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Poster session 09

42P - Developing a photodynamic therapy strategy targeted to endometrial cancer stem cells

Date

21 Oct 2023

Session

Poster session 09

Topics

Cancer Biology;  Targeted Therapy;  Cancer Research

Tumour Site

Endometrial Cancer

Presenters

Beatriz Serambeque

Citation

Annals of Oncology (2023) 34 (suppl_2): S187-S214. 10.1016/S0923-7534(23)01931-2

Authors

B. Serambeque1, S. Ferreira1, M. Piñeiro2, S. Lopes2, B. Costa2, N.A. Pereira2, C.M. Marto3, M.F. Botelho3, M.J. Carvalho4, T. Pinho e Melo2, M. Laranjo1

Author affiliations

  • 1 Coimbra Institute For Clinical And Biomedical Research (icbr) Area Of Environment Genetics And Oncobiology (cimago), Institute Of Biophysics, Faculty Of Medicine; Cibb; Cacc, Univ Coimbra, 3000-548 - Coimbra/PT
  • 2 Coimbra Chemistry Centre-institute Of Molecular Sciences And Department Of Chemistry, Univ Coimbra, 3004-535 - Coimbra/PT
  • 3 Coimbra Institute For Clinical And Biomedical Research (icbr), Area Of Environment, Genetics And Oncobiology Research (cimago), Institute Of Biophysics, Faculty Of Medicine; Institute Of Experimental Pathology; Cibb; Cacc, Univ Coimbra, 3000-370 - Coimbra/PT
  • 4 Gynecology Service, CHUC - Centro Hospitalar e Universitário de Coimbra, EPE, 3000-075 - Coimbra/PT

Resources

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Abstract 42P

Background

Cancer stem cells (CSC) motivate the investigation of novel anticancer-targeted therapies. In endometrial cancer (EC), overexpression of aldehyde dehydrogenase (ALDH) was associated with endometrial CSC, highlighting its therapeutic target potential. Photodynamic therapy (PDT), a minimally invasive anticancer approach, emerges as a promising targeted therapy for endometrial CSC, through a structural modulation of optimized photosensitisers with aldehyde moieties. Thus, the aim is to investigate PDT based on the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins (PX), modulated to target endometrial CSC by incorporation of aldehyde substituents.

Methods

A solution of a mono-esther/mono-alcohol derivative chlorin was added to Dess-Martin periodinane in dichloromethane solution and stirred to synthesise a mono-aldehyde derivative of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorin (A-PX). The presence of the aldehyde group was confirmed by proton nuclear magnetic resonance (1H-NMR). The ALDH1A1-promoted oxidation of A-PX was followed through reverse-phase high-performance liquid chromatography (HPLC). This was done by reacting 50nM ALDH1A1 with 1mM A-PX in a 2% DMSO, Tris pH 7.5, KCl, DTT and β-NAD solution at 37 °C. The reaction was stopped every 30’ with acetonitrile. To evaluate A-PX-based PDT (7.5mW/cm2, 10J) the resazurin assay was performed on endometrial CSC.

Results

The A-PX 1H-NMR revealed a peak at 10.28ppm corresponding to the aldehyde. The kinetics of the enzymatic reaction, followed by HPLC, showed the decreasing relative area of the aldehyde peak (retention = 2’13’’) in parallel with the increase of the carboxylic acid (retention = 3’04’’) formed by ALDH1A1-promoted oxidation, reaching complete conversion at 120'. Preliminary results of the A-PX-PDT cytotoxicity on the endometrial CSC pointed to decreased proliferation, while A-PX per se did not show toxicity.

Conclusions

It was possible to develop chlorins able to interact with ALDH1A1, allowing the in situ modification of the hydrophilicity of the photosensitizer. A-PX seem to be effective PDT agents against endometrial CSC. The promising results encourage further studies to confirm this rationale for endometrial CSC-targeted PDT.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Univ Coimbra.

Funding

Centre for Innovative Biomedicine and Biotechnology (CIBB) (UIDB/04539/2020, UIDP/04539/2020) and Coimbra Chemistry Centre (UIDB/00313/2020, UIDP/00313/2020) are supported by The Fundação para a Ciência e a Tecnologia (FCT), co-funded by COMPETE. Project Prova de Conceito (CENTRO-45-2021-30; 01/SAICT/2021, nº 180078) funded by Portugal2020. Beatriz Serambeque (2020.07672. BD ) and Bruna Costa (2022.12013. BD ) were awarded with a PhD Scholarship from FCT and European Social Fund.

Disclosure

All authors have declared no conflicts of interest.

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