Long-Term Management of Advanced Basal Cell Carcinoma: Current Challenges and Future Perspectives

Abstract

The first-line therapy for locally advanced basal cell carcinoma (laBCC) is Hedgehog pathway inhibitors (HHIs), as they achieve good efficacy and duration of response. However, toxicity in the course of long-term treatment may lead to a decrease in the quality of life, and consequently to interruption or even discontinuation of therapy. As HHI therapy is a balancing act between effectiveness, adverse events, quality of life, and adherence, numerous successful treatment strategies have evolved, such as dose reduction and dose interruptions with on-off treatment schedules or interruptions with re-challenge after progression. As a small percentage of patients show primary or acquired resistance to HHIs, the inhibition of programmed cell death protein 1 (PD-1) has been approved as a second-line therapy, which may also be accompanied by immune-related toxicities and non-response. Thus, optimization of current treatment schedules, novel agents, and combination strategies are urgently needed for laBCC. Here, we narratively model the treatment sequence for patients with laBCC and summarize the current state of approved treatment regimens and therapeutic strategies to optimize the long-term management of laBCC.

Keywords: Hedgehog pathway inhibitors; basal cell carcinoma; immunotherapy; programmed cell death protein 1 inhibitor.

Figure 1

Schematic representation of the Hedgehog (HH) signaling pathway. (A) Binding of the extracellular HH ligand to the Patched 1 (PTCH1) receptor releases Smoothened (SMO) from inhibition. SMO starts an intracellular signaling cascade including Suppressor of Fused (SUFU), which results in activation of the transcription factors of the GLI family; (B) loss-of-function mutations in PTCH1 or activating mutations in SMO activate the HH signaling pathway in basal cell carcinoma (BCC) cells. This process can be inhibited by HH pathway inhibitors (HHI); (C) intrinsic resistance as caused by SMO G497W mutation, or acquired resistance as caused by SMO D473Y mutation impede entry of the drug into the binding site. Modified according to [1].

Figure 2

Median percent change in diameter of all surgically eligible BCCs. Solid lines represent time on vismodegib; dashed lines represent time off vismodegib. Modified according to [48].

Figure 3

Schematic representation of the immunological aspects of the basal cell carcinoma (BCC). (A) The tumor microenvironment is characterized by decreased infiltration of CD4+ and CD8+ T cells and increased presence of regulatory T cells (T reg). Dendritic cells (DC) of an immature phenotype are present in in the tumor microenvironment of laBCC. Increased expression of TH2 cytokines (interleukin [IL]-4, IL-5) and transforming growth factor (TGF)-β, as well as IL-10, supports an immunosuppressive environment surrounding the tumor. In addition to a high mutational load, tumor cells are characterized by the expression of the inhibitory molecules programmed cell death 1 ligand 1 (PD-L1) and PD-L2, which can suppress T cell activity by binding to programmed cell death protein 1 (PD-1) on T cells; (B) loss-of-function mutations in PTCH1 or activating mutations in SMO activate the HH signaling pathway in laBCC cells; (C) decreased expression of the transporter associated with antigen processing-1 (TAP-1) and major histocompatibility complex (MHC)-I lead to decreased recognition of tumor cells by the immune system.

Figure 4

Case history of a patient with Gorlin–Goltz syndrome and multiple BCCs before pembrolizumab treatment (A), 7 months after pembrolizumab (at progression) and before sonidegib treatment (B), and 5 months after sonidegib treatment (C).

Figure 5

Schematic representation of the modes of action of novel drugs for basal cell carcinoma (BCC) therapy. (A) Loss-of-function mutations in PTCH1 or activating mutations in SMO activate the HH signaling pathway in BCC cells. CX-4945 acts on the terminal HH signaling components by inhibiting casein kinase CK2. Thus, the signal transduction pathway is interrupted; (B) STP705 consists of two small interfering RNA (siRNA) oligonucleotides packaged with a histidine-lysine (HK) polymer as a delivery system. The siRNA intermediates bind to an RNA-induced silencing complex (RISC), and then selectively degrade the complementary single-stranded target RNA. As the siRNA of STP705 targets the mRNA of transforming growth factor (TGF)-β1 and cyclooxygenase (Cox)-2, respectively, it downregulates the expression of TGF-β1 and COX-2, resulting in tumor growth inhibition; (C) ASN-002 functions as a recombinant adenovirus vector, delivering the human interferon (IFN)-γ gene into BCC cells. IFN-γ secretion results in a local IFN-γ concentration within the tumor; (D) the checkpoint inhibitor nivolumab blocks binding of programmed cell death protein 1 (PD-1) on T cells to its ligands programmed cell death 1 ligand 1 (PD-L1) and PD-L2 on tumor cells. Relatlimab is an antibody directed against the inhibitory molecule lymphocyte-activation gene (LAG)-3. Binding of cytotoxic T-lymphocyte-associated protein (CTLA)-4 to the B7 molecules as antagonist of CD28 on antigen-presenting cells (APCs) is blocked by ipilimumab. These checkpoint inhibitors may release the T cells from immunosuppressive mechanisms of the tumor microenvironment; (E) Daromun (L19IL2/L19TNF) consist of recombinant interleukin (IL)-2 and tumor necrosis factor (TNF)-α cytokines (respectively), fused to a human single-chain variable fragment directed against the extra-domain B (ED-B) of fibronectin (L19). After binding of the L19 moieties to the fibronectin on tumor cells, the cytokines can trigger an immune response against ED-B fibronectin-expressing tumor cells.