tbuckley/cabot-search huggingface dataset:
Abstract 6145: A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical cancer
Authors: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew
Journal: Cancer Research (2024)

Abstract Introduction: Cervical cancer is the second most common cause of cancer-related deaths among women worldwide. Genome-wide association studies (GWAS) have identified genetic variants associated with cervical cancer. However, these discoveries have been limited by the small sample sizes of the individual cohorts. To identify additional novel loci associated with cervical cancer, we performed a trans-ethnic meta-analysis. Methods: GWAS summary data for trans-ethic meta-analysis were identified in women of European ancestry from the UK Biobank, East Asian ancestry from Biobank Japan, and African ancestries from the pan-UK Biobank and Johannesburg cancer study. Meta-analyses were performed using fixed effect inverse variance weighted method implemented in GWAMA. To localize putative genomic loci associated with cervical cancer, we performed fine mapping using the Bayesian approach by calculating the marginal posterior probability of causality for each single nucleotide polymorphisms (SNPs) and 99% credible set size. Results: Our meta-analysis identified four additional novel genomic loci associated with cervical cancer. These loci include: rs147778467 (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.16, P-value = 3.12 x 10-08) in RGS21, rs53150478 (OR =1.03, 95%CI = 1.01-1.05, P-value = 4.48 x 10-08) in MAN1C1, rs113842373 (OR = 0.68, 95%CI = 0.56-0.81, P-value = 2.31 x 10-09) in LINCO1850 and rs75372437 (OR = 0.80, 95%CI = 0.72-0.88, P-value = 3.32 x 10-08) in RNU6-356P. These loci are implicated in carcinogenic pathways. Moreover, our Bayesian fine mapping identified five loci with a marginal posterior probability of causality &amp;gt; 1 and reduced the 99% credible set sizes. Conclusion: We identified additional novel loci associated with cervical cancer and our fine mapping identified loci with a high posterior probability of being causal. Citation Format: Abram Bunya Kamiza, Jean-Tristan Brandenburg, Michele Ramsay, Christopher Mathew. A trans-ethnic meta-analysis identified additional novel genomic loci associated with cervical 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 6145.
Abstract 6198: <i>TP53</i> mutational clusters stratify the Li-Fraumeni syndrome spectrum
Authors: Nicholas W. Fischer, Brianne Laverty, Ran Kafri, Kara N. Maxwell, Emma R. Woodward, Christian Kratz, David Malkin
Journal: Cancer Research (2024)

Abstract Li-Fraumeni syndrome (LFS) is a highly penetrant cancer predisposition disorder caused by germline variants in the TP53 tumor suppressor gene. LFS has recently been redefined as a ‘spectrum’ disorder to reflect the highly variable cancer types with largely unpredictable ages-of-onset and disease severity. The broad functional gradient associated with different TP53 variants is thought to contribute to LFS heterogeneity, although it is still poorly understood and there is an unmet clinical need for risk stratification strategies to improve variant interpretation and patient care. Here, we performed an unsupervised cluster analysis leveraging p53 mutagenesis datasets (Kato et al., 2003 &amp; Giacomelli et al., 2018) that revealed five TP53 mutational clusters with unique mutation patterns, structural features, and functional consequences. Stratifying germline carriers based on the five clusters exposed important clinical characteristics to consider for patient management, such as ages-of-onset, tumor type development, and survival outcomes. In particular, we discovered an osteosarcoma-prone subgroup comprised of monomeric mutant p53 carriers with aggressive cancer phenotypes. We also identified a cluster of TP53 variants found more often in non-cancer and healthy older populations, and carriers of these variants that developed cancer had less “LFS-like” phenotypes including an older age-of-onset and a significantly higher frequency of colorectal cancers. Remarkably, our TP53 variant clustering strategy could also stratify breast cancer survival among germline carriers. This work provides a new framework to delineate the LFS spectrum toward the development of machine learning-based approaches for personalized cancer surveillance plans. Citation Format: Nicholas W. Fischer, Brianne Laverty, Ran Kafri, Kara N. Maxwell, Emma R. Woodward, Christian Kratz, David Malkin. TP53 mutational clusters stratify the Li-Fraumeni syndrome spectrum [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 6198.
Abstract 6233: Characterizing variants of uncertain significance in the tumor suppressor gene known as phosphatase and tensin homolog (PTEN)
Authors: Ajay P. Singh, Jasmine Wen, David Nguyen, Vedanta Khan, Kiran Dhami, Kaitlynn Meier-Ross, Benjamin Martin, Jesse T. Chao
Journal: Cancer Research (2024)

Abstract PTEN is an important tumor suppressor that plays an essential role in regulating cell proliferation. Loss of PTEN function is implicated in approximately 50% of metastatic cancers. Individuals with pathogenic PTEN variants are at significantly elevated risk of developing hereditary cancer syndromes such as PTEN hamartoma tumor syndrome. While genetic testing for PTEN is valuable for identifying individuals at risk, 47% of 3065 publicly reported PTEN variants are not conclusively classified; they either have conflicting interpretations of pathogenicity or are labeled as “Variants of Uncertain Significance (VUS)” and are not clinically actionable. The lack of a clear interpretation for these PTEN variants hinders the targeted care and surveillance of patients and places a strain on the healthcare system. To overcome this issue, our aim is to develop a clinically relevant tool for assessing the pathogenic effects of PTEN variants.We hypothesize that loss of function (LoF) PTEN variants will lead to changes in cellular phenotypic profiles that can be measured through single-cell phenotypic profiling. Thus, our goal is to investigate the functional status of exogenously expressed PTEN variants in PTEN-/- HEK 293 cells. We developed a multiplexed high content imaging assay to characterize PTEN and its key signaling partners such as phospho-Akt. Additionally, we developed a deep learning based single-cell phenotypic profiling pipeline named Paracell that uses subcellular segmentation to extract 540 phenotypic features. Cells that exhibit abnormal phenotypic profiles are indicative of loss of PTEN function. Preliminary results from testing 73 missense variants of PTEN showed that functional and LoF PTEN variants form distinctive clusters in a two-dimensional UMAP plot based on Paracell outputs, suggesting that our approach can identify potentially pathogenic variants of PTEN.Through characterizing novel VUS, we can elucidate structural domains involved in PTEN’s tumor suppressing activity. The result of these classifications will enable more optimized detection, diagnosis, and surveillance strategies for PTEN-related cancers. Ultimately, we aim to contribute to improving the genetic testing of PTEN and the development of targeted therapies. Citation Format: Ajay P. Singh, Jasmine Wen, David Nguyen, Vedanta Khan, Kiran Dhami, Kaitlynn Meier-Ross, Benjamin Martin, Jesse T. Chao. Characterizing variants of uncertain significance in the tumor suppressor gene known as phosphatase and tensin homolog (PTEN) [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 6233.
Abstract 6168: Sex-distinct patterns of molecular pathways associated with brain tumor edema
Authors: Pamela R. Jackson, Lee Curtin, Sara Ranjbar, Kyle W. Singleton, Maciej M. Mrugala, Richard S. Zimmerman, Bernard R. Bendok, Peter Canoll, Kristin R. Swanson
Journal: Cancer Research (2024)

Abstract Magnetic resonance imaging (MRI) is a centerpiece of clinical management of brain tumor patients, yet the biology underlying even commonly interpreted imaging changes is unclear. The purpose of this project was to understand what biology is associated with brain tumor edema abundance and if that association was sex distinct. We have developed a two-compartment model of MRI signal intensity to quantitatively estimate relative edema abundance from T2-weighted MRIs. Multiparametric MRIs were preprocessed with bias field correction and intensity normalization. The images were co-registered and segmented for abnormal regions and normal tissue. The segmentations and preprocessed images were utilized in the edema mathematical model to estimate the fraction of extracellular space (Fecs) and fraction of intracellular space (Fics). Through an ongoing image-localized biopsy collection protocol, we analyzed 179 samples (Female: 75; Male: 104) from 55 patients (Female: 21; Male: 34) for bulk RNA-Seq. Samples were characterized by their edema Fecs scores and underwent differential expression, gene set enrichment analysis using MSigDB hallmarks and cellular deconvolution using CIBERSORTx. Through differential expression and gene set enrichment analyses of these spatial biopsies, we have identified sex-distinct gene expression and pathways corresponding to regions of high vs low edema. Within highly edematous regions, male samples were amplified for respiratory pathways, while female samples were suppressed. Connecting changes on MRIs with molecular markers from image-localized biopsies provides an opportunity to identify the biological drivers of brain tumor associated imageable edema. Specifically, elucidating the sex-distinct patterns connecting changes on MRI with cellular populations and molecular pathways could be used to better interpret imaging of patients and interpreting treatment response. Citation Format: Pamela R. Jackson, Lee Curtin, Sara Ranjbar, Kyle W. Singleton, Maciej M. Mrugala, Richard S. Zimmerman, Bernard R. Bendok, Peter Canoll, Kristin R. Swanson. Sex-distinct patterns of molecular pathways associated with brain tumor edema [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 6168.
Abstract 6205: Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through <i>in silico</i> approach
Authors: Mei-Chi Su, Adam M. Lee, R. Stephanie Huang
Journal: Cancer Research (2024)

Abstract Prostate cancer (PC) remains a prominent cause of cancer-related mortality among men in the United States. A significant factor contributing to the mortality of PC patients is the development of resistance to second-generation antiandrogen therapies, particularly androgen receptor-signaling inhibitors (ARSI), which is pronounced in patients with late-stage PC, metastatic castration-resistance prostate cancer (mCRPC). Therefore, there is an urgent need for novel therapeutics beyond AR signaling inhibition for patients with mCRPC. One of the key drivers of resistance to ARSI and a critical feature of CRPC is cancer metabolism reprogramming to elevated glycolysis. However, the current research on finding drugs to impede high-glycolytic tumor growth is hurdled by a resistance raised from metabolic plasticity. The aim of this research is to quickly repurpose existing drugs for inhibiting high-glycolytic mCRPC growth while proactively circumstancing resistance from metabolic plasticity through computational approaches. To do this, we imputed a large number of drug responses in patients with mCRPC using a computational algorithm (OncoPredict), identified drugs that were projected to show higher sensitivity in high-glycolytic tumors, and performed in vitro validation. Furthermore, to maximize drug efficacy, we identified biomarkers for drug candidates. By implementing this computational pipeline, we identified a number of drugs with various mechanisms of action that show higher efficacy in mCRPC with high glycolysis. Furthermore, we successfully validated the efficacy of these nominated drug candidates including an anti-parasitic agent, an HSP90 inhibitor, and a CDK inhibitor. These drug candidates exhibited superior tumor growth inhibition in in vitro models of high glycolysis-induced advanced PC. In conclusion, this study introduces an innovative in silico approach to unveil the existing drugs’ unknown potential for the treatment of patients with mCRPC. Our findings hold promise for development of effective therapeutics for combating this challenging disease. Citation Format: Mei-Chi Su, Adam M. Lee, R. Stephanie Huang. Identify drugs for metastatic castration-resistance prostate cancer (mCRPC) patients with high glycolytic activity through in silico approach [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 6205.
Abstract 4718: Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma
Authors: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. There is a growing demand to develop and adapt new therapeutic options in order to combat the five-year survival rate of 6.8% and improve patient quality of life. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. While currently being classified to have an idiopathic mechanism of action, two specific cytotoxic consequences of ATO have emerged: MNK1 activity and oxidative stress. Across six GBM PDX models a 20-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. To correlate this to the proposed mechanisms of action, we observed ATO’s effect on MNK1 activity through eIF4E phosphorylation and glutathione (GSH) levels following treatment. A subset of GBM models exhibited a marked upregulation of eIF4E phosphorylation following treatment with 2 uM ATO. Of the six models, three were chosen to undergo further testing to observe whether this upregulation showed a consistent dose-dependent relationship across the models and correlated with vulnerability to ATO. Combination therapy with the MNK1 inhibitor, ETC-206, displayed mild to moderate synergy on overall cell viability and strong synergy when observing its effects on the glioma stem cell population. This preferential effect on the GSC populations suggests that MNK1i based combination strategies may show greater effectiveness in vivo than indicated by our previous in vitro studies. Nutraceuticals targeting GSH synthesis, Chrysin and Silibinin, displayed a 0.95 to 1.4-fold decrease in ATO IC50 values across all 6 models. To observe whether each nutraceutical impacted GSH levels consistently across all of the tested models, we measured GSH levels following treatment for each individual compound and their combination treatments. These findings further implicate MNK1 activity and cellular response to oxidative stress as markers of ATO sensitivity, however they are not the sole determinates of response. Understanding of the mechanism of action for idiopathic compounds may allow for the discovery of molecular signatures of sensitivity, improving patient selection for clinical trials and the development of new combination approaches to combat resistance in other tumor types. Citation Format: Charles Shaffer, Nanyun Tang, Yue Hao, Karen Fink, George Snipes, Bruce Mickey, Michael Berens. Reclaiming a dirty drug: What is the context of vulnerability to arsenic trioxide in glioblastoma [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 4718.
Abstract 2824: Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line
Authors: Justyna Zdrojewska, Katja Fagerlund, Jenni H. Mäki-Jouppila, Mari I. Suominen
Journal: Cancer Research (2024)

Abstract Prostate cancer is the second most common cancer in men with new cases diagnosed in 1.4 million men each year. Luckily the 5-year survival rates in developed countries are high reaching over 90%. However, approximately one third will develop a metastatic disease. In metastatic patients, prostate cancer almost always progresses despite the androgen deprivation therapy and is then referred to as “castration-resistant (mCRPC)”. Bone is involved in 80% of patients with metastasis, and the bone lesions are typically osteoblastic. The 22Rv1 human prostate carcinoma cell line is androgen sensitive and shown to express androgen receptor (AR). They also express low levels of prostate-specific membrane antigen (PSMA). The aim of this study was to establish orthotopic and intratibial preclinical in vivo prostate cancer models that can be used in drug development when targeting cancer cells and their local environment. Male athymic nude mice (5-6 weeks old) and NOG mice (over 20 weeks old) were used in the study. 2.5 × 105 22Rv1 cells (ATCC) were inoculated orthotopically into the prostate of NOG mice, and 5 × 105 cells were inoculated intratibially into the bone marrow cavity of athymic nude mice. Tumor growth was followed by PSA measurements every second week using Human PSA ELISA assay. In addition, in the intratibial model, tumor-induced bone changes were monitored by X-ray imaging of the hind limbs. Prostates and hind limbs were collected at sacrifice, fixed in 10% NBF, and processed to paraffin blocks for further histological analysis. Sections of prostate were stained with hematoxylin-eosin (HE) and AR. Tumor-bearing and contralateral (healthy) tibias were stained with HE - OrangeG, MGT, TRAP, and AR. The observed tumor take rate was 92% in the orthotopic and 100% in the intratibial models. Confirmed by IHC, tumors formed in both the orthotopic and intratibial models expressed AR. 22Rv1 cells formed osteoblastic - lytic mixed bone lesions in the intratibial model. Based on lesion areas, randomization of the tumor bearing mice in the intratibial model can be done after 2 weeks from cancer cell inoculation. Taken together, the 22Rv1 prostate cancer models are relatively fast growing, express AR and present good take rates. Furthermore, the intratibial model represents robust tumor-induced changes in bone with strong osteoblastic component. Thus, these models have several advantages in efficacy studies of novel drug candidates for prostate cancer. Citation Format: Justyna Zdrojewska, Katja Fagerlund, Jenni H. Mäki-Jouppila, Mari I. Suominen. Establishing prostate cancer models for orthotopic and bone metastatic growth using the 22Rv1cell line [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 2824.
Astrocytes in selective vulnerability to neurodegenerative disease
Authors: Till S. Zimmer, Adam L. Orr, Anna G. Orr
Journal: Trends in Neurosciences (2024)

Selective vulnerability of specific brain regions and cell populations is a hallmark of neurodegenerative disorders. Mechanisms of selective vulnerability involve neuronal heterogeneity, functional specializations, and differential sensitivities to stressors and pathogenic factors. In this review we discuss the growing body of literature suggesting that, like neurons, astrocytes are heterogeneous and specialized, respond to and integrate diverse inputs, and induce selective effects on brain function. In disease, astrocytes undergo specific, context-dependent changes that promote different pathogenic trajectories and functional outcomes. We propose that astrocytes contribute to selective vulnerability through maladaptive transitions to context-divergent phenotypes that impair specific brain regions and functions. Further studies on the multifaceted roles of astrocytes in disease may provide new therapeutic approaches to enhance resilience against neurodegenerative disorders.
Abstract 4090: Gut microbiota mimics as a source of cross-reactive tumor rejection antigens
Authors: Vincent Panneton, Mathieu Gigoux, Abderezak Zebboudj, Norah Sadek, Hyejin Choi, Levi M. Mangarin, Mariam M. George, Guillaume Kulakowski, Joao G. Magalhaes, Jean-Marie Carpier, Thibaud Dugat, Camille Gaal, Francesco Strozzi, Lorenzo Tibaldi, Laurent Chene, Jedd D. Wolchok, Vinod P. Balachandran, Taha Merghoub
Journal: Cancer Research (2024)

Abstract The crosstalk between gut microbiome and anti-tumor immunity has recently gained attention in clinical settings. The administration of antibiotics during immune checkpoint blockade (ICB) therapies has been correlated with poorer outcomes in cancer patients, suggesting that microbiome alterations affect overall responses to ICB. The establishment of microbiota-specific T cell clones with tumor cross-reactivity potential was proposed as one of the mechanisms linking the microbiome to anti-tumor responses. Vaccine-based strategies aimed at reactivating these dormant pools of T cells to help eliminate tumors have been proposed as an alternate approach, but the parameters required for successful responses remain poorly understood. Here, we performed in silico selection of bacterial peptides derived from healthy mice based on their mimicry of either tumor-associated antigens (TAAs) or neoantigens expressed by murine melanoma cells and not healthy tissue. We show that in silico predicted peptide binding affinity to MHC I correlates with experimental MHC I binding, a key factor associated with strong immune responses. Moreover, we confirmed that a significant proportion of selected peptide candidates can provoke an immune reaction in a vaccination setting. From this group of peptides, we selected candidates which triggered cross-reactive immune responses against TAAs or neoantigens. Data from preliminary tumor challenge experiments with prophylactic peptide vaccination and ICB allowed us to define key parameters such as target gene expression levels which can predict the cross-reactive potential of bacterial peptides that mimic tumor antigens. These findings provide novel insights into the design of gut microbiome peptide-based tumor vaccines and pave the way for establishing combinatorial therapies with immunomodulatory drugs. Citation Format: Vincent Panneton, Mathieu Gigoux, Abderezak Zebboudj, Norah Sadek, Hyejin Choi, Levi M. Mangarin, Mariam M. George, Guillaume Kulakowski, Joao G. Magalhaes, Jean-Marie Carpier, Thibaud Dugat, Camille Gaal, Francesco Strozzi, Lorenzo Tibaldi, Laurent Chene, Jedd D. Wolchok, Vinod P. Balachandran, Taha Merghoub. Gut microbiota mimics as a source of cross-reactive tumor rejection antigens [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 4090.