Targeted therapy of prostate cancer stem cells

• Applicant: Professor Dr. Philipp Wolf
• Subject Area: Reproductive Medicine, Urology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 428660029

• Final Report Year: 2024

Final Report Abstract

Prostate cancer (PC) represents the most prevalent malignancy in men, with successful treatment critically dependent on the complete eradication of the tumor to prevent relapse and metastasis. Despite advances in PC therapies, tumor heterogeneity driven by cancer stem cells and the persistence of residual tumor cells in surgical margins frequently result in biochemical relapse. Consequently, novel approaches targeting both PC and PC stem cells are urgently needed to improve therapeutic outcomes and prevent disease progression. Photoimmunotherapy (PIT) is an innovative treatment option that combines antibodies with light-activatable photosensitizers (PSs) to selectively induce cancer cell death upon irradiation with non-ionizing red light, minimizing off-target effects and sparing adjacent healthy tissues. In this project, we evaluated the new silicon phthalocyanine fluorescence dye WB692-CB2 as a PS for the PIT of PC. WB692-CB2 is the first light-activatable PS that can be directly conjugated via a maleimide linker to cysteines. We conjugated WB692-CB2 to humanized antibodies with engineered cysteines in the heavy chains that specifically target the tumor antigens PSMA, CD44 and EpCAM. The resulting antibody-PS conjugates exhibited high affinity and specificity towards antigen-positive PC and PC stem cells and induced rapid cell death following irradiation with red light. Moreover, additive effects were observed by PIT when different antigens on the same cells were targeted. Our studies revealed that PIT triggers the generation of reactive oxygen species, which subsequently induces pyroptosis, a specific form of cell death. This process can induce an immunological reaction of the patient’s immune system against PC cells. In first in vivo experiments, PIT resulted in a significant reduction of tumor growth and enhanced overall survival. In conclusion, our study highlights the potential of the novel phthalocyanine dye WB692-CB2 as PS for the fluorescence-based detection and PIT of cancer. By effectively targeting PC and PC stem cells, and inducing systemic anti-tumor immune response by induction of pyroptosis, this approach holds significant promise for improving therapeutic outcomes in PC patients in future.

Publications

• Prostate Cancer Stem Cells: Clinical Aspects and Targeted Therapies. Frontiers in Oncology, 12.
  Wolf, Isis; Gratzke, Christian & Wolf, Philipp
  
• Lightning the way to cancer cell destruction: our novel photosensitizer WB692 induces pyroptosis in prostate cancer cells during photoimmunotherapy. Research Day of the Faculty of Medicine, University Medical Center, University of Freiburg, 24.11.2023.
  Wolf, Isis; Storz, Jonas; Esser, Philipp R.; Martin, Stefan F.; Lauw, Susan; Gratzke, Christian & Wolf, Philipp
  
• Photoimmunotherapy of HER-2 expressing breast cancer cells. Research Day of the Faculty of Medicine, University Medical Center, University of Freiburg, 24.11.2023.
  Klemenz, Lukas; Schultze-Seemann, Susanne; Gratzke, Christian; Brückner, Reinhard; Wolf, Isis & Wolf, Philipp
  
• A new silicon phthalocyanine dye induces pyroptosis in prostate cancer cells during photoimmunotherapy. Bioactive Materials, 41, 537-552.
  Wolf, Isis; Storz, Jonas; Schultze-Seemann, Susanne; Esser, Philipp R.; Martin, Stefan F.; Lauw, Susan; Fischer, Peer; Peschers, Marie; Melchinger, Wolfgang; Zeiser, Robert; Gorka, Oliver; Groß, Olaf; Gratzke, Christian; Brückner, Reinhard & Wolf, Philipp
  
• Antibody-dye Conjugates Targeting EGFR and HER2 for the Photoimmunotherapy of Bladder Cancer. Anticancer Research, 44(5), 1837-1844.
  Huber, Fabian; Wolf, Isis; Storz, Jonas; Schultze-Seemann, Susanne; Lauw, Susan; Klemenz, Lukas; Miernik, Arkadiusz; Gratzke, Christian; Brückner, Reinhard & Wolf, Philipp
  
• Ein Funke der Hoffnung im Kampf gegen Prostatakrebs: der Photosensibilisator WB692 induziert Pyroptose während der Photoimmuntherapie. Abstracts zum 14. AuF-Symposium Abstracts, Die Urologie, 63 (2024) S. 16
  Wolf, Isis; Storz, Jonas; Esser, Philipp R.; Schultze-Seemann, Susanne; Martin, Stefan F.; Fischer, Peer; Gratzke, Christian; Brückner, Reinhard & Wolf, Philipp
  
• Photoimmunotherapy of HER2-expressing Breast Cancer Cells. Cancer Genomics - Proteomics, 21(4), 361-367.
  Klemenz, Lukas; Wolf, Isis; Storz, Jonas; Schultze-Seemann, Susanne; Gratzke, Christian; Lauw, Susan; Brückner, Reinhard & Wolf, Philipp
  
• Photoimmunotherapy of Prostate Cancer With Antibody and Fab Fragments Targeting the Prostate Specific Membrane Antigen. Anticancer Research, 44(6), 2343-2348.
  Waibel, Sarah; Graf, Nele; Storz, Jonas; Schultze-Seemann, Susanne; Lauw, Susan; Gratzke, Christian; Brückner, Reinhard; Wolf, Philipp & Wolf, Isis
  
• Photoimmuntherapie des Harnblasenkarzinoms. Abstracts zum 14. AuF-Symposium Abstracts, Die Urologie, 63 (2024) S17
  Huber, Fabian; Wolf, Isis; Klemenz, Lukas; Schultze-Seemann, Susanne; Gratzke, Christian; Storz, Jonas; Brückner, Reinhard & Wolf, Philipp
  
• Photoimmuntherapie des Prostatakarzinoms mit anti-PSMA Antikörpern und Antikörperfragmenten. Abstracts zum 14. AuF-Symposium Abstracts, Die Urologie, 63
  Waibel, Sarah; Wolf, Isis; Schultze-Seemann, Susanne; Gratzke, Christian; Storz, Jonas; Brückner, Reinhard & Wolf, Philipp
  
• Silicon phthalocyanine and tribenzophthalocyanine dyes and their use in diagnosis and therapy (Application No. PCT/EP2024/057618, 21.03.2024).
  Wolf, Isis; Storz, Jonas; Brückner, Reinhard & Wolf, Philipp
  
• Targeting CD44 and EpCAM with Antibody Dye Conjugates for the Photoimmunotherapy of Prostate Cancer. Antibodies, 14(1), 5.
  Wolf, Isis; Schultze-Seemann, Susanne; Gratzke, Christian & Wolf, Philipp