Basal-Cell Carcinoma (BCC) Overview - Signaling Pathway. Diagnostics Marker. Targeted Therapy and Clinical Trials.

An Introduction to BCC

Basal cell carcinoma (BCC) is the most common type of skin cancer and the most frequently occurring form of all cancers, which begins in the basal cells that is a type of cell within the skin that produces new skin cells as old ones die off. BCC usually develops on sun-exposed parts of body, especially the head and neck. Symptoms of the cancer often include a pearly white, skin-colored or pink bump, a brown, black or blue lesion, a flat, scaly, reddish patch and a white, waxy, scar-like lesion. The cause of the BCC occurring is one of the skin's basal cells producing a mutation in its DNA. Most BCCs are thought to be caused by long-term exposure to ultraviolet (UV) radiation from sunlight. Some other risk factors may lead to BCC including radiation therapy, fair skin, increasing age, a personal or family history of skin cancer, immune-suppressing drugs, exposure to arsenic and inherited syndromes that cause skin cancer.

1 Main Signaling Pathways in BCC Therapy

1.1 Hedgehog signaling cascade

The Hedgehog (Hh) signaling is an important pathway that regulates the embryonic development and stem cell maintenance. However, its aberrant regulation is associated with the development of many cancers including BCC. Normally, the Hh pathway is mediated by the Ci/GLI family of zinc finger transcription factors, and the transmembrane receptors Patched (PTCH) and Smoothened (SMO) play vital roles in the Hh signaling. In the absence of the Hh ligand, its receptor PTCH can block the function of SMO to inactivate the Hh signaling. Upon the Hh ligand binds to PTCH, the inhibitory effect of PTCH on SMO can be removed triggering the activation of the transcription factor Ci/GLI. Three GLI genes have been identified in vertebrates currently including GLI1, GLI2 and GLI3. Activating mutations of SMO or suppressing mutations of PTCH have been found to constitutively activate the Hh signaling pathway. The constitutive activation of Hh signaling pathway has been found to be a key factor driving the development of BCC.

1.2 Wnt signaling cascade

The Wnt signaling is another pathway involved in BCC development, which plays an important role in patterning and cell proliferation of embryonic and adult tissues. Abnormal activation of the Wnt signaling pathway can cause a variety of human cancers including BCC. β-catenin plays a critical role in the signaling pathway that is activated by Wnt proteins. During the Wnt signaling, β-catenin together with axin, adenomatous polyposis coli (APC), and glycogen synthase kinase β (GSK3β) to form a complex, which is phosphorylated by GSK3β and subsequently ubiquitinated and degraded in the proteasomes. Binding of Wnt proteins to the receptors Frizzled and LDL-receptor related protein (LRP) family results in GSK3β inactivation and the release of unphosphorylated β-catenin from the multiprotein complex. Then β-catenin is translocated into the nucleus and binds to Tcf/Lef to trigger the activation of Wnt target genes. Activation of the Wnt pathway has been found in BCCs, which is characterized by over-expression of Wnt proteins and the presence of β-catenin with stabilizing mutations. In addition, cytoplasmic and/or nuclear localization of β-catenin have been identified in different human BCC tumors.

BCC Diagnosis

2.1 Molecular Markers for BCC

In BCC progress, the main driver is activation of the Hedgehog (Hh) pathway with inactivating mutations of PTCH1 identified in 90% of sporadic BCCs and activating mutations of SMO in approximately 10%. Alterations of the Hh pathway are also found in other Hh-dependent tumors, and all these tumors develop in patients with naevoid basal cell carcinoma syndrome (NBCCS) due to germline mutations in PTCH1, PTCH2, SMO and SUFU. Very few BCCs show no mutations in the Hh pathway. Other driver mutations as molecular markers have also been found including MYCN, PPP6C, STK19, LATS1, ERBB2, PIK23C, N-RAS, K-RAS and H-RAS, as well as loss of function of PTPN14, RB1 and FBXW7. P53 gene mutations are also found frequently.

2.2 Protein Markers for BCC

Over-expression of Sonic Hedgehog (SHH) has been shown to cause BCC, and activation of GLI1 has been identified as a key step in the initiation of the tumorigenic program leading to BCC. GLI1 is highly expressed in human BCC. hTERT has been regarded as the Wnt/β-catenin signaling direct targets in BCC, whose overexpression in cancer cells can leads to the cell immortality, invasion and metastasis. Aberrant activation of the Wnt/β-catenin signaling can increase the BIRC5/Survivin expression that in turn inhibits caspase-3 and -7 and prevent apoptosis adding to the immortality of cancer cells. Musashi-1 and Sox2 are markers overexpressed in many cancers such as BCC and contribute to their tumorigenic phenotype. IGF2BP1 (also known as IMP1, CRD-BP, and ZBP1) is a direct target of the canonical Wnt/β-catenin signaling pathway. It is over-expressed in BCC and positively correlates with the activation of both Wnt and Hh signaling pathways in BCC.

3 Targeted Therapy for BCC

Currently, few options can be used to treat patients with significant locally invasive or advanced metastatic BCC. Over the past years, improved understanding of the signaling pathways in BCC such as the Hedgehog signaling pathway has led to development of several new therapies that target this signaling pathway. Specifically, these agents inhibit the pathway by blocking Smoothened (SMO), a 7-pass transmembrane G protein coupled receptor-like protein. Almost all patients with BCC have defects of the Hedgehog pathway that lead to an inability to block SMO. Thus, blocking SMO in patients with Hedgehog signaling pathway defects can be considered as new targeted therapy approach. Here, we summarize the potential targets and new drugs developed that have been used in recent, ongoing and future clinical trials to try to improve the clinical outcomes of this disease (Table1-6).

3.1 BCC therapy for Hedgehog pathway

A number of targeted agents against the Hh signaling are currently being evaluated. The first FDA-approved is vismodegib (Erivedge) targeting the SMO protein for locally advanced or metastatic BCC treatment. Vismodegib is quite effective at suppressing BCC tumor growth and appears both tumoricidal and tumoristatic. Many tumors will regrow after drug cessation, which indicates that vismodegib as a treatment is the most effective way to reduce the tumor to a controllable level and surgically excise any remaining tumor clones. Other SMO inhibitors under the investigation include LDE225, PF-04449913, Erismodegib, BMS-833923, Saridegib, Itraconazole, CUR61414, ALLO-1 and 2, TAK-442, LY2940680, and LEQ506. One example, LDE225 is a selective and potent inhibitor of SMO currently in phase II studies in patients with BCC and other cancers. Besides, other Hh pathway antagonists include Robotnikinin, 5E1, ATO, GANT-61, GANT-58, HPI-1 through-4, Sirolimus, PF-4708671, PSI, etc.

Table 1 Clinical trials of SMO inhibitor vismodegib

According to statistics, a total of 7 vismodegib projects targeting BCC SMO are currently in clinical stage, of which 2 are recruiting and 5 are not recruiting.

Table 2 Clinical trials of SMO LDE225

According to statistics, a total of 3 LDE225projects targeting BCC SMO are currently in clinical stage, of which 2 are recruiting and 1 is not recruiting.

Table 3 Clinical trials of SMO inhibitor Erismodegib

According to statistics, a total of 3 Erismodegib projects targeting BCC EGFR are currently in clinical stage, of which 2 are recruiting and 1 is not recruiting.

Table 4 Clinical trials of SMO inhibitor Saridegib

According to statistics, a total of 3 Saridegib projects targeting BCC EGFR are currently in clinical stage, of which 2 are recruiting and 1 is not recruiting.

Table 5 Clinical trials of SMO inhibitor Itraconazole

According to statistics, a total of 2 Itraconazole projects targeting BCC EGFR are currently in clinical stage, of which 1 is recruiting and 1 is not recruiting.

Table 6 Clinical trials of GLI inhibitor ATO

According to statistics, a total of 1 ATO project targeting BCC GLI is currently in clinical stage and is not recruiting.