Kurzfassung

Abstract: Malignant melanoma remains one of the leading mortality causes in dermatooncological practice with devastating survival rates for patients with distant metastases. The introduction of targeted therapies or checkpoint inhibitors such as of B-Raf or Anti-PD1 led to a promising improvement in desease control. However, with resistance mechanisms and a large portion of non-responders, investigation of further therapeutic options is inevitable.
Hedgehog-inhibition could be one possible...Abstract: Malignant melanoma remains one of the leading mortality causes in dermatooncological practice with devastating survival rates for patients with distant metastases. The introduction of targeted therapies or checkpoint inhibitors such as of B-Raf or Anti-PD1 led to a promising improvement in desease control. However, with resistance mechanisms and a large portion of non-responders, investigation of further therapeutic options is inevitable.
Hedgehog-inhibition could be one possible treatment. First described in the 1980s it is nowadays known to be crucial in the development and differentation  of stem cells. Moreover, its mutation or abnormal activation has been shown to lead to different tumors such as basal cell carcinoma or medulloblastoma and has attracted a lot of notice in oncological research lately. With further investigation even more entities were associated with this pathway, however, until now there is only rare knowledge on the effects of Hedgehog and its distinct role in malignant melanoma.
In a previous in-vitro study we were not only able to determine the expression of Hedgehog-components in melanoma cells but also were the first to analize the effect of a specific inhibition in comparison to established treatments such as interferon α and γ-radiation. Our study showed that hedgehog is expressed and its components can be found in melanoma cells but even more important that specific inhibition is able to reduce or stop cell proliferation. Depending on the expression level of hedgehog the effect of the inhibition while wildtype cells show no response at all.

The proposed in-vitro study is the first of its kind and our next step to investigate the relationship between Hedgehog and Ras-Raf-MEK-ERK in collaboration with the department of dermatology of the University Medical Center of Mainz.

For this study we set up two hypotheses:
I. Hedgehog inhibition shows an effect only on B-Raf- or N-RAs-mutant melanoma cells.

II. Activation of the Hedgehog-pathway leads to increased activation of the Ras-Raf-MEK-ERK-pathway

In the first part of the proposed study, a series  of Ras- and Raf-mutated as well als wildtype melanoma cells will be cultivated and treated with a specific Hedgehog-inhibitor according to our previously established method. Then the response rates of the different cell groups after treatment with the specific Hedgehog-inhibitor will be collelated to their genetic mutation (Ras-, Raf-mutant or wildtype).
In a second part, the expression levels of the different components of the Ras-Raf-MEK-ERK-pathway will be analyzed concerning changes after Hedgehog-activation. The changes in the expression levels of the different components then will be collelated statistically and will function as indicators for a link between Hedgehog and Ras-Raf-MEK-ERK in melanoma cell lines.

The results of this sutdy will help us to apply for future investigations to the german cancer society in order to examine the proven link between Hedgehog and Ras-Raf-MEK-ERK more detailed. Furthermore, the findings will lead to a better understanding of the Hedgehog-pathway expecially in malignant melanoma and as a
long-term goal can help to establish Hedgehog-inhibitors as a possible therapeutic option in malignant melanoma.

Laufzeit 9 Monate
Summe 14750 €

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