BACKGROUND AND PURPOSE: The optimal neoadjuvant approach in patients with resectable pancreas cancer is unclear. We investigated outcomes after preoperative chemotherapy alone, chemotherapy with conventionally-fractionated radiation (CFRT), or chemotherapy with stereotactic body radiotherapy (SBRT).MATERIALS AND METHODS: The NCDB was queried for patients with resectable pancreatic adenocarcinoma (pretreatment stage T1-3, N0-1, M0) who received preoperative, multiagent chemotherapy and definitive surgery from 2010 to 2015. CFRT was 40-60Gy in 20-35 fractions. SBRT was 20-25Gy in 1 fraction or 30-50Gy using at least 5Gy per fraction. Multivariable regression and propensity score matching were used to adjust for potential confounders, including age, comorbidity score, and pretreatment extent of disease. The primary outcome was overall survival measured from surgery.RESULTS: In total, 1355 patients received preoperative chemotherapy alone, 552 patients received preoperative chemotherapy with CFRT, and 175 patients received preoperative chemotherapy with SBRT. Receipt of SBRT was associated with significantly improved overall survival compared to chemotherapy alone (median 30 vs 21months, p=0.02; adjusted hazard ratio [HR] 0.65, 95% confidence interval [CI] 0.47-0.90, p=0.01). Similarly, SBRT was associated with significantly improved overall survival compared to CFRT (median 29 vs 16months, p=0.002; adjusted HR 0.53, 95% CI 0.37-0.76, p=0.001). Additionally, SBRT was associated with significantly increased rates of pathological complete response and margin-negative resection. Rates of postoperative readmissions and mortality were comparable.CONCLUSIONS: Neoadjuvant chemotherapy with SBRT is associated with favorable survival and pathological outcomes, warranting consideration for prospective validation.
View details for DOI 10.1016/j.radonc.2020.01.007
View details for PubMedID 32044168
Cisplatin with definitive radiotherapy (RT) is considered the standard of care for cervical cancer; however, older women are frequently undertreated and have worse outcomes compared with younger patients. Because women aged ≥65 years have been disproportionately underrepresented in clinical trials, uncertainties exist regarding how much they benefit from the addition of cisplatin to RT.Women aged ≥65 years with nonmetastatic cervical cancer treated with definitive external-beam RT and brachytherapy were identified in the SEER-Medicare database. Death attributable to cervical cancer (cancer-specific mortality [CSM]) was evaluated against competing risks of death using Gray's test. Propensity score analysis and the Fine-Gray multivariable regression model were used to adjust for baseline differences, including comorbidity.The total cohort comprised 826 patients, of whom 531 (64%) received cisplatin, 233 (28%) were FIGO stage I, 374 (45%) were stage II, and 219 (27%) were stage III-IVA. Older age and chronic kidney disease significantly predicted omission of cisplatin. Virtually all cisplatin dosing was weekly, with a median of 5 cycles. Death from cervical cancer was significantly lower with cisplatin than without (5-year CSM, 31% vs 39%; P=.02; adjusted hazard ratio, 0.72; P=.02), which persisted in propensity score analysis. Receiving ≥5 cycles was required for benefit, as no difference in CSM was seen in patients receiving 1 to 4 cycles versus no cisplatin. Subgroup analyses revealed that the benefit of cisplatin persisted in women aged ≥75 years and those with early-stage disease. Incidence of cytopenia, nausea/vomiting, and hypovolemia increased in patients treated with cisplatin.Administration of cisplatin with definitive RT in women aged ≥65 years was associated with a significant benefit in the incidence of death attributable to cervical cancer, despite competing risks for mortality in an older population. Receiving at least 5 cycles of weekly cisplatin was required for benefit.
View details for DOI 10.6004/jnccn.2019.7289
View details for Web of Science ID 000487240600011
View details for PubMedID 31390586
OBJECTIVES: To determine which patients with locoregionally advanced endometrial cancer may benefit from pelvic external beam radiotherapy (EBRT) in addition to chemotherapy compared to chemotherapy alone.METHODS: Patients with FIGO stages III-IVA endometrial carcinoma between 2004 and 2016 who underwent at least total hysterectomy and adjuvant multiagent chemotherapy were identified in the National Cancer Database. The primary outcome was overall survival according to receipt of pelvic EBRT, analyzed using the Kaplan-Meier method and Cox multivariable regression.RESULTS: In total, 13,270 patients were identified (62% pure endometrioid, 38% serous/clear cell or mixed histology; 22.6% stage IIIA, 4.7% stage IIIB, 71.2% stage IIIC, 1.5% stage IVA), of whom 40% received pelvic EBRT. In univariable analysis, EBRT was associated with absolute 5-year survival increases of 5% and 9% in the endometrioid and non-endometrioid cohorts, respectively (P < 0.0001). In multivariable analyses stratified by stage and histology, patients with a significant benefit from EBRT were stage IIIC (specifically IIIC2) endometrioid (adjusted hazard ratio [HR] 0.73, P = 0.01) and stages IIIB and IIIC non-endometrioid (adjusted HR 0.52, P = 0.01 and adjusted HR 0.79, P < 0.0001). The benefit of EBRT in node-positive patients persisted in those who underwent more extensive lymphadenectomy.CONCLUSIONS: Stages III-IVA endometrial cancer comprised a heterogeneous population with respect to the added benefit of radiotherapy compared to chemotherapy alone. Patients with stage IIIC2 endometrioid and stages IIIB-C non-endometrioid cancer may be most likely to benefit from pelvic EBRT.
View details for DOI 10.1016/j.ygyno.2019.06.020
View details for PubMedID 31257010
BACKGROUND: There is a lack of literature guiding treatment of giant cell glioblastoma (gcGBM), a rare subtype of glioblastoma (GBM). We used a national hospital-based registry to explore treatment patterns and outcomes associated with gcGBM.METHODS: Adult patients (age 18+) diagnosed with gcGBM or GBM between 2004-2014 were identified from the National Cancer Database (NCDB). Chi-squared analysis and Wilcoxon rank sum testing were used to compare characteristics between the gcGBM and GBM cohorts. Kaplan-Meier statistics, univariable and multivariable Cox regression, and propensity score matching were used to evaluate association between patient, tumor and treatment factors and survival outcomes. Correlation analysis was used to evaluate historical trends in the treatment of gcGBM. Landmark analysis allowed for accounting of immortal time.RESULTS: In total, 683 patients with gcGBM were identified. Patients with gcGBM had improved survival compared to patients with GBM (15.5 months from landmark vs 11.7, p < 0.001). Increased age (p < 0.001) was associated with worse survival while being of female sex (p = 0.023) and having a median income of higher than $63,000 (p = 0.004) predisposed patients to improved outcomes. Patients receiving trimodal therapy (biopsy and/or surgery, radiotherapy, and chemotherapy) experienced better outcomes compared to those receiving either biopsy and/or surgery only or biopsy and/or surgery and radiotherapy without systemic therapy (median survival 17.55 months vs 6.68 months; p < 0.001).CONCLUSION: gcGBM has favorable prognosis compared with GBM and should be aggressively managed with trimodal therapy. Prospective studies on gcGBM are warranted to better characterize gcGBM treatment outcomes.
View details for PubMedID 31009783
Patients with triple negative breast cancer were identified using the Surveillance, Epidemiology, and End Results database. Competing risks analysis was used to assess the cumulative incidence of breast cancer-specific mortality (BCSM). Multivariable Fine-Gray regression was used to identify predictors of BCSM. Women age 70+ (n=4221) were less likely to receive chemotherapy and radiation treatment (P<0.0001) and had higher BCSM compared to younger women (P<0.0001). There were no differences in BCSM in patients who received adjuvant treatment (P=0.10). Stage II patients derived the greatest relative and absolute benefit from adjuvant treatment. Age was not a significant predictor of BCSM.
View details for DOI 10.1111/tbj.13251
View details for PubMedID 30925635
For definitive chemoradiotherapy (chemoRT) of head and neck squamous cell carcinoma (HNSCC), cisplatin is the preferred concurrent agent, with superiority over cetuximab for HPV-associated oropharyngeal squamous carcinoma recently shown in 2 randomized trials (RTOG 1016 and De-ESCALaTE). Patients who are not candidates for cisplatin may be treated with carboplatin instead, but its comparative efficacy is unclear. We analyzed nationwide patterns of care and cancer-specific outcomes after cisplatin- versus carboplatin-based chemoRT.Patients with locoregionally advanced (stages III-IVB according to the 6th and 7th editions of the AJCC Cancer Staging Manual) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received definitive radiotherapy (RT) were identified in the linked SEER-Medicare database. The concurrent chemotherapy regimen was determined through corresponding Medicare claims. Death caused by HNSCC (cancer-specific mortality [CSM]) was analyzed with competing risks. Propensity score analysis and multivariable Fine-Gray regression were used to adjust for baseline differences, including age and comorbidity.We identified 807 patients who received cisplatin-based chemoRT and 342 who received carboplatin-based chemoRT. Most carboplatin recipients (68%) had combination chemotherapy, predominantly with paclitaxel. Carboplatin- and cisplatin-based chemoRT had similar incidences of death attributable to HNSCC (3-year CSM, 29% vs 26%; P=.19), which persisted in propensity score-matched analysis. In addition, no significant difference in overall survival was seen in the matched cohorts. ChemoRT with either cisplatin or carboplatin was superior to RT alone and RT with concurrent cetuximab. In the multivariable model, the adjusted hazard ratio of CSM for carboplatin relative to cisplatin was 1.01 (95% CI, 0.79-1.28; P=.94).Definitive carboplatin-based chemoRT was equivalent to cisplatin-based therapy and superior to RT alone and RT with concurrent cetuximab. In light of recent results of the RTOG 1016 and De-ESCALaTE trials, our findings suggest that carboplatin-based regimens warrant prospective investigation as an alternative to cisplatin for patients who are not cisplatin candidates.
View details for DOI 10.6004/jnccn.2019.7297
View details for PubMedID 31487677
Gastroesophageal junction (GEJ) cancers can be treated with equipoise using neoadjuvant chemoradiation (NACRT) or chemotherapy alone (NAC), but the comparative outcomes are unclear. Patients with non-metastatic T2-4 or N1-3 GEJ adenocarcinoma who underwent definitive surgery and NAC or NACRT were selected from the National Cancer Database. The primary outcome was overall survival (OS). Multivariable regression and propensity score analysis were used to adjust for age, comorbidity, and other characteristics.We identified 2435 patients treated with NACRT and 648 patients treated with NAC. OS was not significantly different between NACRT and NAC (51% versus 54% at 3 years, respectively, P = 0.11). Extent of pathological downstaging (complete, partial/mixed, none) after NACRT or NAC was highly prognostic of survival. Patients with no response did equally poorly after either preoperative regimen, and NAC was significantly less likely than NACRT to produce any response (adjusted odds ratio 0.62, P < 0.0001). Rate of adjuvant chemotherapy usage was significantly lower after NACRT than after NAC (12% versus 34%, P < 0.0001). In patients with residual tumor and nodal disease, adjuvant chemotherapy was associated with higher OS after NACRT (adjusted hazard ratio 0.81, P = 0.05), but not after NAC. These results were further validated by propensity score analysis.NACRT had similar survival to NAC despite superior pathological downstaging. Adjuvant chemotherapy is relatively underused after NACRT and warrants further study as a risk-adapted means to improve survival, especially in patients with larger burden of residual disease.
View details for DOI 10.1007/s10120-019-00980-6
View details for PubMedID 31230228
To better delineate optimal management of high-risk, early-stage endometrial cancer, as national guidelines permit substantial practice variations.Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IB grade 3 and stage II endometrioid carcinoma who underwent at least total hysterectomy were identified in SEER-Medicare. Adjuvant treatments were brachytherapy (BT), external beam radiation therapy (EBRT), and chemotherapy. Death from endometrial cancer (cancer-specific mortality [CSM]) and local recurrence were analyzed using Gray's test and Fine-Gray regression.In total, 1,095 patients were identified: 52% received BT, 56% received EBRT, 16% received chemotherapy, and 29% received no adjuvant treatment. Survival outcomes were significantly worse for stage IB grade 3 and stage II grade 3 relative to stage II grades 1-2 (5-year CSM: 18% and 23% vs. 10%; p<0.001 and p=0.003, respectively), while there was no difference between stage IB grade 3 and stage II grade 3 (p=0.618). BT had a local control benefit across all patients (p<0.001) that translated into a survival benefit in stage IB grade 3 (adjusted hazard ratio [HR] for CSM=0.47, p=0.003). EBRT had a survival benefit in stage II grade 3 (adjusted HR for CSM=0.36; p=0.031), as did lymph node dissection (p=0.015). Chemotherapy was not significantly correlated with CSM.High-risk, early-stage endometrioid carcinoma is a heterogeneous population. BT was associated with a survival benefit in stage IB grade 3, whereas regional treatment with EBRT and lymphadenectomy was associated with a survival benefit in stage II grade 3.
View details for DOI 10.3802/jgo.2020.31.e39
View details for PubMedID 31912686
OBJECTIVES: To investigate outcomes of adjuvant therapy for serous and clear cell endometrial carcinoma, as prior studies are limited by sample size and/or patient heterogeneity. National guidelines permit substantial variations in treatment, suggesting the need for additional data.METHODS: Patients with FIGO stages I-III serous or clear cell uterine carcinoma who underwent at least total hysterectomy were identified in SEER-Medicare. Adjuvant external beam radiation, brachytherapy, and chemotherapy were determined using SEER fields and Medicare claims. The primary outcome was death from endometrial cancer (cancer-specific mortality [CSM]) evaluated using Gray's test (univariable analysis, UVA) and Fine-Gray regression (multivariable analysis, MVA).RESULTS: A total of 1789 patients (1437 serous, 352 clear cell) were identified. In stages I-II patients (n = 1188), brachytherapy was significant for survival in UVA (P = 0.03) and MVA (P = 0.02). Additionally, in the subset with serous histology (n = 947), chemotherapy was also significant in UVA (P = 0.002) and approached significance in MVA (P = 0.05). The 4-year CSM for stages I-II serous cancers was 25% without brachytherapy or chemotherapy, 15% with one, and 9% with both (P ≤ 0.05 for all pairwise comparisons). In stage III patients (n = 601), chemotherapy was significant in UVA (P = 0.002) and MVA (P = 0.006). Most (81%) patients underwent lymph node dissection, which predicted lower CSM in stage III (P = 0.001) but not stages I-II patients.CONCLUSIONS: Our results suggest brachytherapy benefits stages I-II serous/clear cell cancers, chemotherapy benefits stage III serous/clear cell cancers, and both chemotherapy and brachytherapy benefit stages I-II serous cancers.
View details for PubMedID 30551884
BACKGROUND: Cisplatin and cetuximab are both systemic therapies commonly used in combination with radiation (RT) for the definitive treatment of head and neck cancers, but their comparative efficacy is unclear.METHODS: Patients with locoregionally advanced (American Joint Committee on Cancer stage III-IVB) squamous cell carcinomas of the oropharynx, larynx, or hypopharynx were identified in the Surveillance, Epidemiology, and End Results-Medicare database. Patients received either cisplatin or cetuximab concurrent with RT, as determined by Medicare claims. The primary study outcome was head and neck cancer-specific mortality (CSM) analyzed with competing risks. Filtering, propensity score matching, and multivariable Fine-Gray regression were used to adjust for differences between the cisplatin and cetuximab cohorts, including age, comorbidity, and cycles of systemic therapy received.RESULTS: The total cohort consisted of 1395 patients, of whom 786 (56%) received cisplatin and 609 (44%) received cetuximab; the median follow-up was 3.5 years in the patients who remained alive. In the cetuximab cohort, CSM was significantly higher than in the cisplatin cohort (39% vs 25% at 3 years; P < .0001). In the matched cohorts (n = 414), the adjusted hazard ratio of CSM for cetuximab was 1.65 (95% confidence interval, 1.30-2.09; P < .0001) relative to cisplatin, corresponding to an absolute difference of approximately 10% in both CSM and overall survival at 3 years. Cetuximab was associated with less dysphagia, more dermatitis, and a similar incidence of mucositis.CONCLUSIONS: In this sizeable, national patient population, treatment with cetuximab was associated with significantly higher CSM than cisplatin. These results suggest that cisplatin may be the preferred chemotherapeutic agent in this setting. Cancer 2018;124:000-000.
View details for PubMedID 30332498
View details for Web of Science ID 000432447200037
The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is frequently activated inappropriately in a wide range of hematological and solid cancers, but clinically-available therapies targeting STAT3 are lacking. Using a computational strategy to identify compounds opposing the gene expression signature of STAT3, we discovered atovaquone (Mepron™), an FDA-approved anti-microbial, to be a potent STAT3 inhibitor. We show that, at drug concentrations routinely achieved clinically in human plasma, atovaquone inhibits STAT3 phosphorylation, the expression of STAT3 target genes, and the viability of STAT3-dependent hematological cancer cells. These effects were also observed with atovaquone treatment of primary blasts isolated from patients with acute myelogenous leukemia or acute lymphocytic leukemia. Atovaquone is not a kinase inhibitor, but instead rapidly and specifically downregulates cell-surface expression of glycoprotein 130 (gp130), which is required for STAT3 activation in multiple contexts. The administration of oral atovaquone to mice inhibited tumor growth and prolonged survival in a murine model of multiple myeloma. Finally, in patients with acute myelogenous leukemia treated with hematopoietic stem cell transplantation, extended use of atovaquone for Pneumocystis prophylaxis was associated with improved relapse-free survival. These findings establish atovaquone as a novel, clinically-accessible STAT3 inhibitor with evidence of anti-cancer efficacy in both animal models and humans.
View details for DOI 10.1182/blood-2015-07-660506
View details for Web of Science ID 000385737900012
View details for PubMedID 27531676
View details for PubMedCentralID PMC5054697
Recent retrospective data suggest that brachytherapy (BT) boost may confer a cancer-specific survival benefit in radiation-managed high-risk prostate cancer. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4 + 4 = 8, PSA < 10 ng/ml or T1c, Gleason 6, PSA > 20 ng/ml).We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with external beam radiation therapy (EBRT) only or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT + BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors.EBRT + BT was not associated with an improvement in 5-year PCSM compared to EBRT alone among patients with favorable high-risk disease (1.6% vs. 1.8%; adjusted hazard ratio [AHR]: 0.56; 95% confidence interval [CI]: 0.21-1.52, p = 0.258), and intermediate-risk disease (0.8% vs. 1.0%, AHR: 0.83, 95% CI: 0.59-1.16, p = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with EBRT + BT compared with EBRT alone (3.9% vs. 5.3%; AHR: 0.73; 95% CI: 0.55-0.95; p = 0.022).Brachytherapy boost is associated with a decreased rate of PCSM in some men with high-risk prostate cancer but not among patients with favorable high-risk disease. Our results suggest that the recently-defined "favorable high-risk" category may be used to personalize therapy for men with high-risk disease.
View details for DOI 10.5114/jcb.2016.58080
View details for Web of Science ID 000372138300001
View details for PubMedID 26985191
View details for PubMedCentralID PMC4793071
A randomized trial recently found that adding brachytherapy (BT) boost to external beam radiation therapy (EBRT) improves biochemical recurrence-free survival but not prostate cancer-specific mortality (PCSM). We investigated the relationship between BT boost and PCSM in a modern cohort from a large population-based database.We conducted an analysis of patients in Surveillance, Epidemiology, and End Results diagnosed with intermediate- or high-risk prostate cancer in 2004-2011, treated with EBRT only or EBRT + BT. The cumulative incidence of PCSM was evaluated in the presence of other-cause mortality as a competing risk. Propensity score matching and multivariable Fine and Gray proportional hazard models were used to evaluate the association of combined modality RT on PCSM.A total of 52,535 patients were identified, of which 19.6% were treated with EBRT + BT. One-third of cases were high-risk. On multivariable analysis, the adjusted hazard ratio (AHR) of PCSM for EBRT + BT vs. EBRT alone was 0.69 (95% confidence interval [CI], 0.55-0.87, p = 0.002), and the adjusted incidence of PCSM was 1.8% vs. 2.7% at 8 years, respectively. In subgroup analyses, the AHR for PCSM was also significantly reduced with EBRT + BT for high-risk disease (AHR 0.70; 95% CI, 0.52-0.94, p = 0.02; adjusted incidence of PCSM at 8 years, 5.4% vs. 7.6%), but not for intermediate-risk disease.BT boost was associated with a moderate reduction to PCSM in men with localized unfavorable-risk prostate cancer. Those most likely to benefit are younger patients with high-risk disease.
View details for DOI 10.1016/j.brachy.2015.09.004
View details for Web of Science ID 000366540000006
View details for PubMedID 26489921
View details for PubMedCentralID PMC4833213
Inappropriate expression or activation of transcription factors can drive patterns of gene expression, leading to the malignant behavior of breast cancer cells. We have found that the transcriptional repressor BCL6 is highly expressed in breast cancer cell lines, and its locus is amplified in about half of primary breast cancers. To understand how BCL6 regulates gene expression in breast cancer cells, we used chromatin immunoprecipitation followed by deep sequencing to identify the BCL6 binding sites on a genomic scale. This revealed that BCL6 regulates a unique cohort of genes in breast cancer cell lines compared with B-cell lymphomas. Furthermore, BCL6 expression promotes the survival of breast cancer cells, and targeting BCL6 with a peptidomimetic inhibitor leads to apoptosis of these cells. Finally, combining a BCL6 inhibitor and a signal transducer and activator of transcription3 inhibitor provided enhanced cell killing in triple-negative breast cancer cell lines, suggesting that combination therapy may be particularly useful. Thus, targeting BCL6 alone or in conjunction with other signaling pathways may be a useful therapeutic strategy for treating breast cancer.
View details for DOI 10.1038/onc.2014.61
View details for Web of Science ID 000350122100001
View details for PubMedID 24662818
View details for PubMedCentralID PMC4175367
The transcription factor STAT3 regulates genes that control critical cellular processes such as proliferation, survival, pluripotency, and motility. Thus, under physiological conditions, the transcriptional function of STAT3 is tightly regulated as one part of a complex signaling matrix. When these processes are subverted through mutation or epigenetic events, STAT3 becomes highly active and drives elevated expression of genes underlying these phenotypes, leading to malignant cellular behavior. However, even in the presence of activated STAT3, other cellular modulators can have a major impact on the biological properties of a cancer cell, which is reflected in the clinical behavior of a tumor. Recent evidence has suggested that two such key modulators are the activation status of other STAT family members, particularly STAT5, and the expression of STAT3-regulated genes that are part of negative feedback circuits, including microRNAs such as miR-146b. With attention to these newly emerging areas, we will gain greater insight into the consequence of STAT3 activation in the biology of human cancers. In addition, understanding these subtleties of STAT3 signaling in cancer pathogenesis will allow the development of more rational molecular approaches to cancer therapy.
View details for DOI 10.3390/cancers6020958
View details for Web of Science ID 000209950600017
View details for PubMedID 24762632
View details for PubMedCentralID PMC4074811
The transcription factor signal STAT5 is constitutively activated in a wide range of leukemias and lymphomas, and drives the expression of genes necessary for proliferation, survival, and self-renewal. Thus, targeting STAT5 is an appealing therapeutic strategy for hematologic malignancies. Given the importance of bromodomain-containing proteins in transcriptional regulation, we considered the hypothesis that a pharmacologic bromodomain inhibitor could inhibit STAT5-dependent gene expression. We found that the small-molecule bromodomain and extra-terminal (BET) bromodomain inhibitor JQ1 decreases STAT5-dependent (but not STAT3-dependent) transcription of both heterologous reporter genes and endogenous STAT5 target genes. JQ1 reduces STAT5 function in leukemia and lymphoma cells with constitutive STAT5 activation, or inducibly activated by cytokine stimulation. Among the BET bromodomain subfamily of proteins, it seems that BRD2 is the critical mediator for STAT5 activity. In experimental models of acute T-cell lymphoblastic leukemias, where activated STAT5 contributes to leukemia cell survival, Brd2 knockdown or JQ1 treatment shows strong synergy with tyrosine kinase inhibitors (TKI) in inducing apoptosis in leukemia cells. In contrast, mononuclear cells isolated form umbilical cord blood, which is enriched in normal hematopoietic precursor cells, were unaffected by these combinations. These findings indicate a unique functional association between BRD2 and STAT5, and suggest that combinations of JQ1 and TKIs may be an important rational strategy for treating leukemias and lymphomas driven by constitutive STAT5 activation.
View details for DOI 10.1158/1535-7163.MCT-13-0341
View details for Web of Science ID 000335961600015
View details for PubMedID 24435449
View details for PubMedCentralID PMC4013223
Interleukin-6 (IL-6)-mediated activation of signal transducer and activator of transcription 3 (STAT3) is a mechanism by which chronic inflammation can contribute to cancer and is a common oncogenic event. We discovered a pathway, the loss of which is associated with persistent STAT3 activation in human cancer. We found that the gene encoding the tumor suppressor microRNA miR-146b is a direct STAT3 target gene, and its expression was increased in normal breast epithelial cells but decreased in tumor cells. Methylation of the miR-146b promoter, which inhibited STAT3-mediated induction of expression, was increased in primary breast cancers. Moreover, we found that miR-146b inhibited nuclear factor κB (NF-κB)-dependent production of IL-6, subsequent STAT3 activation, and IL-6/STAT3-driven migration and invasion in breast cancer cells, thereby establishing a negative feedback loop. In addition, higher expression of miR-146b was positively correlated with patient survival in breast cancer subtypes with increased IL6 expression and STAT3 phosphorylation. Our results identify an epigenetic mechanism of crosstalk between STAT3 and NF-κB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis.
View details for DOI 10.1126/scisignal.2004497
View details for Web of Science ID 000331082000004
View details for PubMedID 24473196
View details for PubMedCentralID PMC4233120
The transcription factors STAT3 and STAT5 play important roles in the regulation of mammary gland function during pregnancy, lactation, and involution. Given that STAT3 and STAT5 regulate genes involved in proliferation and survival, it is not surprising that inappropriate activation of STAT3 and STAT5 occurs commonly in breast cancer. Although these proteins are structurally similar, they have divergent and opposing effects on gene expression and cellular phenotype. Notably, when STAT5 and STAT3 are activated simultaneously, STAT5 has a dominant effect, and leads to decreased proliferation and increased sensitivity to cell death. Similarly, in breast cancer, activation of both STAT5 and STAT3 is associated with longer patient survival than activation of STAT3 alone. Pharmacological inhibitors of STAT3 and STAT5 are being developed for cancer therapy, though understanding the activation state and functional interaction of STAT3 and STAT5 in a patient's tumor may be critical for the optimal use of this strategy.
View details for DOI 10.1016/j.mce.2013.03.010
View details for Web of Science ID 000330421600066
View details for PubMedID 23531638
View details for PubMedCentralID PMC3732813
STAT transcription factors play a critical role in mediating the effects of cytokines on myeloid cells. As STAT target genes control key processes such as survival, proliferation and self-renewal, it is not surprising that constitutive activation of STATs, particularly STAT3 and STAT5, are common events in many myeloid tumors. STATs are activated both by mutant tyrosine kinases as well as other pathogenic events, and continued activation of STATs is common in the setting of resistance to kinase inhibitors. Thus, the targeting of STATs, alone or in combination with other drugs, will likely have increasing importance for cancer therapy.
View details for DOI 10.4161/jkst.20006
View details for PubMedID 24058751
View details for PubMedCentralID PMC3670294
The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34(+) bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.
View details for DOI 10.1182/blood-2009-11-255232
View details for Web of Science ID 000288848500025
View details for PubMedID 21233313
View details for PubMedCentralID PMC3069678
The Wilms' tumor suppressor 1 (WT1) gene encodes a DNA- and RNA-binding protein that plays an essential role in nephron progenitor differentiation during renal development. To identify WT1 target genes that might regulate nephron progenitor differentiation in vivo, we performed chromatin immunoprecipitation (ChIP) coupled to mouse promoter microarray (ChIP-chip) using chromatin prepared from embryonic mouse kidney tissue. We identified 1663 genes bound by WT1, 86% of which contain a previously identified, conserved, high-affinity WT1 binding site. To investigate functional interactions between WT1 and candidate target genes in nephron progenitors, we used a novel, modified WT1 morpholino loss-of-function model in embryonic mouse kidney explants to knock down WT1 expression in nephron progenitors ex vivo. Low doses of WT1 morpholino resulted in reduced WT1 target gene expression specifically in nephron progenitors, whereas high doses of WT1 morpholino arrested kidney explant development and were associated with increased nephron progenitor cell apoptosis, reminiscent of the phenotype observed in Wt1(-/-) embryos. Collectively, our results provide a comprehensive description of endogenous WT1 target genes in nephron progenitor cells in vivo, as well as insights into the transcriptional signaling networks controlled by WT1 that might direct nephron progenitor fate during renal development.
View details for DOI 10.1242/dev.045732
View details for Web of Science ID 000275369300018
View details for PubMedID 20215353
View details for PubMedCentralID PMC2835332
The identification of reliable peripheral biomarkers for clinical diagnosis, patient prognosis, and biological functional studies would allow for access to biological information currently available only through invasive methods. Traditional approaches have so far considered aspects of tissues and biofluid markers independently. Here we introduce an information theoretic framework for biomarker discovery, integrating biofluid and tissue information. This allows us to identify tissue information in peripheral biofluids. We treat tissue-biofluid interactions as an information channel through functional space using 26 proteomes from 45 different sources to determine quantitatively the correspondence of each biofluid for specific tissues via relative entropy calculation of proteomes mapped onto phenotype, function, and drug space. Next, we identify candidate biofluids and biomarkers responsible for functional information transfer (p < 0.01). A total of 851 unique candidate biomarkers proxies were identified. The biomarkers were found to be significant functional tissue proxies compared to random proteins (p < 0.001). This proxy link is found to be further enhanced by filtering the biofluid proteins to include only significant tissue-biofluid information channels and is further validated by gene expression. Furthermore, many of the candidate biomarkers are novel and have yet to be explored. In addition to characterizing proteins and their interactions with a systemic perspective, our work can be used as a roadmap to guide biomedical investigation, from suggesting biofluids for study to constraining the search for biomarkers. This work has applications in disease screening, diagnosis, and protein function studies.
View details for PubMedID 18229689
Gene Ontology (GO) has been widely used to infer functional significance associated with sets of genes in order to automate discoveries within large-scale genetic studies. A level in GO's direct acyclic graph structure is often assumed to be indicative of its terms' specificities, although other work has suggested this assumption does not hold. Unfortunately, quantitative analysis of biological functions based on nodes at the same level (as is common in gene enrichment analysis tools) can lead to incorrect conclusions as well as missed discoveries due to inefficient use of available information. This paper addresses these using an informational theoretic approach encoded in the GO Partition Database that guarantees to maximize information for gene enrichment analysis. The GO Partition Database was designed to feature ontology partitions with GO terms of similar specificity. The GO partitions comprise varying numbers of nodes and present relevant information theoretic statistics, so researchers can choose to analyze datasets at arbitrary levels of specificity. The GO Partition Database, featuring GO partition sets for functional analysis of genes from human and 10 other commonly studied organisms with a total of 131,972 genes, is available on the internet at: bcl.med.harvard.edu/proj/gopart. The site also includes an online tutorial.
View details for DOI 10.1093/nar/gkl799
View details for Web of Science ID 000243494600067
View details for PubMedID 17098937
View details for PubMedCentralID PMC1669720