28 april 2022: Zie ook dit boek The medicin of light van Andrei Reshetnikov, waarvan de belangrijkste hoofdstukken zijn vertaald in het Nederlands, waarvan in hoofdstuk 7 een relatief eenvoudige uitleg hoe PDT met bremachlorin als fotosensitizer werkt.

28 april 2022: Zie ook dit artikel: https://kanker-actueel.nl/pdt-fotodynamische-therapie-beloftevol-bij-inoperabele-alvleesklierkanker-blijkt-uit-verschillende-studies.html

Zie ook in gerelateerde artikelen

28 april 2022: Bron: Cancers 2021, 13(17), 4354; Received: 30 June 2021 / Revised: 16 August 2021 / Accepted: 26 August 2021 / Published: 28 August 2021

PDT - Foto Dynamische Therapie zou voor alvleesklierkanker een goede behandelingsoptie kunnen zijn, al of niet in combinatie met andere behandelingen, waaronder immuuntherapie. Blijkt uit een grote reviewstudie.

Alvleesklierkanker - Pancreas ductaal adenocarcinoom (PDAC) is een van de moeilijkst te behandelen vormen van kanker.  Zeker als het al is uitgezaaid bij de diagnose, wat heel vaak voorkomt. Bovendien ligt de alvleesklier dicht bij het hart en grote slagaders waardoor een operatie al snel niet mogelijk is. Slechts 10%–20% van alle alvleesklierkankertumoren zijn operabel en recidieven treden heel vaak op bij alvleesklierkanker. De mediane 5-jaars overleving voor alvleesklierkanker ligt rond de 10 procent. 

Bovendien blijken alvleeskliertumoren veel minder dendritische cellen te hebben waardoor immuuntherapie vaak niet aanslaat bij deze vorm van kanker. (zie dit artikel over dendritische cellen bij o.a. alvleeskliertumoren). 

Hoewel dr. Casper van Eyck in 2020 in de publiciteit kwam met een studie met dendritische celtherapie waarbij 9 van de 10 deelnemende alvleesklierkankerpatiënten na anderhalf jaar nog vrij waren van kanker. (zie dit artikel o.a.) Echter de studie is tot op vandaag nog niet gepubliceerd, althans ik kan de studie niet vinden. Dit was REACtiVe-1 het studieprotocol van de studie maar ik zie nog geen publicatie in een Medisch Vakblad van deze studie.
Wel is er een vervolgstudie REACTiVe-2 in het ErasmusMC geopend en daaraan kunnen nog steeds patiënten aan deelnemen, zie dit studieprotocol. In die studie wordt gebruik gemaakt van een CD40 agonis, zoals ook in deze dierstudie is gedaan. Ook weten we dat er in het Erasmus MC muizenstudies lopen met PDT met bremachlorin in combinatie met vormen van immuuntherapie. Met verrassend goede resultaten. 

Maar alvleesklierkanker is dus heel moeilijk te behandelen. Ook veel studies met verschillende vormen van chemotherapie, radiotherapie - bestraling, personalised medicin en combinatiebehandelingen hebben over het algemeen tot nu toe geen echte verbetering van de overleving opgeleverd voor patiënten met een inoperabele vorm van alvleesklierkanker. 

Fotodynamische therapie (PDT) is een op fotochemie gebaseerde benadering die selectieve celdoding mogelijk maakt met behulp van tumorlokaliserende middelen die worden geactiveerd door zichtbaar of nabij-infrarood licht. PDT - Foto Dynamische Therapie bij alvleesklierkanker biedt verschillende voordelen. Afhankelijk van de lokalisatie van de alvleeskliertumor, kan PDT doelen in tumorcellen direct beschadigen of veranderen. Bovendien, aangezien het zichtbare of nabij-infrarood licht dat in PDT - Foto Dynamische Therapie wordt gebruikt niet-ioniserend is, heeft PDT niet de toenemende toxiciteit die geassocieerd wordt met radiotherapie. [12,23].

In tegenstelling tot ioniserende straling is een groot manco bij PDT dat laserlicht een beperkte penetratie van rode en nabij-infrarode golflengten in weefsel heeft. Lichtafgifte voor interne plaatsen zoals de pancreas vereist een zorgvuldige planning van de behandeling en dosimetrie = berekening van de doses, hoewel er innovatieve oplossingen zijn ontwikkeld en ook bewezen in studies. Zo wordt PDT al langer via licht op een glasvezelkabeltje onder geautomatiseerde tomografische begeleiding gebruikt bij tumoren in het lichaam om de beperking van lichtverzwakking in weefsel te voorkomen. 

Een beeld uit het studieverslag hoe PDT ook kan worden gegeven via een glasvezelkabeltje bij alvleeskliertumoren. 

Cancers 13 04354 g003 550

Andrei Reshetnikov vertelde ons dat hij dat al 15 jaar soms toepast in Rusland. We hebben verschillende oncologische chirurgen in Nederland en België afgelopen half jaar aangeschreven of zij deze manier van PDT - Foto Dynamische Therapie samen met bremachlorin wilden toepassen via bv een kijkoperatie bij tumoren in het buikvlies maar zij durven dit niet aan vertelden zij ons. Is toch wel beetje vreemd als je leest dat deze manier van PDT toepassen wel al veel langer en veelvuldig wordt toegepast wereldwijd. Maar goed het is niet anders. Mocht een oncoloog of oncologisch chirurg dit lezen en belangstelling hebben we kunnen haar of hem altijd in contact brengen met Andrei. 

In het studierapport staat uitgebreid beschreven met literatuurverwijzingen hoe en wanneer PDT - Foto Dynamische therapie bij alvleesklierkanker kan worden toegepast. Klik op de titel van het abstract.

Photodynamic Therapy for Pancreatic Ductal Adenocarcinoma

by 
Vida Karimnia
 1,
Frank J. Slack2 and
Jonathan P. Celli
 1,*
1
Department of Physics, University of Massachusetts at Boston, Boston, MA 02125, USA
2
Department of Pathology, BIDMC Cancer Center/Harvard Medical School, Boston, MA 02215, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Sumit Sahni, Anubhav Mittal, Jaswinder Samra and Michael Höpfner
Cancers 2021, 13(17), 4354; https://doi.org/10.3390/cancers13174354
Received: 30 June 2021 / Revised: 16 August 2021 / Accepted: 26 August 2021 / Published: 28 August 2021
(This article belongs to the Special Issue Recent Advances in Pancreatic Ductal Adenocarcinoma)

Simple Summary

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human cancers. Numerous clinical trials evaluating various combinations of chemotherapy and targeted agents and radiotherapy have failed to provide meaningful improvements in survival. A growing number of studies however have indicated that photodynamic therapy (PDT) may be a viable approach for treatment of some pancreatic tumors. PDT, which uses light to activate a photosensitizing agent in target tissue, has seen widespread adoption primarily for dermatological and other applications where superficial light delivery is relatively straightforward. Advances in fiber optic light delivery and dosimetry however have been leveraged to enable PDT even for challenging internal sites, including the pancreas. The aim of this article is to help inform future directions by reviewing relevant literature on the basic science, current clinical status, and potential challenges in the development of PDT as a treatment for PDAC.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal of human cancers. Clinical trials of various chemotherapy, radiotherapy, targeted agents and combination strategies have generally failed to provide meaningful improvement in survival for patients with unresectable disease. Photodynamic therapy (PDT) is a photochemistry-based approach that enables selective cell killing using tumor-localizing agents activated by visible or near-infrared light. In recent years, clinical studies have demonstrated the technical feasibility of PDT for patients with locally advanced PDAC while a growing body of preclinical literature has shown that PDT can overcome drug resistance and target problematic and aggressive disease. Emerging evidence also suggests the ability of PDT to target PDAC stroma, which is known to act as both a barrier to drug delivery and a tumor-promoting signaling partner. Here, we review the literature which indicates an emergent role of PDT in clinical management of PDAC, including the potential for combination with other targeted agents and RNA medicine.

7. Emerging and Future Directions

Given the noted role of stroma in PDAC progression and as a barrier to drug delivery, the concept of therapeutically targeting PDAC stroma has emerged as a potentially important strategy. As discussed here, multiple lines of evidence suggest that PDT may have some role to play in this context. In a 3D PDAC co-culture model, it was shown that while the nodules in the presence of fibroblasts were more chemoresistant, PDT response was enhanced in the presence of fibroblasts [78]. Another study on PDAC cocultured with fibroblasts in monolayer showed non significantly higher PDAC cell death in the presence of non-activated fibroblasts [127]. Furthermore, a study demonstrated that PDT not only depleted stromal fibroblasts, but also interrupted crosstalk with stromal signaling partners that gave rise to enhance tumor survival [128]. Combined with additional evidence that PDT can induce breakdown of ECM components [129], these preclinical results collectively indicate a potential role for PDT in depleting cellular and non-cellular PDAC stromal components to enhance subsequent drug delivery. Clinically this scenario could be leveraged by activating the PS at early timepoints following delivery when initial stromal accumulation is highest.
In consideration of how PDT may play a role in the next generation of cancer therapeutics, the opportunity for interactions with RNA medicine emerges as a potentially exciting avenue of investigation. In recent years, RNA medicine has demonstrated exciting potential for a wide variety of diseases, including, specifically, PDAC, through targeting of microRNAs (miRNAs) [130,131,132,133]. MiRNAs are small (~18–25 nucleotides) non-coding RNAs that can bind target mRNAs in a sequence-specific fashion to induce post-transcriptional downregulation. Several studies have already identified miRNAs with significantly altered expression between normal pancreas and PDAC tissues; among them, miR-21, miR-196a, and miR-196b, which are strongly correlated with decreased survival [134,135]. In a mouse model of miR-21 over-expression, it has been revealed that the mice develop tumors in tissue where miR-21 is over-expressed, and that these tumors depend on the continued expression of miR-21 for survival [136]. These lines of evidence highlight the role of ‘oncomiR addiction’ in regulating key pathways promoting tumor growth, survival, and chemoresistance [137]. Furthermore, miR-21 depletion using a nanoparticle to carry an anti-miRNA inhibitor also inhibits organoid growth, suggesting the potential of this approach as a therapeutic strategy [130]. At the same time, this approach opens new potential avenues for synergy with PDT. Inhibition of miR-21 has been shown to increase levels of the pro-apoptotic factor BAX, while PDT with verteporfin is known to target anti-apoptotic factors BCL-2 and BCL-XL [138,139]. Similarly, targeting of another PDAC onco-miR, miR-196b, has also been shown to promote resistance to late-stage apoptosis in PDAC cells [140]. Combination of PDT with selective therapeutic inhibition of these oncomiRs could synergistically increase the Bax/Bcl-2 ratio (pro-/anti-apoptotic) in PDAC cells and tip the balance toward apoptosis in these otherwise stubbornly drug-resistant cells. In addition to synergizing at the molecular level, combination with PDT could also enhance delivery of RNA medicines through depletion of stromal components. As noted above, the notoriously dense fibrotic stroma in PDAC is problematic for delivery of virtually all therapeutic agents, and this may be especially true for RNA medicine. While various anti-miRNA strategies have been discussed for the past decade, a lack of adequate delivery to most disease tissues has restricted current therapeutic uses to liver and kidney disease. Collectively, these observations point to the potential benefits of leveraging nanoparticle delivery systems that could simultaneous carry light-activated agents for PDT to target PDAC stroma for enhanced delivery of RNA medicine agents, while at the same time priming tumor cells for enhanced biological response to these therapies.

8. Conclusions

Collectively, the literature points to multiple significant roles for PDT in the clinical management of PDAC. The clinical studies discussed above have established the techniques for light delivery which enable PDT as a primary treatment for locally advanced PDAC, which could play a key role especially for disease which is unresectable. However, biological responses to PDT may also synergize with systemic therapies as part of a complete treatment strategy. At the same time, active and ongoing research continues to reveal new roles for PDT and its potential to interact with other promising strategies that are just beginning to emerge.

Author Contributions

Conceptualization, V.K., F.J.S. and J.P.C.; methodology, V.K. and J.C.; software, V.K.; validation, V.K., F.J.S. and J.P.C.; formal analysis, V.K. and J.P.C.; investigation, V.K. and J.P.C; resources, J.P.C.; data curation, V.K. and J.P.C.; writing—original draft preparation, V.K.; writing—review and editing, V.K. and J.P.C.; visualization, V.K.; supervision, J.P.C.; project administration, J.P.C.; funding acquisition, V.K., F.J.S. and J.P.C. All authors have read and agreed to the published version of the manuscript.

Funding

We gratefully acknowledge funding from the National Cancer Institute to the UMass Boston-Dana Farber/Harvard Cancer Center U54 Partnership (U54CA156734). We thank Oracle and the College of Science and Mathematics at UMass Boston for fellowship support to VK.

Conflicts of Interest

The authors declare no conflict of interest.

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alvleesklierkanker, Pancreas ductaal adenocarcinoom, PDT - Foto dynamische therapie, Andrei Reshetnickov, bremachlorin, immuuntherapie


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