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Cancers of the human skin are divided into melanoma and non-melanoma. Being among the most commonly diagnosed cancer cases globally, non-melanoma skin cancers are comprised of basal and squamous cell carcinomas. In dermato-pathology, basal cell carcinomas (BCCs) are a frequently encountered diagnosis of skin cancer, and most cases are treated with surgical excisions. While sporadic BCC tumors appear primarily due to aging and ultra-violet exposure, the development of numerous BCCs from a young age is one of the main clinical signs in Gorlin syndrome patients. The critical driver of BCC tumor formation is the sonic hedgehog (SHH) pathway, a pivotal developmental signaling pathway that regulates organ development, cell proliferation, and tissue repair. The majority of all sporadic and syndromic BCCs exhibit mutations in two key components in this pathway, the tumor suppressor gene patched 1 (PTCH1) or the proto-oncogene smoothened (SMO), which result in aberrant pathway activation and continued transcription of SHH-dependent genes. In the last decade, SHH inhibitors have emerged as a novel treatment for advanced and metastatic BCCs. Systemic treatment with vismodegib, a potent SMO inhibitor, can effectively reduce BCC tumor burden in adult Gorlin syndrome patients. However, it is associated with chemotherapy-related adverse events, and treatment cessation results in cancer recurrence and formation of a subset of drug resistant BCCs. While aberrant SHH signaling is key, mechanisms that underlie epithelial–stromal crosstalk and reprograming of tumor metabolism can potentially converge with this pathway and promote BCC tumor development. In this study, we investigated the effects vismodegib on the morphology, behavior, and energy metabolism of human BCC cells and human dermal fibroblasts, in individual cultures as well as in co-cultures, that enabled the crosstalk between these two cell types. Computer-assisted bright-field microscopy was used to characterize cell morphology and behavior. Nuclear magnetic resonance (NMR) and metabolomics were used to determine the metabolic activity of these cells. We found that continuous crosstalk between the cells and different concentrations of vismodegib led to distinct changes in cell morphology and growth, as well as consumption of glucose, pyruvate, and glutamine and secretion of acetate, lactate, and glutamate by these cells. Deciphering tumor driver mechanisms that converge with SHH pathway and contribute to changes within the tumor microenvironment are important not only for better understanding of BCC pathobiology, but also for the development of new mechanism-based BCC therapies with improved clinical outcomes. / 2023-02-22T00:00:00Z

Basal cell carcinoma is the most common form of human malignancy, and as such there are varied methods for treating its various forms. Its more advanced and aggressive forms have required both the use of and advent of therapies which offer differing safety profiles, cost, and efficacy. Two therapies which differ substantially in these respects but have overlap in their recommended use are Mohs micrographic surgery and the pharmaceutical drug vismodegib. Few studies have sought to compare the two methods using these criteria, and as vismodegib has only received FDA approval in the past ten years, it is worthwhile to explore the limitations and advantages of each therapy. In exploring previous clinical trials and retrospective studies, the two therapies are put side by side to contrast their results with their shared intended use. The general findings were that Mohs micrographic surgery remains the gold standard for the treatment of locally advanced basal cell carcinoma, and there are few demonstrable instances in which vismodegib could be deemed a more appropriate therapy. The future of vismodegib appears to be in its use as a neoadjuvant therapy for locally advanced basal cell carcinomas for which a decrease in size by vismodegib would allow for better treatment outcomes.

Purpose: The Hedgehog-signalling pathway (Hh) is frequently active in head and neck squamous cell carcinoma (HNSCC). Overexpressed Hh associates with poor prognosis. The Hh inhibitor vismodegib targets smoothened (SMO) and, based on molecular data, may prevent resistance to EGFR targeting. Methods: To elucidate potential roles of vismodegib in HNSCC therapy, its sole effects and those combined with cisplatin, docetaxel, and cetuximab on HNSCC cell lines were assessed by MTT metabolisation and BrdU incorporation. Colony formation (CF) of primary HNSCC cells was studied utilizing the FLAVINO-protocol. Combinatory effects were analysed regarding antagonism, additivity or synergism. Associations between the ex vivo detected mode of action of vismodegib with other treatments related to patient characteristics were assessed and progression-free survival (PFS) in patient groups compared using Kaplan-Meier curves. Results: Vismodegib suppressed BrdU incorporation significantly stronger than MTT turnover; CF was significantly inhibited at ≥20 µM vismodegib while concentrations <20 µM acted hormetic. Combining 20 µM vismodegib plus docetaxel (T), cisplatin (P), and cetuximab (E), additively enhanced antitumoral activity in HNSCC samples from patients with superior PFS highlighting a potential role for ex-vivo testing of this combination for use as a prognostic classifier. Conclusion: We provide ex-vivo evidence for vismodegib’s potential in HNSCC therapies especially if combined with cetuximab, cisplatin and docetaxel.:Abkürzungsverzeichnis 1 Einleitung 1.1 Kopf-Hals-Tumore 1.1.1 Therapie von Kopf-Hals-TumoreN 1.1.2 Limitationen der etablierten Therapien 1.2 Eingesetzte Chemotherapeutika 1.2.1 Cisplatin 1.2.2 Docetaxel 1.2.3 Cetuximab 1.3 Hedgehog-Signaltransduktionsweg 1.3.1 Hedgehog-Signalweg und Karzinogenese 1.3.2 Vermittlung von Tumortherapieresistenz durch den Hedgehog-Signalweg 1.3.3 Zielgerichtete Tumortherapie durch Blockade des Hedgehog-Signalweges 1.4 Vismodegib 1.5 Ex-Vivo-Chemoresponse-Testung mittels FLAVINO-Assay 1.6 Zusammenfassung der Rationale der Untersuchung 1.7 Aufgabenstellung der Promotionsarbeit 2 Publikation 2.1 Reduzierte Proliferation und Koloniebildung von Plattenepithelkarzinomen der Kopf Hals Region unter dualer Inhibition des EGFR- und Hedgehog-Signalweges 3 Zusammenfassung der Arbeit 4 Literaturverzeichnis 5 Anlagen 5.1 Darstellung des Eigenanteils 5.2 Erklärung über die eigenständige Abfassung der Arbeit 5.3 Lebenslauf 5.4 Publikationen 5.5 Danksagung

Medulloblastoma (MB) is a malignant embryonal tumor of the posterior fossa belonging to the family of primitive neuro-ectodermic tumors (PNET). MB generally occurs in pediatric age, but in 14–30% of cases, it affects the adults, mostly below the age of 40, with an incidence of 0.6 per million per year, representing about 0.4–1% of tumors of the nervous system in adults. Unlike pediatric MB, robust prospective trials are scarce for the post-puberal population, due to the low incidence of MB in adolescent and young adults. Thus, current MB treatments for older patients are largely extrapolated from the pediatric experience, but the transferability and applicability of these paradigms to adults remain an open question. Adult MB is distinct from MB in children from a molecular and clinical perspective. Here, we review the management of adult MB, reporting the recent published literature focusing on the effectiveness of upfront chemotherapy, the development of targeted therapies, and the potential role of a reduced dose of radiotherapy in treating this disease.