Person: Matulonis, Ursula
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Matulonis
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Ursula
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Matulonis, Ursula
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Publication Publisher Correction: Nanoparticle conjugates of a highly potent toxin enhance safety and circumvent platinum resistance in ovarian cancer(Nature Publishing Group UK, 2018) Qi, Ruogu; Wang, Yongheng; Bruno, Peter M.; Xiao, Haihua; Yu, Yingjie; Li, Ting; Lauffer, Sam; Wei, Wei; Chen, Qixian; Kang, Xiang; Song, Haiqin; Yang, Xi; Huang, Xing; Detappe, Alexandre; Matulonis, Ursula; Pepin, David; Hemann, Michael T.; Birrer, Michael J.; Ghoroghchian, P. PeterPublication Current Status and Evolution of Preclinical Drug Development Models of Epithelial Ovarian Cancer(Frontiers Media S.A., 2013) Konstantinopoulos, Panagiotis; Matulonis, UrsulaEpithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy and the fifth most common cause of female cancer death in the United States. Although important advances in surgical and chemotherapeutic strategies over the last three decades have significantly improved the median survival of EOC patients, the plateau of the survival curve has not changed appreciably. Given that EOC is a genetically and biologically heterogeneous disease, identification of specific molecular abnormalities that can be targeted in each individual ovarian cancer on the basis of predictive biomarkers promises to be an effective strategy to improve outcome in this disease. However, for this promise to materialize, appropriate preclinical experimental platforms that recapitulate the complexity of these neoplasms and reliably predict antitumor activity in the clinic are critically important. In this review, we will present the current status and evolution of preclinical models of EOC, including cell lines, immortalized normal cells, xenograft models, patient-derived xenografts, and animal models, and will discuss their potential for oncology drug development.Publication Sublethal concentrations of 17-AAG suppress homologous recombination DNA repair and enhance sensitivity to carboplatin and olaparib in HR proficient ovarian cancer cells(Impact Journals LLC, 2014) Choi, Young Eun; Battelli, Chiara; Watson, Jacqueline; Liu, Joyce; Curtis, Jennifer; Morse, Alexander N.; Matulonis, Ursula; Chowdhury, Dipanjan; Konstantinopoulos, PanagiotisThe promise of PARP-inhibitors(PARPis) in the management of epithelial ovarian cancer(EOC) is tempered by the fact that approximately 50% of patients with homologous recombination (HR)-proficient tumors do not respond well to these agents. Combination of PARPis with agents that inhibit HR may represent an effective strategy to enhance their activity in HR-proficient tumors. Using a bioinformatics approach, we identified that heat shock protein 90 inhibitors(HSP90i) may suppress HR and thus revert HR-proficient to HR-deficient tumors. Analysis of publicly available gene expression data showed that exposure of HR-proficient breast cancer cell lines to HSP90i 17-AAG(17-allylamino-17-demethoxygeldanamycin) downregulated HR, ATM and Fanconi Anemia pathways. In HR-proficient EOC cells, 17-AAG suppressed HR as assessed using the RAD51 foci formation assay and this was further confirmed using the Direct Repeat-GFP reporter assay. Furthermore, 17-AAG downregulated BRCA1 and/or RAD51 protein levels, and induced significantly more γH2AX activation in combination with olaparib compared to olaparib alone. Finally, sublethal concentrations of 17-AAG sensitized HR-proficient EOC lines to olaparib and carboplatin but did not affect sensitivity of the HR-deficient OVCAR8 line arguing that the 17-AAG mediated sensitization is dependent on suppression of HR. These results provide a preclinical rationale for using a combination of olaparib/17-AAG in HR-proficient EOC.Publication Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome(American Association for Cancer Research (AACR), 2012) Wang, Z. C.; Birkbak, N; Culhane, Aedin; Drapkin, Ronny; Fatima, Aquila; Tian, R; Schwede, M.; Alsop, K.; Daniels, K. E.; Piao, H.; Liu, Joy; Etemadmoghadam, D.; Miron, A; Salvesen, H. B.; Mitchell, G.; DeFazio, A.; Quackenbush, John; Berkowitz, Ross; Iglehart, James; Bowtell, D. D. L.; Matulonis, UrsulaPurpose—High-grade serous cancer (HGSC) is the most common cancer of the ovary and is characterized by chromosomal instability. Defects in homologous recombination repair (HRR) are associated with genomic instability in HGSC, and are exploited by therapy targeting DNA repair. Defective HRR causes uniparental deletions and loss of heterozygosity (LOH). Our purpose is to profile LOH in HGSC and correlate our findings to clinical outcome, and compare HGSC and high-grade breast cancers. Experimental Design—We examined LOH and copy number changes using single nucleotide polymorphism array data from three HGSC cohorts and compared results to a cohort of high-grade breast cancers. The LOH profiles in HGSC were matched to chemotherapy resistance and progression-free survival (PFS). Results—LOH-based clustering divided HGSC into two clusters. The major group displayed extensive LOH and was further divided into two subgroups. The second group contained remarkably less LOH. BRCA1 promoter methylation was associated with the major group. LOH clusters were reproducible when validated in two independent HGSC datasets. LOH burden in the major cluster of HGSC was similar to triple-negative, and distinct from other high-grade breast cancers. Our analysis revealed an LOH cluster with lower treatment resistance and a significant correlation between LOH burden and PFS. Conclusions—Separating HGSC by LOH-based clustering produces remarkably stable subgroups in three different cohorts. Patients in the various LOH clusters differed with respect to chemotherapy resistance, and the extent of LOH correlated with PFS. LOH burden may indicate vulnerability to treatment targeting DNA repair, such as PARP1 inhibitors.Publication CA125 Immune Complexes in Ovarian Cancer Patients with Low CA125 Concentrations(American Association for Clinical Chemistry (AACC), 2010) Cramer, Daniel; O'Rourke, D. J.; Vitonis, A. F.; Matulonis, Ursula; DiJohnson, D. A.; Sluss, Patrick M.; Crum, Christopher; Liu, B. C.- S.BACKGROUND About 20% of women with ovarian cancer have low concentrations of serum cancer antigen 125 (CA125), and this important tumor marker cannot be used to monitor their disease. The measured concentration for mucin 1 (MUC1), or CA15–3, another tumor marker, can be lowered in breast and ovarian cancer patients when circulating immune complexes (CICs) containing antibodies bound to the free antigen are present. Because CA125 and MUC1 are related members of the mucin family, we sought to determine whether CICs might also exist for CA125 and interfere with its clinical assay. METHODS We developed an antigen capture–based assay to determine the presence of CICs for CA125. We spotted mouse antibodies to CA125 onto nanoparticle slides, incubated them with patient serum, and added Cy5-tagged goat antihuman IgG antibodies. Fluorescence intensities were read and normalized to the intensities for glutathione S-transferase A1 as a control. RESULTS Assay results for 23 ovarian cancer cases with high CA125 concentrations, 43 cases with low CA125 concentrations, and 19 controls (mean CA125 concentrations, 2706, 23, and 11 kilounits/L, respectively) revealed mean fluorescence intensities for CA125 CIC of 2.30, 2.72, and 1.99 intensity units (iu), respectively. A generalized linear model adjusted for batch and age showed higher CA125 CIC fluorescence intensities in low-CA125 cases than in high-CA125 cases (P = 0.03) and controls (P = 0.0005). Four ovarian cancer patients who had recurrent disease and always had low CA125 values had a mean CA125 CIC value of 3.06 iu (95% CI, 2.34–4.01 iu). CONCLUSIONS These preliminary results suggest the existence of CICs involving CA125, which may help explain some ovarian cancer cases with low CA125 concentrations.Publication Influence of Patients' Preferences and Treatment Site on Cancer Patients' End-of-Life Care(Wiley-Blackwell, 2010) Wright, Alexi; Mack, Jennifer; Kritek, Patricia A.; Balboni, Tracy; Massaro, Anthony; Matulonis, Ursula; Block, Susan; Prigerson, HollyBACKGROUND: Research suggests that patients' end-of-life (EOL) care is determined primarily by the medical resources available, and not by patient preferences. The authors examined whether patients' desire for life-extending therapy was associated with their EOL care. METHODS: Coping with Cancer is a multisite, prospective, longitudinal study of patients with advanced cancer. Three hundred one patients were interviewed at baseline and followed until death, a median of 4.5 months later. Multivariate analyses examined the influence of patients' preferences and treatment site on whether patients received intensive care or hospice services in the final week of life. RESULTS: Eighty-three of 301 patients (27.6%) with advanced cancer wanted life-extending therapy at baseline. Patients who understood that their disease was terminal or who reported having EOL discussions with their physicians were less likely to want life-extending care compared with others (23.4% vs 42.6% and 20.7% vs 44.4%, respectively; P≤.003). Patients who were treated at Yale Cancer Center received more intensive care (odds ratio [OR], 3.14; 95% confidence interval [CI], 1.16-8.47) and less hospice services (OR, 0.52; 95% CI, 0.29-0.92) compared with patients who were treated at Parkland Hospital. However, in multivariate analyses that controlled for confounding influences, patients who preferred life-extending care were more likely to receive intensive care (adjusted OR [AOR], 2.91; 95% CI, 1.09-7.72) and were less likely to receive hospice services (AOR, 0.45; 95% CI, 0.26-0.78). Treatment site was not identified as a significant predictor of EOL care. CONCLUSIONS: The treatment preferences of patients with advanced cancer may play a more important role in determining the intensity of medical care received at the EOL than previously recognized. Future research is needed to determine the mechanisms by which patients' preferences for care and treatment site interact to influence EOL care.Publication Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer(Impact Journals LLC, 2016) Strickland, Kyle C.; Howitt, Brooke E.; Shukla, Sachet A.; Rodig, Scott; Ritterhouse, Lauren L.; Liu, Joyce F.; Garber, Judy; Chowdhury, Dipanjan; Wu, Catherine; D'Andrea, Alan; Matulonis, Ursula; Konstantinopoulos, PanagiotisImmune checkpoint inhibitors (e.g., anti-PD-1 and anti-PD-L1 antibodies) have demonstrated remarkable efficacy against hypermutated cancers such as melanomas and lung carcinomas. One explanation for this effect is that hypermutated lesions harbor more tumor-specific neoantigens that stimulate recruitment of an increased number of tumor-infiltrating lymphocytes (TILs), which is counterbalanced by overexpression of immune checkpoints such as PD-1 or PD-L1. Given that BRCA1/2-mutated high grade serous ovarian cancers (HGSOCs) exhibit a higher mutational load and a unique mutational signature with an elevated number of larger indels up to 50 bp, we hypothesized that they may also harbor more tumor-specific neoantigens, and, therefore, exhibit increased TILs and PD-1/PD-L1 expression. Here, we report significantly higher predicted neoantigens in BRCA1/2-mutated tumors compared to tumors without alterations in homologous recombination (HR) genes (HR-proficient tumors). Tumors with higher neoantigen load were associated with improved overall survival and higher expression of immune genes associated with tumor cytotoxicity such as genes of the TCR, the IFN-gamma and the TNFR pathways. Furthermore, immunohistochemistry studies demonstrated that BRCA1/2-mutated tumors exhibited significantly increased CD3+ and CD8+ TILs, as well as elevated expression of PD-1 and PD-L1 in tumor-associated immune cells compared to HR-proficient tumors. Survival analysis showed that both BRCA1/2-mutation status and number of TILs were independently associated with outcome. Of note, two distinct groups of HGSOCs, one with very poor prognosis (HR proficient with low number of TILs) and one with very good prognosis (BRCA1/2-mutated tumors with high number of TILs) were defined. These findings support a link between BRCA1/2-mutation status, immunogenicity and survival, and suggesting that BRCA1/2-mutated HGSOCs may be more sensitive to PD-1/PD-L1 inhibitors compared to HR-proficient HGSOCs.Publication Association of Polymerase e–Mutated and Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1(American Medical Association (AMA), 2015) Howitt, Brooke E.; Shukla, Sachet; Sholl, Lynette; Ritterhouse, Lauren L.; Watkins, Jaclyn Christine; Rodig, Scott; Stover, Elizabeth; Strickland, Kyle C.; D'Andrea, Alan; Wu, Catherine; Matulonis, Ursula; Konstantinopoulos, PanagiotisImportance Immune checkpoint inhibitor therapy has shown benefit in various cancers, but their potential in endometrial cancer (EC) is unknown. Observations Prediction of neoantigen load was performed using sequencing data from the Cancer Genome Atlas data set. Evaluation of tumor-infiltrating lymphocytes (TILs) and PD-1 and PD-L1 expression was performed in 63 patients with EC referred to our institution. The predicted median (range) neoantigen load (predicted neoepitopes per sample) was proportional to the mutational load: highest in ultramutated polymerase e (POLE) tumors (8342 [628-20 440]), less in hypermutated MSI (541 [146-8063]; P < .001), and lowest in microsatellite-stable tumors (70.5 [7-1877]; P < .001). The POLE and MSI ECs exhibited higher numbers of CD3+ (44.5 vs 21.8; P = .001) and CD8+ (32.8 vs 13.5; P < .001) TILs compared with microsatellite-stable tumors. PD-1 was overexpressed in TILs (81% vs 28%; P < .001) and peritumoral lymphocytes (90% vs 28%; P < .001) of POLE and MSI tumors. PD-L1 expression was infrequently noted in tumor cells but was common in intraepithelial immune cells and more frequent in POLE and MSI tumors (39% vs 13%; P = .02). Conclusions and Relevance Polymerase e–mutated and MSI ECs are associated with high neoantigen loads and number of TILs, which is counterbalanced by overexpression of PD-1 and PD-L1. Polymerase e–mutated and MSI EC tumors may be excellent candidates for PD-1–targeted immunotherapies.Publication Angiogenic mRNA and microRNA Gene Expression Signature Predicts a Novel Subtype of Serous Ovarian Cancer(Public Library of Science, 2012) Risch, Thomas; Fan, Jian-Bing; Holton, Kristina; Rubio, Renee; April, Craig; Wickham-Garcia, Eliza; Bentink, Stefan; Haibe-Kains, Benjamin; Hirsch, Michelle; Chen, Jing; Liu, Joyce; Culhane, Aedin; Drapkin, Ronny; Quackenbush, John; Matulonis, UrsulaOvarian cancer is the fifth leading cause of cancer death for women in the U.S. and the seventh most fatal worldwide. Although ovarian cancer is notable for its initial sensitivity to platinum-based therapies, the vast majority of patients eventually develop recurrent cancer and succumb to increasingly platinum-resistant disease. Modern, targeted cancer drugs intervene in cell signaling, and identifying key disease mechanisms and pathways would greatly advance our treatment abilities. In order to shed light on the molecular diversity of ovarian cancer, we performed comprehensive transcriptional profiling on 129 advanced stage, high grade serous ovarian cancers. We implemented a, re-sampling based version of the ISIS class discovery algorithm (rISIS: robust ISIS) and applied it to the entire set of ovarian cancer transcriptional profiles. rISIS identified a previously undescribed patient stratification, further supported by micro-RNA expression profiles, and gene set enrichment analysis found strong biological support for the stratification by extracellular matrix, cell adhesion, and angiogenesis genes. The corresponding “angiogenesis signature” was validated in ten published independent ovarian cancer gene expression datasets and is significantly associated with overall survival. The subtypes we have defined are of potential translational interest as they may be relevant for identifying patients who may benefit from the addition of anti-angiogenic therapies that are now being tested in clinical trials.Publication Detection of ERBB2 Amplification in Uterine Serous Carcinoma by Next-Generation Sequencing: An Approach Highly Concordant With Standard Assays(Springer Science and Business Media LLC, 2020-10-19) Robinson, Carrie; Harrison, Beth; Ligon, Azra; Dong, Fei; Maffeis, Valeria; Matulonis, Ursula; Nucci, Marisa; Kolin, David L.Uterine serous carcinoma is an aggressive subtype of endometrial cancer that accounts for fewer than 10% of endometrial carcinomas but is responsible for about half of deaths. A subset of cases has HER2 overexpression secondary to ERBB2 gene amplification, and these patients may benefit from anti-HER2 therapies, such as trastuzumab. HER2 protein overexpression is currently assessed by immunohistochemistry (IHC) and ERBB2 gene amplification by fluorescence in situ hybridization (FISH). Targeted next-generation sequencing (NGS) is increasingly used to routinely identify predictive and prognostic molecular abnormalities in endometrial carcinoma. To investigate the ability of a targeted NGS panel to detect ERBB2 amplification, we identified cases of uterine serous carcinoma (n=93) and compared HER2 expression by IHC and copy number assessed by FISH with copy number status assessed by NGS. ERBB2 copy number status using a combination of IHC and FISH was interpreted using the 2018 ASCO/CAP guidelines for breast carcinoma. ERBB2 amplification by NGS was determined by the relative number of reads mapping to ERBB2 in tumor DNA compared to control non-neoplastic DNA. Cases with copy number ≥6 were considered amplified and copy number <6 were non-amplified. By IHC, 70 specimens were classified as negative (0 or 1+), 19 were classified as equivocal (2+), and 4 were classified as positive (3+). Using combined IHC/FISH, ERBB2 amplification was observed in 8 of 93 cases (9%). NGS identified the same 8 cases with copy number ≥6; all 85 others had copy number <6. In this series, NGS had 100% concordance with combined IHC/FISH in identifying ERBB2 amplification. NGS is highly accurate in detecting ERBB2 amplification in uterine serous carcinoma and provides an alternative to measurement by IHC and FISH.