6 results on '"John Weroha"'
Search Results
2. Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A.
- Author
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Diogo Torres, Xiaonan Hou, Laurie Bale, Ethan P Heinzen, Matthew J Maurer, Valentina Zanfagnin, Ann L Oberg, Cheryl Conover, and S John Weroha
- Subjects
Medicine ,Science - Abstract
ObjectivesInhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models.MethodsPAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis.ResultsThe addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive.ConclusionsThe addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic.
- Published
- 2019
- Full Text
- View/download PDF
3. Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft.
- Author
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Gretchen Glaser, S John Weroha, Marc A Becker, Xiaonan Hou, Sergio Enderica-Gonzalez, Sean C Harrington, and Paul Haluska
- Subjects
Medicine ,Science - Abstract
Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.
- Published
- 2015
- Full Text
- View/download PDF
4. Association of a novel endometrial cancer biomarker panel with prognostic risk, platinum insensitivity, and targetable therapeutic options
- Author
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Qing Zhang, Jesus Gonzalez Bosquet, Sean C. Dowdy, William A. Cliby, Mark E. Sherman, Ling Cen, Fergus J. Couch, Jamie N. Bakkum-Gamez, S. John Weroha, Benjamin R. Kipp, Karl C. Podratz, Kevin C. Halling, and Amy C. Clayton
- Subjects
Organoplatinum Compounds ,Gene Expression ,Biochemistry ,Transcriptome ,Gene expression ,Medicine and Health Sciences ,Multidisciplinary ,Prognosis ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Chemistry ,Oncology ,Physical Sciences ,Medicine ,Female ,Anatomy ,Research Article ,Chemical Elements ,Histology ,Science ,Biology ,Germline mutation ,Uterine Cancer ,Malignant Tumors ,Downregulation and upregulation ,Uterine cancer ,Cell Line, Tumor ,medicine ,Genetics ,Cancer Genetics ,Biomarkers, Tumor ,Humans ,Neoplasm Invasiveness ,Gene ,Platinum ,Gene Expression Profiling ,Wild type ,Biology and Life Sciences ,Cancers and Neoplasms ,Oncogenes ,medicine.disease ,Endometrial Neoplasms ,Drug Resistance, Neoplasm ,Mutation ,Cancer research ,FOXM1 ,Gynecological Tumors ,Biomarkers - Abstract
During the past decade, the age-adjusted mortality rate for endometrial cancer (EC) increased 1.9% annually with TP53 mutant (TP53-mu) EC disproportionally represented in advanced disease and deaths. Therefore, we aimed to assess pivotal molecular parameters that differentiate clinical outcomes in high- and low-risk EC. Using the Cancer Genome Atlas, we analyzed EC specimens with available DNA sequences and quantitative gene-specific RNA expression data. After polymerase ɛ (POLE)-mutant specimens were excluded, differential gene-specific mutations and mRNA expressions were annotated and integrated. Consequent to TP53-mu failure to induce p21, derepression of multiple oncogenes harboring promoter p21 repressive sites was observed, including CCNA2 and FOXM1 (P < .001 compared with TP53 wild type [TP53-wt]). TP53-wt EC with high CCNA2 expression (CCNA2-H) had a targeted transcriptomic profile similar to that of TP53-mu EC, suggesting CCNA2 is a seminal determinant for both TP53-wt and TP53-mu EC. CCNA2 enhances E2F1 function, upregulating FOXM1 and CIP2A, as observed in TP53-mu and CCNA2-H TP53-wt EC (P < .001). CIP2A inhibits protein phosphatase 2A, leading to AKT inactivation of GSK3β and restricted oncoprotein degradation; PPP2R1A and FBXW7 mutations yield similar results. Upregulation of FOXM1 and failed degradation of FOXM1 is evidenced by marked upregulation of multiple homologous recombination genes (P < .001). Integrating these molecular aberrations generated a molecular biomarker panel with significant prognostic discrimination (P = 5.8×10−7); adjusting for age, histology, grade, myometrial invasion, TP53 status, and stage, only CCNA2-H/E2F1-H (P = .0003), FBXW7-mu/PPP2R1A-mu (P = .0002), and stage (P = .017) were significant. The generated prognostic molecular classification system identifies dissimilar signaling aberrations potentially amenable to targetable therapeutic options.
- Published
- 2021
5. Overcoming platinum resistance in ovarian cancer by targeting pregnancy-associated plasma protein-A
- Author
-
Valentina Zanfagnin, Xiaonan Hou, Cheryl A. Conover, S. John Weroha, Diogo Torres, Ethan P. Heinzen, Matthew J. Maurer, Ann L. Oberg, and Laurie K. Bale
- Subjects
0301 basic medicine ,Pregnancy-associated plasma protein A ,endocrine system diseases ,Physiology ,medicine.medical_treatment ,Cancer Treatment ,Biochemistry ,Carboplatin ,chemistry.chemical_compound ,Antibodies, Monoclonal, Murine-Derived ,Mice ,0302 clinical medicine ,Immune Physiology ,Antineoplastic Combined Chemotherapy Protocols ,Medicine and Health Sciences ,Pregnancy-Associated Plasma Protein-A ,Enzyme-Linked Immunoassays ,Ovarian Neoplasms ,Multidisciplinary ,Immune System Proteins ,Pharmaceutics ,Cytoreduction Surgical Procedures ,Ovarian Cancer ,Chemistry ,Paclitaxel ,Oncology ,030220 oncology & carcinogenesis ,Monoclonal ,Physical Sciences ,Medicine ,Female ,Growth inhibition ,Research Article ,Chemical Elements ,Clinical Oncology ,Combination therapy ,Science ,Immunology ,Research and Analysis Methods ,Antibodies ,03 medical and health sciences ,Cancer Chemotherapy ,Drug Therapy ,medicine ,Chemotherapy ,Animals ,Humans ,Immunoassays ,Platinum ,business.industry ,Ovary ,Biology and Life Sciences ,Proteins ,Cancers and Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,Monoclonal Antibodies ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,Cancer research ,Immunologic Techniques ,Clinical Medicine ,Ovarian cancer ,business ,Combination Chemotherapy ,Gynecological Tumors ,Biomarkers - Abstract
ObjectivesInhibition of pregnancy-associated plasma protein-A (PAPP-A), an upstream activator of the insulin-like growth factor (IGF) pathway, is known to augment sensitivity to platinum-based chemotherapy. This study further tests the efficacy of PAPP-A inhibition with a monoclonal antibody inhibitor (mAb-PA) in ovarian cancer (OC) platinum-resistant patient-derived xenograft (PDX) models.MethodsPAPP-A expression was quantitated in platinum-resistant PDX models by ELISA. A subset with High (n = 5) and Low (n = 2) expression were revived in female SCID/beige mice for studies with either saline, carboplatin/paclitaxel (CP) + mAb-PA, or CP + IgG2a. The primary endpoint was tumor area by ultrasound on day 28 relative to baseline. Conversion to platinum-sensitive was defined by average tumor regression below baseline. Statistical analyses included linear mixed effects modeling and Kaplan Meier curves. Response to therapy was correlated with changes in the ratio of phosphorylated/total AKT and ERK 1/2 using Wes analysis.ResultsThe addition of mAb-PA to CP induced tumor regression below baseline in one High PAPP-A PDX model; another three models exhibited notable growth inhibition relative to CP + IgG2a. None of the Low PAPP-A PDX models regressed below baseline. The PDX model with the greatest magnitude of tumor regression from baseline after combination therapy was maintained on single agent mAb-PA or IgG2a, but no benefit was observed. Decreased phosphorylation of ERK1/2 correlated with conversion to platinum-sensitive.ConclusionsThe addition of mAb-PA to CP overcame platinum-resistance in one of five High PAPP-A PDX models; three other models demonstrated improved platinum-response. This supports further clinical development of this novel therapeutic.
- Published
- 2019
6. Conventional chemotherapy and oncogenic pathway targeting in ovarian carcinosarcoma using a patient-derived tumorgraft
- Author
-
Marc A. Becker, Xiaonan Hou, Sean C. Harrington, S. John Weroha, Gretchen E. Glaser, Sergio Enderica-Gonzalez, and Paul Haluska
- Subjects
endocrine system ,endocrine system diseases ,Maximum Tolerated Dose ,Paclitaxel ,medicine.medical_treatment ,lcsh:Medicine ,Antineoplastic Agents ,Biology ,Targeted therapy ,Carboplatin ,chemistry.chemical_compound ,Mice ,Carcinosarcoma ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Molecular Targeted Therapy ,Ovarian Carcinosarcoma ,lcsh:Science ,Ovarian Neoplasms ,Chemotherapy ,Multidisciplinary ,Ifosfamide ,Gene Expression Profiling ,lcsh:R ,medicine.disease ,Xenograft Model Antitumor Assays ,3. Good health ,Tumor Burden ,Disease Models, Animal ,chemistry ,Cancer research ,lcsh:Q ,Female ,Ovarian cancer ,medicine.drug ,Signal Transduction ,Research Article - Abstract
Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed.
- Published
- 2014
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