Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity

Resistance to chemotherapy presents a serious challenge in the successful treatment of various cancers and is mainly responsible for mortality associated with disseminated cancers. Here we show that expression of HtrA1, which is frequently downregulated in ovarian cancer, influences tumor response to chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease-dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance

Serine protease HtrA1 modulates chemotherapy-induced cytotoxicity

Resistance to chemotherapy presents a serious challenge in the successful treatment of various cancers and is mainly responsible for mortality associated with disseminated cancers. Here we show that expression of HtrA1, which is frequently downregulated in ovarian cancer, influences tumor response to chemotherapy by modulating chemotherapy-induced cytotoxicity. Downregulation of HtrA1 attenuated cisplatin- and paclitaxel-induced cytotoxicity, while forced expression of HtrA1 enhanced cisplatin- and paclitaxel-induced cytotoxicity. HtrA1 expression was upregulated by both cisplatin and paclitaxel treatment. This upregulation resulted in limited autoproteolysis and activation of HtrA1. Active HtrA1 induces cell death in a serine protease-dependent manner. The potential role of HtrA1 as a predictive factor of clinical response to chemotherapy was assessed in both ovarian and gastric cancer patients receiving cisplatin-based regimens. Patients with ovarian or gastric tumors expressing higher levels of HtrA1 showed a higher response rate compared with those with lower levels of HtrA1 expression. These findings uncover what we believe to be a novel pathway by which serine protease HtrA1 mediates paclitaxel- and cisplatin-induced cytotoxicity and suggest that loss of HtrA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance

Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study

10.1016/S1470-2045(10)70203-5The Lancet Oncology1110962-972LOAN

A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer

10.1210/jc.2012-1520Journal of Clinical Endocrinology and Metabolism9793179-3184JCEM

A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H

10.1210/jc.2013-3713Journal of Clinical Endocrinology and Metabolism9951687-1693JCEM

European perspective on 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: Proceedings of an interactive international symposium

Background: The American Thyroid Association (ATA) management guidelines for patients with thyroid nodules and differentiated thyroid cancer (DTC) are highly influential practice recommendations. The latest revision appeared in 2015 ("ATA 2015"). These guidelines were developed predominantly by North American experts. European experts frequently have different perspectives, given epidemiological, technological/methodological, practice organization, and medicolegal differences between the respective regions. Summary: Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015's guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. Rationales included the modality's association with favorable patient outcomes and generally limited toxicity, and lack of high-quality evidence supporting withholding RAIT. Additionally, European panelists favored recombinant human thyrotropin (rhTSH) in more settings than does ATA 2015, citing avoidance of hypothyroid morbidity and quality-of-life impairment, without apparent sacrifice in oncologic outcomes. Based on clinical evidence plus theoretical advantages, European experts advocated dosimetric versus fixed-activity RAIT approaches for advanced DTC. European panelists noted that the ATA 2015 risk-stratification system requires information sometimes unavailable in everyday practice. ATA 2015 recommendations regarding RAI-refractory DTC should consider potential palliative benefits of RAIT in patients who also have RAI-susceptible lesions. Conclusions: European panelists suggested modifications to approximately one-third of ATA 2015 recommendations. Varying European and ATA 2015 perspectives can stimulate analysis and discussion of the literature and performance of primary research to resolve discrepant recommendations and potentially improve patient outcomes. © Copyright 2019, Mary Ann Liebert, Inc., publishers 2019