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Induced phenotype targeted therapy: radiation-induced apoptosis-targeted chemotherapy
Beom Suk Lee1, Yong Woo Cho1, Gui Chul Kim1
1Department of Otolaryngology (BSL, GCK, SYK) and Department of Neurosurgery (DHL, CJK), Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, Republic of Korea (BSL, YWC, KK, ISK, ICK, SYK); Department of Chemical Engineering, Hanyang University, Gyeonggido, Republic of Korea (YWC); Department of Chemistry, Sogang University, Seoul, Republic of Korea (HSK, DYC); Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, Republic of Korea (YB); College of Pharmacy, Korea University, Sejong, Republic of Korea (SHY); Department of Biochemistry and Cell Biology, School of Medicine and Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea (ISK); KU-KIST School, Korea University, Seoul, Republic of Korea (ICK).
Background:
Tumor heterogeneity and evolutionary complexity may underlie treatment failure in spite of the development of many targeted agents. We suggest a novel strategy termed induced phenotype targeted therapy (IPTT) to simplify complicated targets because of tumor heterogeneity and overcome tumor evolutionary complexity.
Methods:
We designed a caspase-3 specific activatable prodrug, DEVD-S-DOX, containing doxorubicin linked to a peptide moiety (DEVD) cleavable by caspase-3 upon apoptosis. To induce apoptosis locally in the tumor, we used a gamma knife, which can irradiate a very small, defined target area. The in vivo antitumor activity of the caspase-3-specific activatable prodrug combined with radiation was investigated in C3H/HeN tumor-bearing mice (n = 5 per group) and analyzed with the Student's t test or Mann-Whitney U test. All statistical tests were two-sided. We confirmed the basic principle using a caspase-sensitive nanoprobe (Apo-NP).
Results:
A single exposure of radiation was able to induce apoptosis in a small, defined region of the tumor, resulting in expression of caspase-3. Caspase-3 cleaved DEVD and activated the prodrug. The released free DOX further activated DEVD-S-DOX by exerting cytotoxic effects on neighboring tumor or supporting cells, which repetitively induced the expression of caspase-3 and the activation of DEVD-S-DOX. This sequential and repetitive process propagated the induction of apoptosis. This novel therapeutic strategy showed not only high efficacy in inhibiting tumor growth (14-day tumor volume [mm(3)] vs radiation alone: 848.21 ± 143.24 vs 2511.50 ± 441.89, P < .01) but also low toxicity to normal cells and tissues.
Conclusion:
Such a phenotype induction strategy represents a conceptually novel approach to overcome tumor heterogeneity and complexity as well as to substantially improve current conventional chemoradiotherapy with fewer sequelae and side effects.
Insights
Induced phenotype targeted therapy (IPTT) uses a novel prodrug and radiation to trigger a cascade of apoptosis, effectively inhibiting tumor growth with reduced toxicity. This approach simplifies complex tumor targets and overcomes resistance.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- Tumor heterogeneity and complexity often lead to treatment failure with targeted therapies.
- A novel strategy, induced phenotype targeted therapy (IPTT), is proposed to address these challenges.
- IPTT aims to simplify complex tumor targets and overcome evolutionary resistance.
Purpose of the Study:
- To develop and evaluate a novel therapeutic strategy combining a specific prodrug with localized radiation.
- To investigate the potential of IPTT to overcome tumor heterogeneity and complexity.
- To assess the efficacy and toxicity of this new approach in a preclinical model.
Main Methods:
- A caspase-3 specific activatable prodrug, DEVD-S-DOX, was designed, linking doxorubicin to a peptide cleavable by caspase-3.
- Localized tumor apoptosis was induced using a gamma knife, triggering local caspase-3 expression.
- In vivo antitumor activity was assessed in tumor-bearing mice, with statistical analysis performed.
Main Results:
- Radiation successfully induced local apoptosis and caspase-3 expression, activating the DEVD-S-DOX prodrug.
- Activated prodrug released doxorubicin, which further activated neighboring cells, creating a self-propagating apoptotic cascade.
- This sequential activation led to significant tumor growth inhibition and low toxicity to normal tissues.
Conclusions:
- The phenotype induction strategy offers a novel approach to combat tumor heterogeneity and complexity.
- IPTT demonstrates potential to significantly improve conventional chemoradiotherapy outcomes.
- This strategy promises enhanced efficacy with reduced side effects and sequelae.
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