Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

Autor:	Gunhild von Amsberg, Mirjam Zilles, Wael Mansour, Philipp Gild, Winfried Alsdorf, Moritz Kaune, Lukas Böckelmann, Jessica Hauschild, Christoph Krisp, Tina Rohlfing, Ceren Saygi, Malik Alawi, Alexandra Zielinski, Claudia Langebrake, Su Jung Oh-Hohenhorst, Sven Perner, Derya Tilki, Hartmut Schlüter, Markus Graefen, Sergey A. Dyshlovoy, Carsten Bokemeyer
Rok vydání:	2022
Předmět:	Male Proteomics Salvage Therapy Paclitaxel Organic Chemistry cisplatin ifosfamide paclitaxel TIP combinational therapy aggressive variant of prostate cancer metastatic castration-resistant prostate cancer DNA damage DDR alteration General Medicine Docetaxel Catalysis Computer Science Applications Inorganic Chemistry Prostatic Neoplasms Castration-Resistant Treatment Outcome Antineoplastic Combined Chemotherapy Protocols Humans Physical and Theoretical Chemistry Cisplatin Molecular Biology Spectroscopy Retrospective Studies
Zdroj:	International Journal of Molecular Sciences; Volume 23; Issue 23; Pages: 14948
ISSN:	1422-0067
Popis:	Significant progress has been achieved in the treatment of metastatic castration-resistant prostate cancer (mCRPC). However, results in patients with aggressive variant prostate cancer (AVPC) have been disappointing. Here, we report retrospectively collected data from intensively pretreated AVPC patients (n = 17; 88.2% visceral metastases; 82% elevation of neuroendocrine markers) treated with salvage chemotherapy consisting of cisplatin, ifosfamide, and paclitaxel (TIP). At the interim analysis, 60% of patients showed radiographic response or stable disease (PFS = 2.5 months; OS = 6 months). In men who responded to chemotherapy, an OS > 15 months was observed. Preclinical analyses confirmed the high activity of the TIP regimen, especially in docetaxel-resistant prostate cancer cells. This effect was primarily mediated by increased cisplatin sensitivity in the emergence of taxane resistance. Proteomic and functional analyses identified a lower DNA repair capacity and cell cycle machinery deficiency to be causative. In contrast, paclitaxel showed inconsistent effects, partially antagonizing cisplatin and ifosfamide in some AVPC models. Consequently, paclitaxel has been excluded from the TIP combination for future patients. In summary, we report for the first time the promising efficacy of TIP as salvage therapy in AVPC. Our preclinical data indicate a pivotal role for cisplatin in overcoming docetaxel resistance.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3908f98ffeab745db9d4c3fa68240db7 https://pubmed.ncbi.nlm.nih.gov/36499277 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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