Guideline-based physical activity and physical quality of life among individuals with nonmetastatic prostate cancer: A target trial emulation in the Health Professionals Follow …

Epidemiology

Background:Observational studies are used for estimating vaccine effectiveness under real-world conditions. The practical performance of two common approaches—cohort and test-negative designs—need to be compared for COVID-19 vaccines.Methods:

Cancer

Background Plant‐based diets have many health benefits, including a lower risk of fatal prostate cancer, and greater environmental sustainability. However, less is known regarding the impact of plant‐based diets on quality of life among individuals diagnosed with prostate cancer. The authors' objective was to examine the relationship between plant‐based diet indices postdiagnosis with quality of life. Methods This prospective cohort study included 3505 participants in the Health Professionals Follow‐Up Study (1986–2016) with nonmetastatic prostate cancer. Food‐frequency questionnaires were used to calculate overall and healthful plant‐based diet indices. Quality‐of‐life scores were calculated using the Expanded Prostate Cancer Index Composite. Generalized estimating equations were used to examine associations over time between plant‐based diet indices and quality‐of‐life domains (sexual …

Journal of Urology

Purpose:Family history and germline genetic risk single nucleotide polymorphisms (SNPs) have been separately shown to stratify lifetime risk of prostate cancer. Here, we evaluate the combined prognostic value of family history of prostate and other related cancers and germline risk SNPs among patients with favorable-risk prostate cancer.Materials and Methods:A total of 1367 participants from the prospective Health Professionals Follow-up Study diagnosed with low-or favorable intermediate-risk prostate cancer from 1986 to 2017 underwent genome-wide SNP genotyping. Multivariable Cox regression was used to estimate the association between family history, specific germline risk variants, and a 269 SNP polygenic risk score with prostate cancer‒specific death.Results:Family history of prostate, breast, and/or pancreatic cancer was observed in 489 (36%) participants. With median follow-up from diagnosis of …

Cancer Research

Background: While prostate cancer is the second leading cause of cancer death in U.S. males, most men with prostate cancer die from other causes. We prospectively examined the potential benefits of adhering to established healthy dietary patterns on overall and cause-specific mortality among men living with prostate cancer. Methods: We studied men with incident prostate cancer in the Health Professionals Follow-up Study from 1986-2022. Five dietary indices-Alternative Healthy Eating Index (AHEI), the Mediterranean diet, Dietary Approaches to Stop Hypertension (DASH), anti-insulinemic, and anti-inflammatory diet scores-were derived from validated food frequency questionnaires administered every 4 years. Post-diagnosis scores were cumulatively averaged, and time-varying changes in scores from pre- to post-diagnosis were calculated. We used multivariable-adjusted Cox models to estimate hazard …

Cancer Research

Background: Cardiovascular disease (CVD) is a major cause of morbidity and mortality among men diagnosed with prostate cancer. We evaluated the extent to which men with prostate cancer develop CVD accounting for potential factors that may contribute to the CVD burden in this population. Methods: We prospectively followed men diagnosed with prostate cancer and free from CVD (stroke and coronary heart disease, including myocardial infarction, coronary artery bypass graft, and percutaneous coronary intervention) before their cancer diagnosis in the Health Professionals Follow-up Study, between 1986 and 2016. Men were categorized by D’Amico prostate cancer risk groups as low-risk (stage T1-2a, Gleason score ≤6, and PSA at diagnosis ≤10 ng/mL), intermediate-risk (T2b and/or Gleason score 7 and/or PSA >10-20), or high-risk (≥T2c/N1/M1 or Gleason score 8-10 or PSA >20). Incident fatal and non …

Background: The TMPRSS2:ERG gene fusion is the most common somatic alteration in primary prostate cancer and an early event in carcinogenesis. There are emerging data highlighting etiologic differences in prostate cancer by TMPRSS2:ERG status. This systematic review synthesized evidence from epidemiologic studies on prostate cancer risk factors for tumors with and without the TMPRSS2:ERG fusion. Methods: A systematic literature search was performed in Ovid MEDLINE, EMBASE, and Web of Science without language restriction for studies published by September 27, 2022. Studies that assessed associations between epidemiologic and genetic factors and prostate cancer risk by tumor TMPRSS2:ERG (ERG) fusion status in human populations were included. Results: Of 3,071 records identified, 20 publications comprising prospective cohort and case-control studies from five study populations …

Background Prostate cancer is the most diagnosed cancer in African American men, yet prostate cancer screening regimens in this group are poorly guided by existing evidence, given underrepresentation of African American men in prostate cancer screening trials. It is critical to optimize prostate cancer screening and early detection in this high-risk group because underdiagnosis may lead to later-stage cancers at diagnosis and higher mortality while overdiagnosis may lead to unnecessary treatment. Methods We performed a review of the literature related to prostate cancer screening and early detection specific to African American men to summarize the existing evidence available to guide health-care practice. Results Limited evidence from observational and modeling studies suggests that African American men should be screened for prostate cancer …

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 …

Genome Medicine

BackgroundAlthough polygenic risk score (PRS) has emerged as a promising tool for predicting cancer risk from genome-wide association studies (GWAS), the individual-level accuracy of lung cancer PRS and the extent to which its impact on subsequent clinical applications remains largely unexplored.MethodsLung cancer PRSs and confidence/credible interval (CI) were constructed using two statistical approaches for each individual: (1) the weighted sum of 16 GWAS-derived significant SNP loci and the CI through the bootstrapping method (PRS-16-CV) and (2) LDpred2 and the CI through posteriors sampling (PRS-Bayes), among 17,166 lung cancer cases and 12,894 controls with European ancestry from the International Lung Cancer Consortium. Individuals were classified into different genetic risk subgroups based on the relationship between their own PRS mean/PRS CI and the population level threshold …

Cancer Epidemiology, Biomarkers & Prevention

Background Low levels of 6-sulfatoxymelatonin, the primary urinary metabolite of melatonin, have been linked to cancer and cardiometabolic outcomes in White and female populations. Methods We examined the association between adulthood adiposity and 6-sulfatoxymelatonin levels in a racially and ethnically diverse population. Our study included 4,078 men in the Multiethnic Cohort with adiposity measurements at enrollment (1993–1996) and biomarkers measured in urines collected in 1995 and 2005. Multivariable linear regression models were used to estimate the percent change in 6-sulfatoxymelatonin levels and 95% confidence intervals (CI). Associations were examined separately by racial/ethnic group. Results The prevalence of obesity varied by race and ethnicity, from 10% for Japanese American men to 34% for Native Hawaiian men …

British Journal of Cancer

BackgroundMultivitamin use is common among cancer patients. Whether post-diagnostic multivitamin supplementation is beneficial for prostate cancer survival is largely unknown, and some evidence even suggests potential harm.MethodsWe prospectively assessed post-diagnostic multivitamin use in relation to prostate cancer survival among 4756 men with nonmetastatic prostate cancer at diagnosis in the Health Professionals Follow-up Study (1986–2016). Cox regression models were used to evaluate the association between post-diagnostic multivitamin use and frequency and risk of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality.ResultsWe observed 438 lethal prostate cancer and 2609 deaths during a median follow-up of 11 years. Compared to non-users, post-diagnostic multivitamin use was not associated with risk of lethal prostate cancer (HR [95% CI …

Cancer Research

Although gliomas are relatively rare, they are among the most lethal malignancies. Yet, with the exception of ionizing radiation and family history, their etiologic factors remain largely unknown. We conducted an untargeted metabolomics investigation pooling nested case-control studies from 9 prospective cohorts (median age 63 years, 59% women) in the Consortium of Metabolomics Studies (COMETS). One cancer-free control was individually matched to each of the 803 glioma cases based on age, sex, self-identified race/ethnicity, and blood collection date. Using an ultrahigh-performance LC-MS/MS platform (Metabolon, Inc.), we identified 874 known metabolites in pre-diagnostic serum or plasma, and logistic regression models conditioned on the matching factors) estimated odds ratios (ORs) and 95% confidence intervals for the associations between 1-SD increases in circulating metabolites and glioma risk …

Cancer Research

Prostate cancer (PCa) is the second leading cause of cancer-related death in men in the US. Epidemiology studies on primary PCa cohorts in Physicians' Health Study and Health Professionals Follow-up Study (PHS and HPFS) have shown that high levels of whole-genome aneuploidy, featured by imbalanced chromosome numbers, correlate with lethal progression in PCa. However, details of the mechanisms of how aneuploidy drives PCa aggressiveness are still unclear. Here, we used the case of chromosome 8q (chr 8q, the long arm of chr 8) gain to study aneuploidy-associated prostatic malignancies. Chr 8q gains are the most frequent gain events that occur in approximately 23% of PCa cases. By using the PHS and HPFS cohorts, we modeled the increased expression of each gene located on chr 8q, for predicting the risks for lethal progression, and obtained each corresponding gene’s odds ratio (OR). By …

Cancer Research

Background: Fine Particulate Matter (PM2.5) is associated with higher mortality among people with chronic conditions. Breast cancer (BC) survivors may be particularly vulnerable during cancer treatment. We assessed the association between PM2.5 during 9-months following BC diagnosis and all-cause and BC-mortality using policy relevant PM2.5 cut-offs. Methods: Using SEER-Medicare linked with a high-resolution model-based PM2.5 by residential zipcode (2007-2016), we assembled a cohort of women ≥66 years with incident stage I-IV BC. We assessed PM2.5 exposure, categorized as <8 µg/m3 (low), 8-12 µg/m3 (moderate) and >12 µg/m3 (high—above air quality standard), and types of cancer treatments (surgery [SX], chemotherapy [CTX], radiation therapy [RTX]) during a 9-month landmark period. We identified all-cause and BC death within 5 years of diagnosis. We fit multivariable Cox proportional …

Environmental research

ImportanceDespite biological plausibility, very few epidemiologic studies have investigated the risks of clinically significant bleeding events due to particulate air pollution.ObjectiveTo measure the independent and synergistic effects of PM2.5 exposure and anticoagulant use on serious bleeding events.DesignRetrospective cohort study (2008–2016).SettingNationwide Medicare population.ParticipantsA 50% random sample of Medicare Part D-eligible Fee-for-Service beneficiaries at high risk for cardiovascular and thromboembolic events.ExposuresFine particulate matter (PM2.5) and anticoagulant drugs (apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin).Main outcomes and measuresThe outcomes were acute hospitalizations for gastrointestinal bleeding, intracranial bleeding, or epistaxis. Hazard ratios and 95% CIs for PM2.5 exposure were estimated by fitting inverse probability weighted marginal …

EBioMedicine

BackgroundTumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear.MethodsWe meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P < 5.0 × 10−8) cis-acting SNPs (i.e., in or ±250 kb from the gene encoding the relevant protein) in weak linkage …

Cancer Research Communications

Bone pain is a well-known quality-of-life detriment for individuals with prostate cancer and is associated with survival. This study expands previous work into racial differences in multiple patient-reported dimensions of pain and the association between baseline and longitudinal pain and mortality. This is a prospective cohort study of individuals with newly diagnosed advanced prostate cancer enrolled in the International Registry for Men with Advanced Prostate Cancer (IRONMAN) from 2017 to 2023 at U.S. sites. Differences in four pain scores at study enrollment by race were investigated. Cox proportional hazards models and joint longitudinal survival models were fit for each of the scale scores to estimate HRs and 95% confidence intervals (CI) for the association with all-cause mortality. The cohort included 879 individuals (20% self-identifying as Black) enrolled at 38 U.S. sites. Black participants …

JNCI Cancer Spectrum

Multi-parametric magnetic resonance imaging (mpMRI) has emerged as an important tool for identifying clinically-significant prostate cancer. We examined if the addition of a 400-variant multi-ancestry polygenic risk score (PRS) to mpMRI has the potential to improve identification. Based on data from 24,617 men from the Mass General Brigham Biobank, we identified 1,243 men who underwent mpMRI. Men in the top PRS quartile were more likely to have clinically-significant prostate cancer (47.1% vs 28.6% in the bottom PRS quartile, adjusted relative proportion 1.72 [95% CI 1.35-2.19]). Both among men with a positive and a negative mpMRI, men in the top PRS quartile had the highest frequency of clinically-significant cancer. In a constructed scenario for selecting men to undergo biopsy, use of the PRS lowered the frequency of missed clinically-significant cancers from 9.1% to 5.9%. Our study provides …

Cancer Research

Prostate cancer (PCa) is a highly heritable cancer. While polygenic risk scores (PRS) stratify overall PCa risk among cancer-free men, they have not been reported to predict lethal outcomes in PCa patients. We aimed to examine to what extent PRS modifies associations between tumor biomarkers with cancer prognosis after diagnosis. We included men with primary, non-metastatic PCa in the Health Professionals Follow-up Study (HPFS) and Physicians’ Health Study (PHS). The PRS was constructed with 451 risk variants identified from prior PCa GWAS, measured on DNA from blood or buccal, standardized by adjusting for mean and standard deviation (SD) based on men without PCa with array-based genotyping data in HPFS/PHS. Prostate tumor biomarkers of molecular subtypes (TMPRSS2:ERG fusion, PTEN loss, and TP53 missense mutations from validated immunohistochemistry assays), insulin/lipid …

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 …