Basal Cell Carcinoma and Hedgehog Pathway Inhibitors: Focus on Immune Response

Abstract

Basal cell carcinoma (BCC) is the most common form of skin cancer, affecting more often elderly patients, but sometimes even younger ones, particularly if immunocompromised or genetically predisposed. Specifically, the Gorlin-Goltz syndrome, an autosomal dominant genodermatosis, also known as nevoid basal cell carcinoma syndrome, characterizes for multiple early onset BCCs. It is caused by a germline mutation in PTCH1, a tumor suppressor gene whose product is the key component of Hedgehog (Hh) signaling pathway, which also appears somatically mutated in more than 85% of sporadic BCCs. Hh pathway inhibitors vismodegib and sonidegib are currently indicated for BCC, in adults with advanced or recurred tumor following surgery or radiation therapy. The principal mechanism of action of these drugs is the inhibition of Smoothened (SMO), a transmembrane protein involved in Hh signal transduction, that plays a role in both cellular differentiation and cancer development. Some studies have reported effects of Hh pathway inhibitors at different levels of the immune response, from cytotoxic T cells to a modified local cytokines pattern. Given the specific relation between immune system and BCC development in some conditions, we will review BCC with focus on immune system changes mediated by Hh signaling pathway and induced by the inhibitors vismodegib and sonidegib in the treatment of BCC. Thus, we will give an overview of their effects on the local immune response, as well as a brief note on the supposed function of Hh pathway inhibition on the systemic one.

Pathophysiology, Histopathology, and Differential Diagnostics of Basal Cell Carcinoma and Cutaneous Squamous Cell Carcinoma—An Update from the Pathologist’s Point of View

“…Thus, the transcription factor GLI1 is involved in the activation of transcription, and GLI2 and GLI3 have both activatory and inhibitory functions in transcription. Any mutation that occurs within the transcription factors leads to the impairment of the normal cell proliferation process [36,37].…”

Pre‐operative high‐frequency ultrasound: a reliable management tool in auricular and nasal non‐melanoma skin cancer

“…For locally advanced or metastasized SCC patients who are not candidates for surgery or curative radiation, Cemiplimab, a human monoclonal antibody directed against programmed cell death‐1 receptor (PD‐1) that blocks T‐cell inactivation and that was approved in 2018, shows good and durable response rates 7,8 . Similarly, for advanced or metastatic BCCs, two small molecules targeting Smoothened (SMO), a transmembrane protein involved in the Hedgehog signal transduction that plays a role in cellular differentiation and cancer development, were approved in 2012 (Vismodegib) and 2015 (Sonidegib), respectively 5,9 . In other cases of NMSC where surgery or systemic treatment is not feasible, radiation therapy with curative or palliative intention also presents an alternative 10,11 …”

“…7,8 Similarly, for advanced or metastatic BCCs, two small molecules targeting Smoothened (SMO), a transmembrane protein involved in the Hedgehog signal transduction that plays a role in cellular differentiation and cancer development, were approved in 2012 (Vismodegib) and 2015 (Sonidegib), respectively. 5,9 In other cases of NMSC where surgery or systemic treatment is not feasible, radiation therapy with curative or palliative intention also presents an alternative. 10,11 In the evolving field of dermato-oncology, highfrequency ultrasound (HFUS) in the pre-surgical setting is becoming increasingly popular, as sonography can provide clinicians with essential information regarding tumor extension and infiltration depth while also facilitating the detection of relevant adjacent neurovascular structures.…”

Präoperativer Hochfrequenzultraschall: Ein zuverlässiges Managementinstrument bei nichtmelanozytärem Hautkrebs der Ohrmuschel und der Nase

“…Im Jahr 2012 (Vismodegib) beziehungsweise 2015 (Sonidegib) wurde diese orale Therapie zugelassen. 5,9 In anderen Fällen von NMSC, bei denen eine Operation oder systemische Behandlung nicht durchführbar ist, stellt auch die Strahlentherapie in kurativer oder palliativer Intention eine Alternative dar. 10,11 Der Einsatz von Hochfrequenzultraschall (HFUS) vor Operationen gewinnt in der Dermatoonkologie zunehmend an Bedeutung, da die Sonographiegeräte immer leistungsfähiger werden und die Methode den Ärzten wichtige Informationen über die Tumorausdehnung und die Infiltrationstiefe liefert und gleichzeitig die Erkennung relevanter benachbarter neurovaskulärer Strukturen erleichtert.…”

“…Bei diesen Tumoren zeigt eine zielgerichtete Therapie gegen den reaktivierten Sonic‐Hedgehog‐Signaltransduktionsweg gute Ansprechraten. Im Jahr 2012 (Vismodegib) beziehungsweise 2015 (Sonidegib) wurde diese orale Therapie zugelassen 5,9 . In anderen Fällen von NMSC, bei denen eine Operation oder systemische Behandlung nicht durchführbar ist, stellt auch die Strahlentherapie in kurativer oder palliativer Intention eine Alternative dar 10,11 …”