abundance of SFRP4+ CAF and clinical outcomes, i.e., high SFRP4+CAF abundance was consistently associated with shorter survival of GC patients across cohorts. Thus, we present SFRP4+ CAFs as major fibroblast subtypes in GC TME. Spatial cellular architectures and in vitro evidence support that SFRP4+fibroblasts activate the EMT of malignant cells along with their association with patient prognosis. This study advances our understanding into the mechanistic roles of SFRP4+ fibroblasts in GC pathogenesis and progression, paving the way for potential targeted therapeutic strategies. Citation Format: Seungho Lee, Austin Cho, Hyoung-Il Kim, Hoon Hur, Jae-Ho Cheong, Tae-Min Kim. SFRP4+ cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach 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 282.
Abstract 721: Novel and distinctive anti-HLA-G antibody, IMB-201, inhibits tumor progression by breaking immune escape mechanism and enhancing cytotoxicity
Authors: Hyeonju Kang, Seungil Baek, Inyoung Lee, Manseok Ju, Seonggu Han, Eunjung Han, Sungmuk Kang, Jihye Koo, Yoojin Kim, Suho Park, Eunyoung Cho, Chungmin Lee, Gyongsik Ha
Journal: Cancer Research (2024)

Abstract Human leukocyte antigen-G (HLA-G), a type of MHC class I, is known to be expressed only in the placenta and acts as an immune suppressor to protect the fetus from maternal immunity. Recent studies have revealed that HLA-G suppresses various tumor-infiltrated immune cells, such as T cells, NK cells, and macrophages, through interaction with inhibitory receptors Ig-like transcript 2 (ILT2). HLA-G has recently emerged as an attractive anticancer target because HLA-G is a highly specific tumor antigen and has a role in immune evasion of cancer cells. Additionally, the expression pattern of ILT2 differs from that of PD-1 in tumor-infiltrated CD8+ T cells. Therefore, an HLA-G targeting strategy is expected to be an alternative to address unmet medical needs for those not responding to anti-PD(L)1 therapies. In this study, we screened the novel anti-HLA-G antibody, IMB-201, using phage display technique and confirmed that IMB-201 selectively bound to the membrane HLA-G of cancer cells. It exhibited superior activities in ILT2 blockade, NK cell activation, and antibody-dependent cellular cytotoxicity (ADCC) compared to the reference antibody. Furthermore, IMB-201 demonstrated more efficient suppression of tumor growth compared to the reference antibody in subcutaneous gastric cancer xenograft model. Notably, the group administered IMB-201 with NK92MI cells (CD16-negative NK cells) in the ovarian cancer xenograft model showed stronger tumor growth inhibition compared to the group treated only IMB-201, indicating that NK92MI cells were activated by IMB-201. This result indicates that one of the mechanisms of action (MoA) of IMB-201 worked effectively in vivo. In addition, to maximize the efficacy of IMB-201 and differentiate it from competitors, various efficacy enhancing modality could be applicable. We aim to develop biopharmaceuticals by selecting the optimized modality. Based on these results, IMB-201 could overcome the limitations of existing cancer immunotherapy, potentially becoming highly influential in cancer treatment as a novel immune checkpoint inhibitor. It is also expected to exhibit higher anticancer efficacy in combination therapy with immune checkpoint inhibitors. Citation Format: Hyeonju Kang, Seungil Baek, Inyoung Lee, Manseok Ju, Seonggu Han, Eunjung Han, Sungmuk Kang, Jihye Koo, Yoojin Kim, Suho Park, Eunyoung Cho, Chungmin Lee, Gyongsik Ha. Novel and distinctive anti-HLA-G antibody, IMB-201, inhibits tumor progression by breaking immune escape mechanism and enhancing cytotoxicity [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 721.
Abstract 1465: Studying basal cell adaptation in the airways in response to chronic tobacco exposure
Authors: David Osuna de la Peña, Zornitsa Stoichkova, Moritz Jakob Przybilla, Charlotte Percival, Sarah E. Clarke, Kate H. Gowers, Peter J. Campbell, Sam M. Janes
Journal: Cancer Research (2024)

Abstract Premalignant lesions in the airways are preceded by the accumulation of cells with a high mutational load, many of which carry driver mutations. Our previous work suggests this is a dynamic process: tobacco smoking increases the size of mutated clones, which contain shorter telomeres and higher Ki67, while smoking cessation appears to be associated with the expansion of clones with near-normal mutational burden and an overall reduction in Ki-67 expression. To understand how these long-term changes take place, we have performed ex vivo functional assays to quantify the competitive advantage imparted by smoke. We have then explored the transcriptomic landscape of these cultures to determine how differential smoke exposure modulates epithelial cell dynamics before and after smoking cessation. Primary basal cells from bronchial explants were co-cultured following different regimes of exposure to cigarette smoke extract (CSE). We find that, upon acute exposure, pre-exposed cells have a ~20% higher chance of proliferating per week than smoke-naïve cells. To test this in a more physiological model, long-term epithelioid cultures were established with chronic exposure to low-dose CSE for months. As before, we observe that over time, pre-exposed cells outcompete the smoke-naïve, suggesting that smoke imparts a beneficial adaptation on re-exposed cells even at low doses. To elucidate this mechanism, we performed RNA sequencing of 48 different combinations of acute and chronic exposure to CSE. Genes were classified into distinct modules according to their regulation following exposure, re-exposure and cessation. Differential expression analysis and gene set enrichment analysis showed that metabolic pathways, including both nutrient and detoxification pathways, are predominantly enriched in these modules. In particular, following cessation, cells with the highest cumulative exposure to CSE displayed senescent-like features which are suppressed with chronic re-exposure. Further analysis and in vivo validation of these results will help elucidate how these changes affect the likelihood of premalignancy and may provide valuable targets for cancer prevention. Citation Format: David Osuna de la Peña, Zornitsa Stoichkova, Moritz Jakob Przybilla, Charlotte Percival, Sarah E. Clarke, Kate H. Gowers, Peter J. Campbell, Sam M. Janes. Studying basal cell adaptation in the airways in response to chronic tobacco exposure [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 1465.
Abstract 2080: SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant cancer
Authors: Matthew J. Sale, Neal Mukherjee, Martín Koch, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Thomas Madensky, Robyn L. Schenk, Anke Baum, Kaja Kostyrko, Daniel Gerlach, Marco H. Hofmann, Frank McCormick
Journal: Cancer Research (2024)

Abstract SOS1 is a principal guanine nucleotide exchange factor for canonical RAS GTPases and activates RAS signaling. Mutations in SOS1 are found in several prominent cancer types, including 2-4% of NSCLC, CRC, and melanoma. The recent development of novel SOS1 inhibitors (SOS1i), including BI-3406, that block interaction between SOS1 and RAS, presents a potential therapy for SOS1-driven cancers. Here we show that the majority of SOS1 mutations observed in patients enhance RAS guanine nucleotide exchange in cells and activate RAS-MAPK signaling. We treated 11 SOS1 mutant cancer cell lines without RAS co-mutation with a SOS1i and found that 10 were sensitive to SOS1 inhibition in 2D and/or 3D cell culture. In contrast, cell lines with SOS1 and RAS co-mutations were resistant to SOS1 inhibition. In vitro treatment of SOS1 mutant cells with a SHP2 inhibitor, which is presumed to inhibit the activity of both SOS1 and SOS2, revealed a subset of four cell lines that were more sensitive to SHP2 inhibition than SOS1 inhibition. This implied that, in certain contexts, SOS2 can compensate for the loss of SOS1 activity. Accordingly, these cells exhibited a SOS2-dependent rebound in RAS-MAPK signaling after treatment with SOS1i. SOS2 knock-down further sensitized these cells to SOS1 inhibition, resulting in responses equivalent to SHP2 inhibition. Thus, upon SOS1 inhibition relief of ERK1/2-dependent negative regulation likely contributes to receptor tyrosine kinase-driven SOS2 activation that may mediate SOS1 inhibitor resistance in some contexts. In vivo, SOS1i efficiently inhibited tumor growth in four SOS1-mutant NSCLC, CRC, and AML xenograft models. The tumor-suppressive effects of SOS1i in these models were comparable to or stronger than the effects of SHP2i or MEKi. Thus, our results suggest that SOS1 inhibition could be an effective therapeutic approach in RAS wild-type cancer patients with SOS1 mutations. Citation Format: Matthew J. Sale, Neal Mukherjee, Martín Koch, Regina Ruzicka, Robin Jacob, Christoph Albrecht, Teresa Zanin, Thomas Madensky, Robyn L. Schenk, Anke Baum, Kaja Kostyrko, Daniel Gerlach, Marco H. Hofmann, Frank McCormick. SOS1 inhibition is an effective therapeutic strategy in SOS1-mutant 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 2080.
Abstract 4661: A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models
Authors: Lu Yang, Arup Bhattacharya, Darrell Peterson, Yun Li, Xiaozhuo Liu, Elisabetta Marangoni, Valentina Robila, Yuesheng Zhang
Journal: Cancer Research (2024)

Abstract Background: HER2 is an oncogenic receptor tyrosine kinase (RTK) implicated in several types of human cancer. It is strongly expressed in about 20% of breast cancer (BC), known as HER2-positive BC (HER2+ BC), due to gene amplification. HER2 amplification or overexpression is a strong predictor of poor disease prognosis. HER2-targeted therapies are the linchpin of treating HER2+ BC. However, drug resistance is common. The main resistance mechanism is unknown. We exploited cell lines and mouse models (orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of therapy-resistant HER2+ BC) for experiments of genetic and pharmacologic depletion of HER2 and its family member EGFR, analysis of RTKs and no-RTKs, and evaluation of cell and tumor growth, to delineate the mechanism of HER2+ BC resistance to HER2 inhibitors and assess the therapeutic activity of PEPDG278D. PEPDG278D, a recombinant human protein, is the first-in-class dual degrader of HER2 and EGFR. Results: Trastuzumab-resistant HER2+ BC cells and tumors are highly vulnerable to targeted degradation of HER2 and EGFR. Trastuzumab is the most commonly used HER2 inhibitor in the clinic. Targeted degradation of HER2 and EGFR by PEPDG278D, which binds to their extracellular domains, causes extensive inhibition of oncogenic signaling proteins in HER2+ BC cells resistant to trastuzumab. This is accompanied by strong growth inhibition of cultured cells, orthotopic patient-derived xenografts, and metastatic lesions in the brain and lung of trastuzumab-resistant HER2+ BC. siRNA knockdown shows that eliminating both HER2 and EGFR is important to maximize therapeutic outcome. Collectively, our results reveal the key vulnerability of trastuzumab-resistant HER2+ BC and shows a promising strategy that overcomes trastuzumab resistance by targeting this vulnerability. Conclusions &amp; Therapeutic Relevance: This study identifies a key therapeutic vulnerability of drug-resistant HER2+ BC and shows that an agent that targets this vulnerability is highly effective in overcoming drug resistance in this disease. The findings provide new insights and innovations to advance treatment of drug-resistant HER2+ BC that remains an unmet problem. Citation Format: Lu Yang, Arup Bhattacharya, Darrell Peterson, Yun Li, Xiaozhuo Liu, Elisabetta Marangoni, Valentina Robila, Yuesheng Zhang. A dual degrader of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer 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 4661.