tbuckley/cabot-search huggingface dataset:
Abstract A002: In-silico screening of race-specific endometrial cancer methylation markers using machine learning techniques
Authors: Huma Asif, Grace Foley, Julie Kim
Journal: Clinical Cancer Research (2024)

Abstract Targeted molecular therapy is a promising strategy for cancer treatment. Despite the benefits of these therapies, racial disparities in cancer therapy efficacy persist. To close this racial gap, there is a need to find race-specific biomarkers at the molecular level. Since abnormal DNA methylation has been linked with cancer and has a great potential to transform the diagnosis and treatment of cancer, the main objective of this study was to combine differential DNA methylation and machine learning techniques to identify race-specific methylation signature biomarkers in endometrial tumor samples from White and Black women. We performed genome wide Differentially Methylated CpG (DMCs) analysis in tumors from White patients (TWP) samples compared to tumors from Black patients (TBP) samples using Endometrial Carcinoma (EC) methylation and clinical data from The Cancer Genome Atlas (TCGA). We used supervised and unsupervised machine learning techniques to filter and select signature biomarkers. To evaluate the prognostic capacity of these genes, we performed univariate and multivariate survival analyses using Cox proportional hazards regression model from survival R package. By combining differential methylation CpGs and machine learning techniques, we reduced 704 differentially methylated CpGs to reliable race-specific epigenetic signature genes (ESGs) and Core- epigenetic signature genes (core-ESGs). An area under the curve (AUC) of 0.98 was achieved based on these signature genes. We further found that ESGs showed statistically significant overall survival differences between two racial groups. In addition, comparison of the mutational landscape showed differences in mutation frequencies in the ESGs between the two groups. By combining differential methylation analysis and machine learning techniques, we identified novel race-specific epigenetic signature genes in Black and White women with endometrial cancer. We further showed the potential of these gene in predicting survival differences, mutation, and transcriptomic differences in Black and White women. We propose that combined methylation and somatic mutation profiling of these novel race-specific signature genes can be used to develop potential therapeutic targets for diagnosis and treating endometrial cancer. Citation Format: Huma Asif, Grace Foley, Julie Kim. In-silico screening of race-specific endometrial cancer methylation markers using machine learning techniques [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A002.
Abstract A018: A phase 2, open-label, single-arm, prospective, multicenter study of <i>nab</i>-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer
Authors: Lauren E. Dockery, Anna Priebe, Linda Duska, Angela K. Green, Cara Mathews, Fernanda Musa, David O'Malley, Allison Puechl, Li Ding, Anita N. Schmid, Willis H. Navarro, Brian Slomovitz, Kathleen Moore
Journal: Clinical Cancer Research (2024)

Abstract Introduction/Objective: This trial in progress is designed to evaluate the anti-tumor activity of nab-sirolimus in combination with letrozole in patients with advanced or recurrent endometrioid endometrial carcinoma (EEC). Despite recent pivotal data demonstrating improved outcomes with immunotherapy plus chemotherapy, regardless of mismatch repair status, alternative treatment options, particularly for advanced or recurrent EEC remain necessary. Dysregulation of mammalian target of rapamycin (mTOR) signaling is implicated in the pathology of EEC, in which &amp;gt;80% harbor PTEN or PI3K/AKT/mTOR pathway alterations. Moreover, crosstalk between mTOR and estrogen receptor signaling pathways is associated with endocrine resistance. GOG-3007 and other phase 2 studies have demonstrated that the combination of conventional mTOR inhibitors (mTORis) and endocrine therapy provides clinical benefit in patients with EC. nab-Sirolimus, a nanoparticle injectable form of mTORi, is approved in the USA for malignant perivascular epithelioid cell tumor. Preclinical data of nab-sirolimus demonstrated improved tumor accumulation, mTOR inhibition, and tumor growth suppression compared with conventional mTORis. We hypothesize that nab-sirolimus in combination with letrozole may produce synergistic antitumor activity in patients with recurrent EEC. Methods: In this phase 2, open-label, single-arm, multicenter study (NCT05997017), nab-sirolimus (100 mg/m2, intravenous, on days 1 and 8 of each 21-day cycle) and letrozole (2.5 mg, oral, daily) are administered to patients (~29 planned) with clinically confirmed, advanced, or recurrent EEC. Eligibility criteria include age ≥18 years, ≤1 prior chemo-based regimen, Eastern Cooperative Oncology Group performance status score 0 or 1, naïve to mTORi, and measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). The primary endpoint is best overall response rate by RECIST v1.1. Key secondary endpoints include duration of response, progression-free survival, overall survival, and safety. The relationship between biomarkers and response outcomes is an exploratory endpoint. Citation Format: Lauren E. Dockery, Anna Priebe, Linda Duska, Angela K. Green, Cara Mathews, Fernanda Musa, David O'Malley, Allison Puechl, Li Ding, Anita N. Schmid, Willis H. Navarro, Brian Slomovitz, Kathleen Moore. A phase 2, open-label, single-arm, prospective, multicenter study of nab-sirolimus plus letrozole in advanced or recurrent endometrioid endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A018.
Abstract B007: Investigation of the mechanism of PADI2 regulation by the FBXW7 tumor suppressor
Authors: Chandra Mani Kafle, Daphne W. Bell
Journal: Clinical Cancer Research (2024)

Abstract Serous endometrial cancer (SEC) is an aggressive form of cancer that frequently exhibits recurrent somatic mutations in FBXW7 at residues 465, 479, and 505. FBXW7 is a tumor suppressor and is part of a Skp1-Cullin-F-box containing (SCF) complex that targets various proteins, including certain oncoproteins, for ubiquitin-mediated proteasomal degradation. FBXW7 interacts with Cdc4 phosphodegron (CPD) motif(s) within substrate proteins. We previously reported upregulation of peptidyl arginine deiminase 2 (PADI2), a potentially druggable protein, in FBXW7-mutant SEC cell lines compared to the isogenic FBXW7-wildtype cells. The purpose of this study is to investigate the mechanism by which FBXW7 regulates PADI2 levels. We searched for the CPD motif in the PADI2 protein sequence. We used co-immunoprecipitation and immunoblotting to study FBXW7-PADI2 interactions after transiently transfecting HEK293 cells with constructs expressing MYC-tagged FBXW7 and/or HA-tagged PADI2, in the presence or absence of bortezomib. We identified three putative CPD motifs in PADI2, leading us to hypothesize that wildtype FBXW7 binds PADI2 and thus targets PADI2 for degradation via a proteasome-dependent mechanism. Our experimental data show that FBXW7 interacts with PADI2, in the presence of bortezomib, a proteasome inhibitor, in transiently transfected HEK293 cells. Additionally, we have shown that mutation of the putative CPD motifs of PADI2 abrogates the PADI2-FBXW7 interaction. Our findings implicate PADI2 as a novel substrate of the FBXW7 tumor suppressor. Citation Format: Chandra Mani Kafle, Daphne W. Bell. Investigation of the mechanism of PADI2 regulation by the FBXW7 tumor suppressor [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B007.
Abstract B022: Conversion from minimally invasive surgical approaches to open surgery among endometrial cancer patients in a national cancer patients’ registry
Authors: Abdelrahman Yousif, Julie Ngo, Deena Abdel-Gadir, Jenny Lachance, Benjamin Mize, Ilana Chefetz
Journal: Clinical Cancer Research (2024)

Abstract Endometrial cancer (EC) ranks as the predominant gynecological malignancy in the US. While minimally invasive surgical (MIS) techniques have revolutionized EC management, conversion to laparotomy remains a concern, with reported rates varying widely. Factors influencing this conversion, including patient characteristics and tumor attributes, have not been fully understood. Addressing this gap, our study employs a national registry to analyze patient, tumor, and surgeon-related factors contributing to the transition from MIS to laparotomy in EC cases. Results: 0ur results showed, 3.4% (135/4028) experienced planned MIS-to-open conversion. Demographic disparities were absent between conversion and MIS groups. Conversion was more prevalent in obese (29%) and morbidly obese (37%) patients (P=0.04), linked to prior abdominal surgery (63% vs 52%; P=0.001). Endometrioid EC predominated (59%) in the converted group, with higher non-endometrioid rates (serous carcinoma 16%, clear cell carcinoma 4%, carcinosarcoma 5%, mixed histology 12%; all P&amp;lt;0.01). Advanced FIGO stages were more common in conversions (stage II: 5%, stage III: 25%, stage IV: 9%; all P&amp;lt;0.001). Type II (24%) and type III (5%) hysterectomies were more frequent in conversions (P&amp;lt;0.001). Logistic regression indicated BMI, prior surgery, FIGO stage, histology, and operation type affected conversion (p&amp;lt;0.001), explaining 12.3% of variance. Indications for conversion included uterine size, adhesions, and disease extent. Conclusion: the adoption of minimally invasive surgery (MIS) has become increasingly popular for managing endometrial cancer (EC), attributed to enhanced perioperative outcomes. However, prudent patient selection and surgical planning are imperative to mitigate the risk of unplanned transition to open surgery. Predictive factors for such conversion include uterine size, prior abdominal surgeries, surgical complexity, disease extent, and histologic types. Further prospective research is warranted to validate these findings and identify individuals at conversion risk. Ultimately, a personalized surgical approach, tailored to individual patient attributes, remains pivotal for optimizing outcomes in EC management. Citation Format: Abdelrahman Yousif, Julie Ngo, Deena Abdel-Gadir, Jenny Lachance, Benjamin Mize, Ilana Chefetz. Conversion from minimally invasive surgical approaches to open surgery among endometrial cancer patients in a national cancer patients’ registry [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B022.
Abstract A019: Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer
Authors: Charlie Chung, Aaron Nizam, Brian Yueh, Santhilal Subhash, Marina Frimer, Gary L. Goldberg, Semir Beyaz
Journal: Clinical Cancer Research (2024)

Abstract Endometrial cancer is the most common gynecologic malignancy with increasing incidence and mortality rates. Recurrent endometrial cancers, which are mostly from high-grade endometrial cancers (HGEC), have limited treatment options and display extremely poor response rate upon chemotherapies, thus showing very poor prognosis. Immunotherapy revolutionized the field of cancer medicine, but lack of scalable and sustainable pre-clinical models for HGEC poses a significant challenge in studying critical immunological aspects of HGEC. We therefore established a comprehensive endometrial cancer biobank comprising primary tissues, patient-derived organoids (PDO), and their matching immune cells from all existing HGEC types, enabling us to establish an autologous interaction between cancer and immune cells in vitro. Inactivation of antigen processing and presentation (APP) pathways is one of the major mechanisms for immune evasion in many cancer types including HGEC. Using a subset of our biobank, we performed bulk RNA-seq on 11 normal-cancer PDO pairs and found that genes involved in APP pathways, MHC-II in particular, are downregulated in HGEC organoids. We found that dampened MHC expression can be reverted by external stimuli such as IFNγ and Tazemetostat. We then assessed the effects of enhanced MHC-I and -II expression mediated by the two molecules on cancer-immune cell interactions by setting up organoid-immune cell co-cultures using autologous PBMC, CD4, and CD8 T cells. Our results suggest that cell signaling and epigenetic manipulations on HGEC can be exploited to enhance immune cell-mediated apoptosis. Using our co-culture platform, we next evaluated the efficacy of different immunotherapeutic modalities such as NK cell transfer, bi-specific T-cell engagers, and CAR-T cells on HGEC. Our proof-of-principle experiments demonstrate the utility of our co-culture system in studying the autologous cancer-immune cell interactions from the same patient ex vivo. Our sustainable and scalable testing platform could be used to assess the safety and efficacy of current therapeutics or to identify new therapeutics that enhance immune responses against advanced cancers lacking effective treatment options such as HGEC. Citation Format: Charlie Chung, Aaron Nizam, Brian Yueh, Santhilal Subhash, Marina Frimer, Gary L. Goldberg, Semir Beyaz. Autologous patient-derived organoid-immune cell co-culture platform for therapeutics discovery in high-grade endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A019.
Abstract A023: Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer
Authors: Dollina D. Dodani, Aline Talhouk
Journal: Clinical Cancer Research (2024)

Abstract Recent associations between vaginal microbiota and gynecological cancer have led to high-throughput sequencing datasets identifying diagnostic biomarkers for Endometrial Cancer (EC). However, lack of bioinformatics standards results in inconsistent independent studies with poor reproducibility, making them clinically inapplicable. This study leverages publicly available amplicon sequence data to address the reproducibility of EC microbiome studies. We implemented bioinformatics pipelines from five studies to reproduce and measure the replicability of published results across cohorts using metrics such as alpha diversity, beta diversity and differentially expressed taxa. We further evaluated separability between benign and cancer patients at different taxonomic levels (phylum, class, order, family, and genus) within and across datasets using boosted tree classifiers and Area Under the Curve (AUC) as the performance metric. While we reproduced the general trend of observing higher microbial diversity in EC compared to healthy controls, we found irregularities in two cohorts. Using beta diversity distance metrics, we identified that histology alone explains less than 3% of the variance in all cohorts. Three microbiome differential abundance methods were used in the five studies. While they all agree on a decrease in the Lactobacillus genus in EC patients, there is no consensus on other taxa associated with EC. We also found that separability between benign and cancerous conditions is highest at the class level, having an AUC score of 0.86. In subsequent steps, we will perform an integrative analysis to identify an EC vaginal microbiome predictive signature that is preserved across all five cohorts, benefiting screening programs. Citation Format: Dollina D. Dodani, Aline Talhouk. Assessing the reproducibility crisis in vaginal microbiome studies for clinical applications in endometrial cancer [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A023.
Abstract A022: Detecting cardiovascular disease risk in early-stage endometrial cancer survivors: preliminary evidence of pulse wave velocity and social vulnerability index
Authors: Lauren C. Bates-Fraser, Victoria Bae-Jump, Lee Stoner, Erik D. Hanson
Journal: Clinical Cancer Research (2024)

Abstract BACKGROUND: Endometrial cancer survivors (ECS) experience high rates of cardiovascular disease (CVD) likely due to lifestyle and social-environmental factors, including high obesity rates up to 60%. Early detection of CVD is crucial in order to intervene; however, strategies to identify ECS most at risk for CVD are currently lacking. The gold-standard methodology to non-invasively measure CVD is pulse wave velocity (PWV), and one way to identify social-environmental susceptibility is the Centers for Disease Control social vulnerability index (SVI). PURPOSE: Therefore, the purpose of this study is to investigate (1) CVD risk in stage 1 ECS using PWV and (2) the social-environmental influence on CVD risk using SVI. METHODS: Stage 1 ECS who were 1-12 months post-treatment, with a BMI ≥ 25.0 kg/m2, age 50-80 years, and English speaking were recruited in the gynecology-oncology clinic. Oscillometric PWV was measured in a supine position via Mobil-O-Graph. Body composition [body fat percentage (%)] was measured via Bioelectrical Impedance Analysis. Participant zip code was used to determine SVI of their county of residence. SVI is defined as low-medium (0.00-0.49), medium-high (0.50-0.69), and high (0.70-1.00). Linear regression was used to compare PWV and SVI. RESULTS: Seventeen ECS (65% White, 25% Black, 5% Asian, 5% American Indian, 64 ± 7 years old, 6 ± 4 months post-treatment, 44 ± 6% body fat) participated in the study. Participants resided in counties with low-medium (18%), medium-high (24%), and high (58%) SVI and PWV was measured as 8.2 ± 0.8 m/s, 9.1 ± 0.8 m/s, and 9.7 ± 1.0 m/s respectively. The overall regression was not statistically significant (R=0.38, R2=0.14, F=1.15, p=0.34). DISCUSSION: Overall, PWV was elevated in ECS residing in counties with medium-high and high SVI categories compared to normative data. PWV can be used to non-invasively measure CVD risk in clinic in early-stage ECS. Despite failing to reach statistical significance, a 1.0 m/s change is considered to be a clinically meaningful difference in PWV. Therefore, ECS residing in counties with high SVI may be at greater CVD risk compared to those living in less vulnerable communities. Further research is needed, including a larger sample size, to identify successful interventions to reduce CVD in ECS most at risk. Citation Format: Lauren C. Bates-Fraser, Victoria Bae-Jump, Lee Stoner, Erik D. Hanson. Detecting cardiovascular disease risk in early-stage endometrial cancer survivors: preliminary evidence of pulse wave velocity and social vulnerability index [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr A022.
Assessing hypercoagulability and <scp>VTE</scp> risk using thromboelastography and Khorana score in women with cancers receiving chemotherapy
Authors: Yousra Tera, Yoon Jin Suh, Karina Fainchtein, Anita Agrawal, Mihaela Mates, Maha Othman
Journal: American Journal of Hematology (2024)

Abstract Venous thromboembolism (VTE) is a common occurrence in cancer and chemotherapy increases thrombosis risk. Current risk assessment models such as the Khorana score (KS) and its modifications have limitations in female cancers. We assessed the coagulation profile of a group of women cancer patients under chemotherapy using thromboelastography (TEG) to determine if this can inform VTE risk assessment. Cancer patients who planned to receive chemotherapy were recruited. Baseline demographics, cancer data, BMI, Khorana Score (KS), and VTE risk factors were recorded and patients were followed for 6 months, for any thrombotic events. A total of 36 patients aged 35–85 (18 breast, 11 endometrial, 7 ovarian cancer) were evaluated. Hypercoagulability was detected in 63% of patients post‐chemo cycle 1 and 75% post‐cycle 2, with a significant increase in MA (maximum amplitude) and CI (clotting index), reduction in R (reaction time), K (clot kinetics), and LY30 (lysis time after 30 min of MA). KS showed only 7% of patients were high risk, 23% were low, and 70% were intermediate risk. MA and CI significantly increased in patients with intermediate and high‐risk KS when compared with the low‐risk patients and MA was positively correlated with KS. Five patients developed actual VTE; 100% of the tested ones were hypercoagulable either post‐cycle 1 or 2 and 80% were KS intermediate risk. TEG is a hypercoagulability marker and TEG‐MA and CI can potentially assess VTE risk. Larger studies are needed to assess the utility of TEG as an adjuvant to KS to better predict VTE in specific female cancers.
Randomized comparison between <scp>KTd</scp> and <scp>KRd</scp> induction therapy followed by maintenance therapy with K or observation in transplant‐ineligible patients with newly diagnosed multiple myeloma
Authors: Heinz Ludwig, Thomas Melchardt, Siegfried Sormann, Martin Schreder, Johannes Andel, Bernd Hartmann, Christoph Tinchon, Niklas Zojer, Eberhard Gunsilius, Klaus Podar, Alexander Egle, Wolfgang Willenbacher, Ewald Wöll, Reinhard Ruckser, Boris Bozic, Maria‐Theresa Krauth, Andreas Petzer, Clemens Schmitt, Sigrid Machherndl‐Spandl, Hermine Agis, Michael Fillitz, Song‐Yau Wang, August Zabernigg, Stefan Knop, Bruno Paiva, Richard Greil
Journal: American Journal of Hematology (2024)

Randomized comparison between KTd and KRd induction followed by second randomization to carfilzomib in transplant-ineligable patients with newly diagnosed multiple myeloma.