2. Academic Validation
  3. Salvage Chemotherapy with Cisplatin, Ifosfamide, and Paclitaxel in Aggressive Variant of Metastatic Castration-Resistant Prostate Cancer

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

  • Int J Mol Sci. 2022 Nov 29;23(23):14948. doi: 10.3390/ijms232314948.
Gunhild von Amsberg 1 2,  Mirjam Zilles 1,  Wael Mansour 3 4,  Philipp Gild 5,  Winfried Alsdorf 1,  Moritz Kaune 1,  Lukas Böckelmann 1,  Jessica Hauschild 1 2,  Christoph Krisp 6,  Tina Rohlfing 1,  Ceren Saygi 7,  Malik Alawi 7,  Alexandra Zielinski 3,  Claudia Langebrake 8,  Su Jung Oh-Hohenhorst 2 9,  Sven Perner 10 11 12,  Derya Tilki 2 5,  Hartmut Schlüter 6,  Markus Graefen 2,  Sergey A Dyshlovoy 1 2,  Carsten Bokemeyer 1
Affiliations

Affiliations

  • 1 Department of Oncology, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 2 Martini-Klinik Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 3 Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 4 Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 5 Department of Urology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 6 Institute of Clinical Chemistry and Laboratory Medicine, Section Mass Spectrometry and Proteomics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 7 Bioinformatics Core, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 8 Pharmacy, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
  • 9 Department of Urology, Centre Hospitalier de l'Université de Montreal (CHUM)/Centre de recherche du CHUM, Montreal, QC 3840, Canada.
  • 10 Institute of Pathology, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, 23562 Lübeck, Germany.
  • 11 Pathology, Research Center Borstel, Leibniz Lung Center, 23845 Borstel, Germany.
  • 12 German Center for Lung Research (DZL), 35392 Gießen, Germany.
PMID: 36499277 DOI: 10.3390/ijms232314948
Abstract

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.

Keywords

DDR alteration; DNA damage; TIP combinational therapy; aggressive variant of prostate cancer; cisplatin; ifosfamide; metastatic castration-resistant prostate cancer; paclitaxel.

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