Abstract PO3-09-01: Integrating pathomic and radiomic images to classify risk of subsequent events among women with DCIS

Cancer Research

Background: It is clinically important to refine strategies to manage women with dense breasts as they represent approximately 50% of all women screened. Change in breast density is related to risk of breast cancer.1 We also must understand this change in density over time in women with dense and non-dense breasts. While population level data have been reported to estimate decrease in density with age, this has largely used digitized film images.2 Expanding use of digital mammography and repeated screening generates a large library of images for each woman, offering the potential to use more of the image data. Methods: We use longitudinal latent class analysis to cluster women and estimate their change in density over time. To evaluate the groups of women with different patterns of change in density we fit latent class models to our previously published data.1 This includes 289 pathology confirmed …

The Annals of Applied Statistics

Tables, figures, and additional simulation and application results.

Cancer Medicine

Background Treatments for multiple myeloma (MM) have evolved over time and improved MM survival. While racial differences in MM treatment and prognosis between non‐Hispanic African American (NHAA) and non‐Hispanic White (NHW) patients are well‐established, it is unclear whether they have persisted after the introduction of novel agents. Methods Using the Surveillance, Epidemiology, and End Results‐Medicare linked database, our study investigated racial difference in the receipt of treatment within 1 year following diagnosis and assessed survival outcomes among Medicare beneficiaries (≥66 years) diagnosed with MM from 2007 to 2017. We applied multivariable Cox proportional hazards models to estimate the association between race and survival and presented hazard ratios (HRs). Results Of 2094 NHAA and 11,983 NHW older patients with MM, 59.5% and 64.8% received treatment …

Cancer Research

Introduction: Breast cancer incidence is rising in premenopausal, hence, there is a critical need to understand factors underlying premenopausal breast cancer development in order to guide targeted prevention. Mammographic breast density is a strong risk factor for, as well as an intermediate phenotype for premenopausal breast cancer. Yet, the molecular mechanisms underlying the associations of dense breasts with breast cancer are not well understood. Our objectives in this study are to perform proteomic analysis in breast tissues to (i) identify proteins that are associated with breast cancer development in premenopausal women; (ii) determine which of these proteins are also associated with dense breasts. Methods: We performed proteomic analysis on tumor and adjacent normal tissues from 50 premenopausal women with breast cancer who had breast tissue samples archived at the St. Louis Breast Tumor …

Breast Cancer Research

Early life factors are important risk factors for breast cancer. The association between weight gain after age 18 and breast cancer risk is inconsistent across previous epidemiologic studies. To evaluate this association, we conducted a meta-analysis according to PRISMA guidelines and the established inclusion criteria. We performed a comprehensive literature search using Medline (Ovid), Embase, Scopus, Cochrane Library, and ClinicalTrials.gov to identify relevant studies published before June 3, 2022. Two reviewers independently reviewed the articles for final inclusion. Seventeen out of 4,725 unique studies met the selection criteria. The quality of studies was assessed using the Newcastle-Ottawa Scale (NOS), and all were of moderate to high quality with NOS scores ranging from 5 to 8. We included 17 studies (11 case-control, 6 cohort) in final analysis. In case-control studies, weight gain after age 18 was …

Journal of Clinical Oncology

PURPOSETo identify dietary factors that are related to premature aging in adult survivors of childhood cancer, we examined the associations between plant food intakes and age-related deficit accumulation.METHODSA total of 3,322 childhood cancer survivors (age 18-65 years, mean = 31, standard deviation = 8.4) in the St Jude Lifetime Cohort had total fruit, total vegetables and subgroups, whole grains, refined grains, nuts/seeds, and nutrients intake assessed using a food frequency questionnaire. Premature aging at baseline was assessed by the deficit accumulation index (DAI) and categorized as low, medium, and high risk. Multinomial logistic regressions (reference: low risk) adjusting for confounders estimated odds ratios (ORs) and 95% CIs. Multivariable linear regression of a continuous intake against a continuous DAI was also performed.RESULTSDark green vegetable (ORhigh v low = 0.47 [95% CI, 0.28 …

Statistics in Medicine

Mammography remains the primary screening strategy for breast cancer, which continues to be the most prevalent cancer diagnosis among women globally. Because screening mammograms capture both the left and right breast, there is a nonnegligible correlation between the pair of images. Previous studies have explored the concept of averaging between the pair of images after proper image registration; however, no comparison has been made in directly utilizing the paired images. In this paper, we extend the bivariate functional principal component analysis over triangulations to jointly characterize the pair of imaging data bounded in an irregular domain and then nest the extracted features within the survival model to predict the onset of breast cancer. The method is applied to our motivating data from the Joanne Knight Breast Health Cohort at Siteman Cancer Center. Our findings indicate that there was no …

Cancer Causes & Control

PurposeAccurate pectoral muscle removal is critical in mammographic breast density estimation and many other computer-aided algorithms. We propose a novel approach to remove pectoral muscles form mediolateral oblique (MLO) view mammograms and compare accuracy and computational efficiency with existing method (Libra).MethodsA pectoral muscle identification pipeline was developed. The image is first binarized to enhance contrast and then the Canny algorithm was applied for edge detection. Robust interpolation is used to smooth out the pectoral muscle region. Accuracy and computational speed of pectoral muscle identification was assessed using 951 women (1,902 MLO mammograms) from the Joanne Knight Breast Health Cohort at Washington University School of Medicine.ResultsOur proposed algorithm exhibits lower mean error of 12.22% in comparison to Libra’s estimated error of 20.44 …

screening

○ In the United States (US), cancer is the leading cause of death among adults≤ 80 years1

Cancer Causes & Control

PurposeUnderstanding how stage at cancer diagnosis influences cause of death, an endpoint that is not susceptible to lead-time bias, can inform population-level outcomes of cancer screening.MethodsUsing data from 17 US Surveillance, Epidemiology, and End Results registries for 1,154,515 persons aged 50–84 years at cancer diagnosis in 2006–2010, we evaluated proportional causes of death by cancer type and uniformly classified stage, following or extrapolating all patients until death through 2020.ResultsMost cancer patients diagnosed at stages I–II did not go on to die from their index cancer, whereas most patients diagnosed at stage IV did. For patients diagnosed with any cancer at stages I–II, an estimated 26% of deaths were due to the index cancer, 63% due to non-cancer causes, and 12% due to a subsequent primary (non-index) cancer. In contrast, for patients diagnosed with any stage IV cancer …

Cancer Research

Background: Increasing use of digital screening mammography opens potential to add individualized dynamic measures of breast image history to predict future breast cancer risk. Current prediction models use a single mammogram measure, usually breast density, at one point in time, to add to prediction models based on established risk factors. Our previous work has shown that change in each breast over time is related to risk of diagnosis with breast cancer. Methods: We apply a dynamic prediction model that includes full field digital mammogram in each breast to predict future 5-year risk. Data from Joanne Knight Breast Health Cohort (JKBHC) serve as training population with 290 pathology-confirmed breast cancer cases and 658 controls sampled with a total number of 8,712 craniocaudal (CC) view mammograms for analysis. Nurses’ Health Study 2 (NHS2) serves as the external validation with 188 cases …

Among the various aspects of the present disclosure are the provision of an image alignment and registration system and a breast cancer risk prediction system.

Handbook of Health and Rehabilitation Psychology

Increasing exercise and physical activity participation is currently a major health objective in the United States (US Department of Health and Human Services, 1990). People who are active and fit are likely to live longer than those who are not and they are more likely to avoid several debilitating chronic disease conditions. In fact, evidence relating exercise to health now suggests that a larger propor-

Cancer Research

Introduction: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder with an annual risk of ~1% of progression to more advanced diseases, including multiple myeloma (MM). Few studies reported mortality risk in patients with MGUS, among which the diagnosis of MGUS was typically incidental due to unrelated symptoms or laboratory abnormalities. This study aims to compare the survival of MGUS patients with the U.S. general population using a nationally representative screening-based survey. Methods: Data were obtained from the third National Health and Nutrition Examination Survey (NHANES III) 1988-1994 and continuous NHANES 1999-2004, with follow-up all-cause mortality data through December 31, 2019. Participants were screened for MGUS by protein electrophoresis, immunofixation, and kappa and lambda free light chain assays in …

Urology

ObjectiveTo prospectively examine the influence of weight status on urinary and sexual function in clinically localized prostate cancer patients treated by radical prostatectomy (RP).MethodsThe Prostatectomy, Incontinence and Erectile dysfunction study recruited patients at 2 US institutions between 2011 and 2014. At baseline, height and weight were measured, and urinary and sexual function were collected by the modified Expanded Prostate Cancer Index Composite-50. This index was repeated at the 5-week, 6-month, and 12-month postsurgical assessments and compared to baseline using linear generalized estimating equations. Logistic equations were used to evaluate the likelihood of functional recovery at the 6- and 12-month assessments.ResultPresurgery, nonobese patients (68.8% of 407 patients) had similar urinary function as those with obesity (P = .217), but better sexual function (P = .006). One year …

Journal of Telemedicine and Telecare. First published online January 19, 2023. https://doi.org/10.1177/1357633X221149.

IntroductionTelemedicine infectious diseases consultations (tele-ID consults) improves access to healthcare for underserved/resource-limited communities. However, factors promoting or hindering implementation of tele-ID consults in low-resource settings are understudied. This study sought to fill this gap by describing perceived barriers and facilitators tele-ID consults at three rural hospitals in southeastern Missouri.MethodsTwelve in-depth, semi-structured interviews were conducted with a purposively sampled group of information-rich hospital stakeholders from three rural, southeastern Missouri hospitals with partial or no on-site availability of ID physicians. Our literature-informed interview guide elicited participants’ knowledge and experience with tele-ID consults, perceptions on ID consultation needs, and perceived barriers to and facilitators of tele-ID consults. Interview transcripts were coded using an iterative …

Cancer Research

PURPOSE To examine incremental values of estrogen receptor (ER) status, body mass index (BMI), menopausal status, and a previously reported multi-gene classifier over commonly used clinical factors (i.e. age, tumor grade, comedonecrosis, surgical margins, and treatment) in predicting risk of any ipsilateral recurrence (IR) event within five years after DCIS diagnosis. METHODS A derivation cohort consisted of participants in the Translational Breast Cancer Research Consortium (TBCRC) 038, a retrospective multicenter cohort study in women undergoing surgical resection for DCIS between 01/01/1998 and 02/29/2016 (n=216). The validation cohort, the Repository of Archival Human Breast Tissue (RAHBT) at Washington University School of Medicine, provided cases meeting the same eligibility criteria as TBCRC038 (n=97). Participants in both cohorts had RNA-seq data and either developed IR 1-5y …

10538Background: Obesity is a known risk factor for the development of multiple myeloma (MM) and for progression of its asymptomatic premalignant state, monoclonal gammopathy of undetermined significance (MGUS) to MM. Prior studies have demonstrated that monoclonal protein (M-spike) at MGUS diagnosis as well as high M-spike velocity within a year following MGUS diagnosis predict progression of MGUS to MM, making M-spike a useful, readily available, and less invasive (compared to bone marrow biopsy) marker to assess progression risk. However, no studies have evaluated to what extent exposure to high body mass index (BMI) over time influences M-spike trajectory. Methods: Patients diagnosed with MGUS from 1999-2021 in the Veterans Health Administration were identified. We used a natural language processing-based algorithm to confirm MGUS diagnosis and progression to smoldering MM …

Dietary factors account for a large proportion of human cancers, particularly overnutrition that results in weight gain and obesity. The evidence linking diet and cancer has been developing since the early 1900s, beginning with early laboratory studies and ecologic studies of cancer rates in different parts of the world. Modern epidemiologic methods, including case–control studies, cohort studies, Mendelian randomization studies, randomized controlled trials, and meta-analyses (particularly of individual participant data) have helped define in detail the associations between specific dietary factors and cancer. Factors with strong links to an increased risk of various cancers include: overnutrition/obesity, alcohol, red and processed meat, and salt. Factors with strong links to a decreased risk include: fruits, vegetables, whole grains, fiber, dairy, calcium, and coffee.

Cancer Research

INTRODUCTION: Black women are 41% more likely to die from breast cancer compared to White women yet remain underrepresented in clinical trials and population studies. We have previously shown a higher proportion of Black women with HR+HER2- tumors further classify as Basal-Type compared with White women, using BluePrint molecular subtyping. Other studies have demonstrated higher 3-year recurrence rates in patients with BluePrint Basal-Type tumors compared to Luminal-Type. To determine whether the increased frequency of HR+/Basal-Type tumors impacts long-term outcomes in this cohort, we compared 3-year outcomes with BluePrint and the risk of distant recurrence signature, MammaPrint (MP), between Black and White women with HR+HER2- breast cancer. We also evaluated the association of MP and BluePrint with 10-year outcomes in a subset of Black women. METHODS: This study …

Cancer Research

The pancreatic ductal adenocarcinoma (PDAC) microenvironment is populated by distinct subtypes of cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) that synthesize and remodel the stromal matrix and inflammatory CAFs (iCAFs) that secrete cytokines and growth factors. Subpopulations of CAFs reside in regions of tumor hypoxia, which may play a role in determining CAF behaviors. We tested the hypothesis that iCAFs preferentially drive ductal cell epithelial-mesenchymal transition (EMT), which promotes PDAC chemoresistance, and that hypoxia promotes the iCAF phenotype. Cell-cell communication analysis using publicly available single-cell RNA sequencing (scRNA-seq) data of human tumors indicated that iCAFs secrete growth factors predicted to promote ductal cell EMT. This inference was confirmed in experiments showing that PDAC cells exhibit stronger EMT in …

Cancer Research

Epithelial-mesenchymal transition (EMT) is a developmental process that is aberrantly activated in cancers such as pancreatic ductal adenocarcinoma (PDAC) to promote disease progression and chemoresistance. EMT occurs heterogeneously among PDAC ductal cells, which frustrates efforts to identify the underlying signaling regulatory mechanisms. We hypothesize that cell-to-cell variation in the activities of specific signaling pathways explains EMT heterogeneity. To test this, we developed a workflow integrating: 1) iterative indirect immunofluorescence imaging (4i) to quantify the activities of up to seven purported EMT-regulating pathways with single-cell resolution and 2) a multivariate mutual information computational model to predict the pathways that are most informative of the EMT phenotype. In cultured PDAC cells, EMT was induced by treating cells with growth factors present in the tumor …

Cancer Research

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a …

Cancer Research

Despite the considerable success of immune checkpoint therapies targeting T cells, a sizable proportion of patients experience resistance or relapse due to the immunosuppressive nature of the tumor microenvironment. Myeloid cells, a major component that suppresses effector lymphocytes, have emerged as an alternative and promising therapeutic target. However, there is a deep lack of widely accessible immunological models capable of representing the intricate three-way interaction between tumor cells, T cells, and myeloid cells. To address this need, we conducted a comprehensive protein profiling of human tumor and immune cell lines available at ATCC for various established and novel immune checkpoint molecules. Cell lines with high endogenous expression of the immune checkpoint proteins, such as programmed death-ligand 1 and 2 (PD-L1 and PD-L2), cluster of differentiation 155 (CD155), B7 …

Cancer Research

Monosomy 7 (-7) or del(7q) are recurrent in high-risk myeloid neoplasms, including up to 50% of myeloid neoplasms arising after prior exposure to chemotherapy and/or radiation. Although putative chromosome 7 tumor suppressor genes have been identified, the effects of combinatorial 7q gene loss remain unclear. A barrier to understanding the pathogenesis of -7/del(7q) is the challenge of modeling aneuploidy in animal models. To address this knowledge gap, we established an in vivo model of del(7q) clonal hematopoiesis and drug resistance using multiplex CRISPR-Cas9 to simultaneously target four 7q genes (Cux1, Ezh2, Kmt2c, and Kmt2e) in murine hematopoietic stem cells. After chemotherapy exposure, we observe significant myeloid expansion of clones edited for both Cux1 and Ezh2. Compared to the transcriptomes of control or single gene edited cells, Cux1;Ezh2-deficient cells fail to induce DNA …

Cancer Research

We have developed multiple novel preclinical syngeneic triple negative breast cancer(TNBC) genetically engineered mouse (GEM) models, which have been characterized genomically and with respect to their immune microenvironments. By integrating the immunological characterization of murine syngeneic mammary tumor models with analyses of human breast cancer datasets, we have demonstrated a relationship between EMT and myeloid cells, specifically tumor-associated macrophages (TAMs). We also have leveraged our syngeneic GEM models to define the response to immune checkpoint blockade therapy (ICBT) with emphasis on the myeloid cell environment. We have used our GEM models to test single agent drugs along with standard-of-care therapies for appropriate durations. Finally, we have tested these treatment regimens on established metastases with sufficient tumor burdens. Specifically …

Cancer Research

Background: Increased macrophage infiltration and elevated levels of Epithelial to Mesenchymal Transition (EMT) gene signatures are associated with a poor outcome following neo-adjuvant chemotherapy in patients with triple negative breast cancer (TNBC). Further, metastatic disease with overall the poorest survival rates has a cold tumor immune microenvironment (TIME), especially in lung and liver metastases. Interestingly, an abundance of macrophages are observed at these metastatic sites. We have extensively characterized multiple preclinical syngeneic Trp53-/- tumor models that have extensive Tumor Associated Macrophage (TAM) infiltration. These tumor models transcriptionally resemble “claudin-low”, “basal-like” and “luminal-like” breast cancers. From these models the “claudin-low” closely phenocopy the high EMT/TAM subtype observed in patients. Objective: Accordingly, we asked if SNDX …

Cancer Research

Background: The mammary gland exhibits extensive proliferative and differentiation potential throughout development. Wnt signaling has been recognized as a crucial player in multiple stages of mammary gland development, including mammary placode specification, gland branching morphogenesis, stem cell maintenance, and alveolar development. In our laboratory, prior research has revealed the importance of the β-catenin-independent noncanonical Wnt receptor, Ror2, in branching morphogenesis, cell differentiation, and actin-cytoskeletal dynamics within the mammary epithelium. However, the specific roles of Ror2 in the myoepithelial and luminal cell compartments have yet to be fully elucidated. Methods and Results: In this study, we investigated the functional role of Ror2 in these two distinct cell populations by developing mouse models with lineage-specific deletion of Ror2 in myoepithelial versus …

Cancer Research

Triple-negative breast cancer (TNBC) is a biologically heterogeneous and clinically important breast cancer subtype because if considered a distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC patients resistant to standard-of-care therapies have poor survival. Tumor-associated immune cells such as neutrophils and macrophages can display a pro-tumoral phenotype and contribute to therapy resistance. Epigenetic enzymes have been shown to reprogram both the tumor cells and tumor-associated immune cells. Thus, targeting epigenetic enzymes is a potential strategy to improve the response of TNBC to standard-of-care therapies. Previously, our laboratory performed an epigenetic drug screen and identified several epigenetic inhibitors. We selected IACS-70654, a novel selective p300/CBP BRD inhibitor, to be the primary focus of this study. We determined the effects …

Cancer Research

Introduction: Efforts to overcome resistance to immune checkpoint inhibition (ICI) are paramount, and novel combination strategies are in development. Image-guided percutaneous cryoablation is an established minimally invasive oncologic treatment that has demonstrated immune modulatory effects. We hypothesized that cryoablation may prime the tumor microenvironment (TME) through direct modulation of the tumor, thereby generating an anti-tumor response in ICI refractory tumors. Methods: In this non-randomized phase II single-center study, subjects with unresectable melanoma progressing on ICI underwent cryoablation of an enlarging metastasis, and ICI was continued for a minimum of two additional cycles. The primary endpoint was safety and feasibility, with objective response rate (ORR) and disease control rate (DCR) in non-ablated lesions a key secondary endpoint. To better understand the …

Cancer Research

Background: Rhabdomyosarcoma (RMS) is an aggressive pediatric solid tumor with poor survival and new targeted therapies are needed. Aims: Using an integrative proteogenomic quantitative approach, we sought to identify candidate immunotherapeutic targets then validate top targets in RMS preclinical models. Methods: We first performed plasma membrane enrichment followed by mass spectrometry (MS) to define the surfaceome of 7 fusion-positive (FP) and 14 fusion-negative (FN) RMS patient-derived xenograft models. Surface proteins were scored by IMMUNOTAR, our custom pipeline which extracts and integrates quantitative features from diverse proteogenomic and annotation datasets to provide a score for each protein, using mean-average-precision for score optimization. Cell surface expression of IMMUNOTAR-prioritized proteins was validated using flow cytometry, focusing on targets with …

Cancer Research

Background: More than 60,000 U.S. adults are diagnosed with non-muscle invasive bladder cancer (NMIBC) each year. These patients are recommended to undergo surveillance via repeated cystoscopies. However, the ideal frequency of post-diagnostic cystoscopy surveillance remains unknown, and efforts are underway to de-escalate surveillance given uncertainty regarding its effect on mortality. We therefore aimed to compare the effectiveness of different post-diagnostic cystoscopy surveillance strategies on bladder cancer specific mortality. Methods: We used observational data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linkage to emulate a target trial, i.e., a hypothetical, pragmatic randomized trial that would answer our causal question. Eligible individuals were aged 66 years or older, diagnosed with NMIBC (Ta, Tis, or T1) classified as urothelial carcinoma between January 1 …

Cancer Research

Introduction: Randomized trials have shown that physical activity can improve quality of life (QOL) among individuals with cancer. In the absence of a randomized trial of adequate size and follow-up to comprehensively evaluate this relationship for prostate cancer, we aim to emulate a target trial of guideline-based physical activity strategies and 6-year physical QOL. Methods: We will use observational data on individuals in the Health Professionals Follow-up Study diagnosed with nonmetastatic prostate cancer between 2010-2016 and free of conditions that could preclude following current physical activity recommendations at baseline (first post-diagnostic questionnaire). The physical activity strategies of interest are (1) engage in ≥150 minutes of moderate activity, or ≥75 minutes of vigorous activity per week, or an equivalent combination (i.e., ≥7.5 metabolic equivalent of task [MET]-hours/week of vigorous or …

Cancer Research

Introduction: Social support is associated with improved cancer survivorship, but literature on its association with prostate cancer specific physical and psychosocial quality of life (QoL) is lacking. We investigated the associations of social support with physical and psychosocial QoL in individuals with prostate cancer in HPFS. Methods: We included 1,692 men (ages 61-95 years, mean: 71 years) diagnosed with non-metastatic prostate cancer between 2008 and 2016. Social support was measured by the Berkman-Syme Social Network Index (SNI) (a composite measure of marital status, sociability, membership in religious groups or other community organizations: socially isolated, moderately isolated, moderately integrated, socially integrated) and marital status (married, not married). Physical (measured by EPIC-CP: bowel function, urinary incontinence, urinary irritation/obstruction, sexual function, vitality/hormonal …

Cancer Research

Metastasis of cancer cells to vital organs remains the leading cause of cancer related deaths, emphasizing a strong need for actionable targets in advanced stage cancer. To address this, we study novel dysregulated mitochondrial signaling mechanisms that cells utilize to metastasize. Here, we focus on how outer mitochondrial membrane protein—Mitochondrial Rho GTPase 2 (MIRO2)—promotes tumor cell invasion and metastasis. Our previous work identified higher MIRO2 mRNA expression in cancer vs. normal patient samples in a multitude of cancer types, which correlated with worse patient outcomes. Furthermore, we demonstrated that MIRO2 was critical for prostate cancer cell growth and survival in vitro and in vivo. However, it remains unknown if MIRO2 only affects primary tumor growth or if this protein is important throughout tumor progression. Using siRNA mediated knockdown (KD) of MIRO2 we find …

Cancer Research

Medulloblastoma is one of the most common malignant brain tumors of children, and 30% of medulloblastomas are driven by gain-of-function genetic lesions in the Sonic Hedgehog (SHH) signaling pathway. EYA1, a haloacid dehalogenase phosphatase and transcription factor, is critical for tumorigenesis and proliferation of SHH medulloblastoma (SHH-MB). Benzarone and benzbromarone have been identified as allosteric inhibitors of EYA proteins. Using benzarone as a point of departure, we developed a panel of 35 derivatives and tested them in SHH-MB. Among these compounds, DS-1–38 functioned as an EYA antagonist and opposed SHH signaling. DS-1–38 inhibited SHH-MB growth in vitro and in vivo, showed excellent brain penetrance, and increased the lifespan of genetically engineered mice predisposed to fatal SHH-MB. These data suggest that EYA inhibitors represent promising …

Cancer Research

Checkpoint inhibitors have achieved durable responses and long-lasting immunologic memory in cancer patients. However, the initial and acquired resistance remains an unsolved problem. It’s urgent to learn the molecular mechanisms causing resistance. microRNAs (miRNAs) are short transcripts that regulate many pathophysiological processes. Here, we investigated the miRNAs expression changes after GVAX combined with monoclonal PD-1 antibody treatment in the murine melanoma B16F10 tumors and identified microRNAs down-regulated in responsive tumors. Deletion of this family member in three different syngeneic mouse tumors did not affect their in vitro nor in vivo proliferation but sensitized anti-PD1 immunotherapy. The miRNA deletion with anti-PD1 therapy increased total CD45+ leukocyte infiltration with all types of hematopoietic cells except macrophages. Both tumor bulk RNA sequencing and …

Cancer Research

In human lung adenocarcinoma that carry Epidermal Growth Factor Receptor (EGFR) sensitizing mutations, targeting the EGFR pathway with the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs) has emerged as a promising therapeutic strategy providing initial clinical benefit to many patients. Unfortunately, resistance to EGFR-TKIs eventually develops leading to disease progression. In addition to genetic mutations, transcriptional and epigenetic mediated changes in gene expression remain an important mechanism contributing to EGFR-TKI resistance. Here, we report a novel function of the transcriptional corepressor Transducin-Like Enhancer of Split-1 (TLE1) in mediating EGFR-TKI resistance in EGFR mutant LUAD cells through its survival promoting gene transcriptional program. In EGFR mutant, EGFR TKI sensitive LUAD cells, sole activation of the TLE1 nuclear function attenuates EGFR TKI sensitivity …

Cancer Research

Introduction: While inverse associations have been reported in epidemiologic studies of breast feeding and ovarian cancer risk, little is known about the biologic pathways impacted by breastfeeding that leads to risk reduction. Therefore, we aimed to identify individual metabolites and pathways associated with breastfeeding among parous women in the Nurses’ Health Study (NHS) (n=7,111) and NHSII (n=2,793), and ultimately develop a breastfeeding metabolite score to quantify the association of this score with ovarian cancer risk using a nested case control study within NHS/NHSII (n=504 cases and controls). Methods: To identify individual metabolites associated with breastfeeding, we conducted a cross-sectional analysis using data from all nested studies of metabolites and various disease outcomes (e.g., ovarian cancer, type 2 diabetes, stroke) within the NHS/NHSII. Liquid chromatography tandem mass …