Verteporfin

Erstellt am 12 May 2019 23:10
Zuletzt geändert: 10 Aug 2020 17:34

FACHINFORMATIONEN; Produktinformationen:

Photodynamische Therapie

Methods: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg(-1) verteporfin. After 60-90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently.
Conclusions: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.

Sonstiges

YAP/TAZ

Laborstudien, unter anderem an Organoiden aus Patienten-Zellen.

"In summary, we provide evidence that although Verteporfin induces both a rapid drop in YAP/TAZ protein levels and a reduction in melanoma cell numbers in culture, it does not inhibit melanoma tumor initiation and progression in vivo in BrafCA, Tyr-CreERT2, Ptenf/f mice. These data suggest that a role for Verteporfin as a candidate for melanoma therapeutics is limited."

"… there have been numerous others that have found that verteporfin can inhibit the growth of YAP/TAZ-TEAD dependent cancer cells in vitro or in vivo. These studies were promising because verteporfin is an FDA approved photodynamic therapy. However, verteporfin’s promise as a YAP/TAZ-TEAD inhibitor is outweighed by high toxicity and the accounts of YAP/TAZ-TEAD independent effects. Although verteporfin prevents YAP-TEAD activity by preventing YAP-TEAD interaction, other evidence shows it can also activate the Hippo pathway, and regulate YAP and TAZ protein expression. This apparent lack of specificity further diminishes its therapeutic potential. Other porphyrin compounds, including those mentioned above, also inhibit YAP/TAZ activity, but they are not as widely studied and additional work is needed to characterize their mechanisms of action, toxicity, and specificity. Thus, although verteporfin and other existing YAP/TAZ inhibitors are useful tools to test the impact of YAP/TAZ inhibition in pre-clinical models, they are not likely to be useful therapeutically, so new therapies need to be developed and tested."

Treating BRAF inhibitor-resistant melanoma is an important therapeutic goal. Thus, it is important to identify and target mechanisms of resistance to improve therapy. The YAP1 and TAZ proteins of the Hippo signaling pathway are important drivers of cancer cell survival, and are BRAF inhibitor resistant factors in melanoma. We examine the role of YAP1/TAZ in melanoma cancer stem cells (MCS cells). We demonstrate that YAP1, TAZ and TEAD (TEA domain transcription factor) levels are elevated in BRAF inhibitor resistant MCS cells and enhance cell survival, spheroid formation, matrigel invasion and tumor formation. Moreover, increased YAP1, TAZ and TEAD are associated with sustained ERK1/2 activity that is not suppressed by BRAF inhibitor. Xenograft studies show that treating BRAF inhibitor-resistant tumors with verteporfin, an agent that interferes with YAP1 function, reduces YAP1/TAZ level, restores BRAF inhibitor suppression of ERK1/2 signaling and reduces tumor growth. Verteporfin is highly effective as concentrations of verteporfin that do not impact tumor formation restore BRAF inhibitor suppression of tumor formation, suggesting that co-treatment with agents that inhibit YAP1 and BRAF(V600E) may be a viable therapy for cancer stem cell-derived BRAF inhibitor-resistant melanoma.

"Background: Verteporfin is a porphyrinic photosensitizer clinically used for the photodynamic treatment of age-related macular degeneration. It has been identified almost simultaneously as a YAP/TEAD and an autophagosome inhibitor. Over the last few years, YAP (TAZ), the downstream effectors of the Hippo pathway, have emerged as promising anticancer targets, as shown by several experimental lines of evidence, showing the overproduction of YAP in several cancers. However, YAP was also found to be closely connected to autophagy, mitochondria and reactive oxygen/nitrogen species. We herein, review the recent studies where VP was used without photoactivation as a YAP/TEAD inhibitor or protein oligomerization promoter, focusing on its effects on the YAP/TEAD gene targets and other biomarkers related to autophagy. Results: Since the identification of VP as YAP/TEAD inhibitor, several in vitro and in vivo studies have revealed the new potential of this molecule in different cancers, where YAP is overexpressed. However, detailed structural information about its interaction with YAP is still lacking. Concomitantly, VP was identified as autophagosome inhibitor by promoting oligomerization of p62. Moreover, VP proves to be tumor-selective proteotoxic (by oligomerization of p62, STAT3) in colorectal cancer. Knowledge on the biological properties of the only YAP inhibitor available to date is vital for its pharmacological use on cellular and animal models. Conclusion: VP is a multi-target drug interacting with several proteins implicated in major cellular processes. Although this does not impact its clinical use, VP does not seem to be the ideal drug for pharmacological inhibitions of YAP/TEAD."

Integrin-Rezeptor-Signalkaskade

Zitat aus der Pressemeldung:

"Konkret zeigten die Wissenschaftler, dass die Komponenten der extrazellulären Matrix über einen Integrin-Rezeptor ein Signal in die Zelle hinein senden. Dies wiederum führt zu Änderungen mechanischer Kräfte, die über das Actin-Zytoskelett übertragen werden. Das yes-assoziierte Protein (YAP) nimmt diese Kräfte wahr und schaltet entsprechend spezifische Gene an oder aus. Diese Signalkaskade bestimmt letztendlich das Entwicklungsschicksal der Vorläuferzelle. “Besonders spannend ist für uns, dass unsere Daten eine Frage beantworten, die unser Forschungsfeld seit Jahrzehnten umtreibt“, so Henrik Semb. „Wie reifen manche Vorläufer zu Gerüstzellen, während andere durch Aktivierung des sogenannten Notch-Signalwegs zu endokrinen Zellen werden.“ Die Wissenschaftler zeigen, dass die vermeintlich zufällige Steuerung dieses Signalwegs in Wahrheit durch den Kontakt der Vorläuferzellen mit der extrazellulären Matrix und dem mechanosensitiven Gen-Regulator YAP vermittelt wird."

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