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Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies Expert Rev. Anticancer Ther. 14(6), 741–749 (2014)
Veronica Ruiz Salas*, Marta Alegre, Joan Ramo´n Garce´s and Lluis Puig Department of Dermatology, Hospital de la Santa Creu I Sant Pau, C/ Sant Antoni Maria Claret 167, 08025 Barcelona, Spain *Author for correspondence: Tel.: +34 696 197 868 Fax: +34 932 919 427 [email protected]
The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development. KEYWORDS: basal cell carcinoma • hedgehog • locally advanced • metastatic • vismodegib
Basal cell carcinoma (BCC) is the most common of all human malignancies and the most common keratinocyte skin cancer in persons of Caucasian ancestry. The true incidence of this disease is unknown since it is often seen and treated in the outpatient setting, thus not being reflected in hospital statistics [1]. Certain risk factors for the disease (e.g., UV light exposure [2] and fair complexion [3]) are not constant worldwide, so the incidence of BCC varies by geographical location [2]. The precise origin of BCC is still unknown, but it seems to develop from epidermal stem cells of the outer root sheath of the hair follicle [3]. More common in men than in women, BCC usually occurs at an average age of 60 years. Predisposing factors include environmental exposure to arsenic, ionizing radiation, oral methoxsalen (psoralen), history of chronic trauma (burns, radiodermitis, wound and ulceration) and immunosuppressive therapy such as in organ transplant recipients [4]. Persons with a phototypes I and II, history of intermittent sun exposure and severe sunburn informahealthcare.com
10.1586/14737140.2014.895326
during childhood and patients with some genodermatoses such as albinism, xeroderma pigmentosum, rombo syndrome (RS), gorlin syndrome (GS), bazex-dupre-christol syndrome (BDCS), dugois-colomb-berthon syndrome, bloom syndrome (BS), Rothmund–Thompson syndrome (RTS), muir-torre syndrome (MTS) and linear unilateral BCC are at highest risk [5]. RS is an extremely rare condition characterized by acral and facial erythematous lesions, atrophoderma vermiculatum on the face and elbows, facial hypotrichosis, multiple vellus hair cysts with a milia-like appearance, telangiectasias on sun-exposed areas and predisposition to BCCs [6]. Although some of these features are shared with BDCS, the disease evolution and the absence of congenital manifestations in RS support their noslogical differentiation. The disease usually starts at the end of the first decade of life with skin atrophy and erythematous and, occasionally, painful skin lesions of the extremities and face. Subsequently, vellus hair cysts and telangiectasias superimposed on erythematous lesions develop.
2014 Informa UK Ltd
ISSN 1473-7140
741
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Multiple BCCs are the last sign to appear, usually after the age of 35 years [7]. RS has been reported in only three families [6–8] although in one of them [8], the diagnosis has been questioned. In two cases, RS occurred sporadically, while in the original report, vertical male-to-male transmission suggests an autosomal-dominant inheritance pattern. The molecular basis of RS remains unknown. BDCS or Bazex syndrome is an uncommon genodermatosis first reported in 1964 and is so far described in 90 patients [9]. Its main features include congenital hypotrichosis, generalized or facial hypohidrosis, atrophoderma follicularis on the dorsum of the hands and more rarely the elbows [10], multiple milia with histological features of follicular cysts and multiple BCCs and trichoepitheliomas, both mainly localizing on the face. Consistent ancillary features include a typical face with pinched nose [11], facial and flexural hyperpigmentation, hidradenitis suppurativa and hair shaft abnormalities [12]. BDCS displays the dual association of defective skin organogenesis (i.e., ectodermal dysplasia) and proneness to cutaneous tumors. Such a combination is shared by few other conditions, including RS, scho¨pf–schulz–passarge syndrome, generalized follicular basaloid hamartoma syndrome and, partially, GS [12]. In BDCS, skin neoplasms may appear very early with the youngest patients with BCC aged 3 years [13]. However, ectodermal defects are usually the first to appear, leading to the possible misdiagnosis of pure ectodermal dysplasia. MTS is characterized by the association of sebaceous tumors (or keratoacantomas) and visceral cancers, mainly involving the gastrointestinal tract, urinary apparatus and endometrium. MTS is inherited as an autosomal-dominant trait and is due to mutations of the mismatch repair genes such as MLH1 (3p21.3) or MSH2 (2p22–p21). The diagnosis is established by microsatellite instability and/or immunohistochemical examination of a tumor followed by molecular testing of DNA from peripheral blood [14]. In MTS, multiple BCCs, occasionally with sebaceous differentiation, have been reported. BS is a genomic instability syndrome caused by recessive mutations in RECQL3 (15q26.1), encoding for a specific human helicase. Diagnosis of BS is first performed by cytogenetic analysis, which shows tetraradial figures and increased sister chromatid exchanges, and then by molecular testing. BS is mainly characterized by the triad of short stature of prenatal onset (i.e., primordial dwarfism), photosensitivity manifesting with erythematous butterfly-like sun-sensitive skin lesions on the nose and cheeks and occasionally on the dorsum of hands and feet, multiple cafe´au-lait spots and immune dysregulation [15]. BCCs appear more commonly in BS than in the general population. Given the increased chromosome instability of BS, surveillance and management of cancer should avoid the use of ionizing radiation. RTS, or poikiloderma congenitale, is caused by recessive mutations in the gene coding for human helicase type 4, namely RECQL4 (8q24), in two of the three cases. Similar to BS, RTS is transmitted as an autosomal-recessive trait and shows proneness to various neoplasms. The most common cancers in RTS are osteosarcoma and cutaneous neoplasms, occurring in 30 and 5% of the patients, respectively. Skin cancers include SCC, BCC 742
and Bowen’s disease and appear at a mean age of 34.4 years [16]. A patient with RTS and amelanotic melanoma has recently been reported [17]. While genotype–phenotype correlation for proneness to osteosarcomas in RTS has been outlined [18], such a molecular definition is still lacking for skin neoplasms. GS, also known as basal cell nevus syndrome (BCNS) and naevoid BCC syndrome, is an autosomal-dominant genodermatosis that is characterized by a wide range of developmental defects and proneness to various cancers, mainly BCCs. GS is the best-known genetic disorder associated with BCCs. Its manifestations are highly variable including a least 100 different associated features. At present, the diagnosis of GS is clinical and based on established diagnostic criteria including major and minor features [19]. Major criteria consist of multiple (>5) and/or early-onset (2 cm, incomplete excision and perivascular involvement, metastases only occur after years of existence in 0.028–0.55% of all cases. If metastasis appear (more commonly in the regional lymph nodes, followed by bone, liver and lung), the prognosis is poor with a mean survival of 3.6 years after diagnosis [21]. A wide range of several effective therapeutic options is available for the therapy of BCC. Intended to be curative or at least locally controlling, the treatment can either be surgical or nonsurgical depending on several tumor or patient-related factors. Especially, tumor size, location, histological subtype, patient’s health and wishes, possible complications and aesthetic results should be taken into account. Curettage, electrodesiccation and cryosurgery are surgical approaches that are easily applied in low-risk lesions with nonaggressive histological features such as superficial BCC. With conventional surgery, depending on the safety margins of excision, a higher rate of residual tumor cells and thus increased recurrence rate of 4–34% is reported. With Mohs micrographic surgery, the reported 5-year recurrence rates range from 1 to 3% for primary BCC and 3–7% for recurrent tumors. Nonsurgical treatment options include radiotherapy, photodynamic therapy and topical application of imiquimod and 5-fluorouracyl [22]. Locally advanced BCC is defined as the tumor in which radiation or surgery would not be curative or surgery would be mutilating. More than 300 cases of metastatic BCC have been reported in the literature. Some patient and primary tumor characteristics that could predict for metastatic disease have been suggested, including male gender primary lesion in the headand-neck region, especially the ear and face [23], large and locally invasive (e.g., T4) lesions and recurrence following surgery and/or radiation. Also, immunosuppression, especially impairment of cell-mediated immunity (e.g., AIDS, therapeutic immunosuppression) may predispose to the development of metastatic disease [21]. The most common sites of metastatic disease in patients with BCC are regional lymph nodes. The survival of patients with hematogeneous metastases (bone, lungs, internal organs) is reported to be about 10 months [24]. If only regional node(s) are involved, then potentially curative local therapy, for example, surgery and/or radiation, is often an option, and the prognosis is better with an average survival of 3.6 years (range:10 months to 9 years) [25]. Initial evidence that BCC may respond to cytotoxic chemotherapy originated from observations in patients being treated for squamous cell carcinomas of the head and neck. The drugs used at that time for head-and-neck cancer included methotrexate, bleomycin and vincristine, which were given in various combinations for metastatic BCC without significant responses [26]. The first report of successful treatment for metastatic BCC was published in 1978, when one complete and one partial response were noted in a Phase I trial of cisplatin [27]. Woods and Stewart demonstrated a durable partial informahealthcare.com
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response (lasting >12 months) with cisplatin and cyclophosphamide in a patient who had previously failed methotrexate, vincristine and bleomycin [26]. In 1983, Wieman et al. reported another patient who had a complete response to cisplatin [28]. Guthrie et al. reported their experience using a combination of cisplatin and doxorubicin for eight patients with metastatic BCC in 1985 [29]. They noted five complete and two partial responses, suggesting that this combination was highly effective. In 1990, the same investigators reported four complete, five partial and three no responses in 12 patients with that combination [30]. Interestingly, of the eight patients who received the drugs neoadjuvantly for large primary BCC, six had a response (one CR, five PR), thereby allowing surgery or radiation, which would have been difficult otherwise. In 1996, Moeholt and colleagues reviewed the published data on cisplatin-based therapy. Of the 53 cases reported, a response rate of 83% with 17 complete (37%) and 21 partial remissions (46%) was observed. Eight patients (17%) did not respond. The median time to progression was 24 months. Based on these data, platinum-based chemotherapy emerged as the standard of care in this population [31]. In 2004, Jefford and colleagues reported a patient with a dramatic, but short-lived response to a combination of cisplatin and paclitaxel [32]. This patient developed peripheral neuropathy, so the authors hypothesized that substituting carboplatin for cisplatin might result in decreased neuropathy without necessarily decreasing efficacy. Platinum therapy shows good efficacy data but has a significant toxicity (mainly neurological, renal, otologic and myelosuppression) and may not be administered in many elderly patients, so recently there has been a need to develop noveltargeted therapies aimed to treat this type of tumors. Two signaling pathways have been described as the most relevant in the genesis of these neoplasms: EGF receptor pathway
EGFR is a member of the family of tyrosine kinase receptors whose activation results in an intracellular autophosphorylation initiate a cascade of events that lead to the progression of the cell cycle, angiogenesis, metastasis and apoptosis reduction. Is expressed normally in human cells, but has high levels of expression in multiple neoplasms like 80% of squamous carcinomas and in 57% of BCC. Strong expression of the EGF receptor (EGFR) is present in approximately 38% of BCC, and weak expression is present in a further 19% [33]. Triple expression of EGFR/HER2/HER3 is seen in approximately 30% of all BCC. This suggests a prominent role for the EGFR pathway in the pathogenesis of BCC and thereby a potential role for agents targeting this pathway in the treatment of BCC. The first report of the use of anti-EGFR therapy in BCC was by Mu¨ller et al. [34]. They reported a dramatic response in an 87-year-old male with an extensive midfacial rodent ulcer who was treated with the monoclonal anti-EGFR antibody cetuximab. Hh pathway
The Hh gene was initially discovered by C Nusslein-Volhard and EF Weischaus in 1980 in their screen for mutations that 743
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disrupt the Drosophila larval body plan. The name Hh originates from the short and ‘spiked’ phenotype of the cuticle of the Hh mutant Drosophila larvae, which resembled the spikes of a Hh [5]. The Hh family of proteins has since been recognized as key mediators of many fundamental processes in vertebrate embryonic development playing a crucial role in controlling cell fate, patterning, proliferation, survival and differentiation of many different regions. Hh signals have diverse functions in different contexts. The crucial developmental function of Hh signaling is illustrated by the dramatic consequences in human fetuses, with defects in the Hh signaling pathway resulting in fetuses with brain, facial and other midline defects such as holoprosencephaly (failure of forebrain development) or microencephaly, cyclopia, absent nose or cleft palate. In adults, the Hh pathway remains active only in hair follicles and stem cells, in which this signaling pathway drives their maintenance; in all other cells except stem cells, the pathway is no longer active and is involved in regulation of tissue homeostasis, continuous renewal and repair of adult tissues and stem cell maintenance [35]. The Hh signaling pathway has also been recognized to be one of the most important signaling pathways and a therapeutic target in cancer. In adults, mutation or deregulation of this pathway plays a key role in both proliferation and differentiation, leading to tumorigenesis or tumor growth acceleration in a wide variety of tissues. BCC and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Inappropriate activation of the Hh signaling pathway has been implicated in the development of several other types of cancer including lung, prostate, breast and pancreas, colon, as well as hematological malignancies including leukemia, lymphoma and multiple myeloma as examples [36,37]. The first Hh pathway inhibitor to be identified was the naturally occurring plant alkaloid, cyclopamine. This was discovered as a teratogenic compound causing cyclopia and holoprosencephaly in lambs whose mothers had ingested corn lilies [38]. Hh proteins are secreted as signaling proteins that were first discovered in Drosophila along with many other components of their signal transduction machinery. The mechanism of Hh protein processing, secretion and signaling appears to be more or less conserved in evolution between Drosophila and higher organisms although some differences exist. Drosophila has only one Hh gene, whereas vertebrate Hh signal transduction involves three Hh homologs with different spatial and temporal distribution pattern: Shh, Indian Hh (Ihh) and Desert Hh. Shh is known to be important for the embryonic development and maintenance of the nervous system, axial skeleton, lungs, skin, hair and stem cells [39]. Indian Hh is important for bone and cartilage development; desert Hh is involved in the development of male germ cells. In mammals, one of three Hh pathway ligands (Desert, Indian and Sonic) binds to the transmembrane receptor Ptch to initiate pathway signaling [40]. When Ptch is inactive, it exerts an inhibitory effect on the signal transduced smoothened (Smo), and no downstream signaling occurs. When Hh ligand binds to Ptch, the inhibition of Smo is released and activate the downstream 744
signaling, regulating the expression of the transcription factors Gli1–3. When ligand binds and Ptch inhibition of Smo is released, Ptch moves out of the primary cilia and Smo moves in to facilitate the interaction with Glis and associated proteins [41]. They subsequently enter the nucleus and regulate expression of Hh target genes among others GLI1, PTCH1, MYC, BCL-2 and Cyclin D1. There are numerous other cellular components engaged in the activation of Hh pathway, especially in the steps regulating GLI activity downstream from Smo. These components include suppressor of fused (SUFU), KIF7, PKA, glycogen synthase kinase 3b and casein kinase 1 [42]. SUFU is a negative regulator of this pathway; it achieves this effect via several mechanisms. Physically, SUFU sequesters GLI transcription factors, whereas functionally SUFU affects GLI transcription ability [43]. The kinase protein KIF7 acts as both a positive and negative regulator of Hh pathway. It interacts with GLI proteins and inhibits GLI-dependent transcriptional activation [44]. Conversely, KIF7 may assume a positive role via its movement to cilia tip after pathway activation where it antagonizes the activity of SUFU. However, the actual functions of most of these proteins are still subject to intensive studies and not fully understood. The mechanisms by which aberrant activations of Hh signaling can lead to cancer are complex, but in general, they include activating mutations of members in the Hh pathway (ligand independent) and excessive/inappropriate expression of Hh ligands (ligand dependent). Loss-of-function mutations in Ptch1 were initially identified in patients with BCNS. Further studies also showed that Ptch1 mutations occur in sporadic cases of BCC and medulloblastoma. More than 40 different Ptch1 mutations have been reported, which mostly result in truncated protein and are scattered throughout the gene [45]. Gain-of-function mutations in Smo are also present in some cases of sporadic BCCs [46]. One mutation at base pair 1604 (G-to-T transversion) of exon 9 of the Smo gene changes codon 535 from tryptophan to leucine and has been reported in about 20% of sporadic BCCs. Genetic alterations of other components of Hh pathway, such as GLI and SUFU mutations, have also been observed. Germline mutations of SUFU have been reported in 3% of sporadic and -10% of desmoplastic medulloblastomas [47]. Aberrant activation of the Hh signaling pathway in cancers may also be ligand dependent and has been reported in several malignancies [48]. Ligand-dependent activation of the Hh pathway was initially described to occur in autocrine mode, but there is an increasing understanding that paracrine or reverse paracrine modes may also occur. In the autocrine mode, tumor cells selfsecrete Hh ligands to which they subsequently respond and culminate in activation of the signaling pathway; that occurs in tumors like prostate lung, glioblastoma, breast, leukemia and gastrointestinal tract. In the paracrine mode, Hh ligands are secreted by tumor cells and induce activity within infiltrating stromal cells like in prostate, pancreas and colorectal cancer. This in turn results in the production of unknown factors within the tumor environment, which ultimately support tumor growth. Reverse paracrine stimulation occurs when Hh Expert Rev. Anticancer Ther. 14(6), (2014)
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ligands produced by surrounding stromal cells activate the tumoral cell Hh pathway like in leukemia and non-Hodgkin lymphoma [41]. BCC carcinogenesis probably constitutes a mechanism of interactions between various signaling pathways and mutated genes that regulate pigmentation, the DNA repair and apoptosis. We know that the fox family proteins are overexpressed in BCC compared with normal keratinocytes. A relationship with ras/raf pathway is less defined. Also Wnt pathway would be involved; this is a cell signaling pathway highly conserved along the phylogenetic scale. It is not exclusive of bone but is involved in other processes such as embryogenesis and tumorigenesis. The high incidence of BCC in elderly people may be a consequence of a decrease in the DNA repair, and mutations in specific genes have been associated with development of BCC like XRCC1, XRCC3, SPA and XPD [5]. Hh inhibition & cancer stem cell theory
According to the cancer stem cell (CSC) theory, tumors contain two distinct populations of cells: a majoritary of population differentiated tumor cells that phenotypically characterize the disease; and a second population of CSC or tumorinitiating cells, with properties of self-renewal and differentiation responsible for disease maintenance and relapse [49]. CSC theory tries to explain the complete response to initial chemotherapy followed by relapsed disease propagated by a small population of residual cancer cells that were undetectable following initial therapy. For many cancers, conventional chemotherapy is effective against the differentiated tumor cells. For this reason, we need novel strategies targeting the residual CSCs responsible for disease recurrence to prolong remissions, eradicate the tumor-initiating cells and result in long-term cure. Hh signaling has been identified as a potential CSC-specific target in various cancers [41]. Preclinical data have suggested a possible regulatory role of Hh pathway in CSCs across a number of malignancies such as glioblastoma, breast cancer, pancreatic adenocarcinoma and hematological malignancies [50]. CSC theory remains controversial due to the varying techniques for identification and the discrepancies in CSC numbers identified in primary samples and required to recreate tumors in mice by different researchers with varying techniques. Regardless of the exact criteria for identifying CSC, the clinical observation holds that rare populations of cancer cells persist following initial therapy and play a role in disease recurrence, and novel strategies to target these resistant, persistent cells are needed [41]. Vismodegib
Vismodegib is a potent orally bioavailable small molecule inhibitor of the Hh pathway that acts by binding and inhibiting Smo [51]. It is the first drug approved by US FDA for the treatment of locally advanced and metastatic BCC (Erivedge, Genentech, January 2012). Antitumor activity of this drug was initially shown in preclinical models of medulloblastoma, colon and pancreatic tumors. A Phase I clinical trial of this agent informahealthcare.com
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involved 68 patients with refractory, locally advanced or metastatic solid tumors; it demonstrated an acceptable safety profile with no dose-limiting toxicity. The most frequently reported adverse events (AEs) have been muscle spasms, dysgeusia, fatigue, alopecia and nausea. Seven grade 4 AEs (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma and paranoia with hyperglycemia) were reported in six patients (9%). Grade 3 AEs were observed in 28% of patients; they most commonly included hyponatremia (10%), abdominal pain (7%) and fatigue (6%). The Phase I clinical trial of vismodegib has shown significant clinical activity in tumors with driver mutations of the Hh pathway. The overall response rate (defined as both complete and partial responses) in advanced BCC was achieved in 19 out of 33 patients (58%). Complete response was achieved in two patients. The authors reported a median response duration of 12.8 months (range: 3.7–26.4 months) among evaluable patients [52,53]. The clinical benefit of vismodegib has also been reported in medulloblastoma. Treatment of a patient with refractory widespread metastatic medulloblastoma with a somatic mutation in Ptch1 (Ptch1-W844C) and loss of heterozygosity resulted in a rapid, although transient, regression of disease at all tumor sites and improvement of symptoms [54]. As the maximum-tolerated dose was not reached, the recommended Phase II dose was chosen as 150 mg orally daily based on the pharmacokinetic data showing saturable plasma concentrations of vismodegib. An attempt was made to reduce the frequency to 150 mg three-times per week or once weekly following a loading dose of 150 mg daily for 11 days, but this maneuver failed to achieve unbound plasma concentration associated with efficacy in patients with BCC and medulloblastoma. Two published clinical trials have further demonstrated the remarkable clinical benefit of this agent in BCC. In a study by Sekulic et al. vismodegib at a dose of 150 mg daily was associated with objective response rates of 30 and 43% in patients with locally advanced and metastatic BCC, respectively. In the group of locally advanced BCC, 13 out of 63 patients (21%) had a complete response. Median duration of response for both groups was 7.6 months [55]. In addition, vismodegib had promising results in a randomized placebo-controlled trial in patients with BCNS developed by Tang et al. [56]. They tested the antiBCC efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the BCNS at three clinical centers from September 2009 through January 2011. The primary endpoint was reduction in the incidence of new BCCs that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary endpoints included reduction in the size of existing BCCs. In 41 patients followed for a mean of 8 months (range: 1–15) after enrollment, the per patient rate of new surgically eligible BCCs was lower with vismodegib than with placebo (2 vs 29 cases per group per year, p < 0.001), at a daily dose of vismodegib of 150 mg as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant BCCs (-65 vs -11%; p = 0.003). In some patients, 745
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all BCCs clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 AEs of loss of taste, muscle cramps, hair loss and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to AEs. At 1 month, vismodegib use had reduced the Hh target gene expression by BCC by 90% (p < 0.001) and diminished tumor cell proliferation, but apoptosis was not affected. No residual BCC was detectable in 83% of biopsy samples taken from sites of clinically regressed BCCs. Although no tumors progressed during treatment with vismodegib, BCCs and palmar plantar pits associated with BCNS both recurred after stopping the treatment. Both studies reported notable drugrelated toxicity profiles. Muscle spasms, alopecia, dysgeusia, nausea, decreased appetite, diarrhea, fatigue and weight loss were the most commonly reported AEs. Although most of these toxicities were low grade in nature, they led to treatment discontinuation in 54% of patients in the BCNS study. Furthermore, in the study by Sekulic et al. seven fatal events were reported [55]. Although all seven patients had coexisting conditions at baseline, it is relevant to note that three of the deaths were due to unknown causes. Resistance to Hh inhibitors antagonizing Smo
Acquired resistance to kinase inhibitors is especially frequent and relevant. The recent introduction of vismodegib as an inhibitor of the Hh pathway has prompted the first reports of resistance to targeted therapies and has highlighted the phenomenon of acquired resistance to drugs targeted against molecules related with the G protein receptor. Rudin et al. [54] reported the first case of medulloblastoma treated with vismodegib; the patient had an impressive clinical and radiological response at 2 months but relapsed at 3 months after treatment initiation. Analysis of the patient’s primary and metastatic tumors taken prior to treatment revealed a somatic mutation in Ptch1 (Ptch1–W844C), as well as upregulated expression of Hh target genes, supporting the premise that the disease was driven by hyperactivation of the Hh pathway. To explore the mechanisms of acquired resistance to vismodegib, Yauch and colleagues [57] analyzed a sample from a progressing lesion taken from the medulloblastoma patient to assess the status of known components of the Hh pathway. Sequencing of Ptch1 confirmed the presence of the previously detected Ptch1-W844C mutation, which was accompanied by loss of heterozygosity. Intriguingly, in addition to the Ptch1 mutation, they identified a Smo mutation, a heterozygous G-toC missense mutation at position 1697 that is predicted to change codon 473 from Asp to His (D473H). Smo-D473H was not detected in the pretreatment biopsies although it is possible that the mutation was present at a frequency below detection levels. Alternatively, it may have arisen at a tumor site different from the one initially biopsied and reseeded all of the metastatic sites following the initial response to vismodegib. Dijkgraaf et al. performed further investigations into mechanisms of resistance to vismodegib and determined that E518 is an important residue in vismodegib activity on Smo and its mutation conferred complete 746
resistance to vismodegib [58]. Amplifications of Gli2 transcription factor and Hh target gene Cyclin D1 have been identified as alternative mechanisms for the development of resistance to Hh inhibitors [58]. Compensatory upregulation of the IGF-1R/PI3K pathway may also play a role in resistance development to Smo antagonists. This is based on the observation of increased upregultion of the IGF-1R/PI3K pathway in LDE-225-resistant tumor samples [59]. An effort to identify second-generation Smo antagonists that display activity in vismodegib-resistant tumors revealed that HhAntag (a benzimidazole) exhibited a similar degree of efficacy in its inhibition of Smo-WT and Smo-D473H [60]. In addition, a member of the bisamide class of Smo inhibitors (compound 5) showed activity against vismodegib-resistant Smo in both cell-based assays and a vismodegib-resistant mouse model (described below), supporting the possibility of developing secondgeneration inhibitors of mutant Smo [58]. An attractive alternative is the use of antagonists with a mechanism of action clearly distinct from that of vismodegib. Itraconazole, a systemic azole antifungal agent that targets cytochrome P450, was recently shown to inhibit Hh signaling, although it is significantly less potent than the pathway inhibitors currently in clinical development [61]. Itraconazole acts on Smo by a mechanism distinct from that of cyclopamine although exactly how it functions remains to be determined. Considering this distinct mode of binding, it is possible that itraconazole will retain its efficacy against vismodegib-resistant Smo mutants. The use of antagonists that target the Hh pathway downstream of Smo, such as GANT61, which blocks GLI function, is likewise an appealing therapeutic strategy in the context of resistance driven by SMO mutations. Additional molecules in development, antagonizing Smo, for treatment of locally advanced & metastatic BCC BMS-833923 (XL139)
BMS-833923 is another potent, oral, small molecule antagonist of Smo. A Phase I trial of BMS-833923 has shown good clinical tolerance at doses up to 360 mg. In this study, one patient with BCNS achieved complete response, one patient with nonsmall-cell lung cancer had a partial response and 21% (6 of 28 patients) remained on treatment longer than 100 days at the time of report. Combination regimens of BMS-833923 with chemotherapy in several tumor types are currently underway. The most common AEs include dysgeusia (44%), muscle spasms (44%), alopecia (15%), diarrhea (11%), myalgia (11%), dry mouth (11%) and nausea (11%). Grade 2 pancreatitis and lipase elevation occurred in one patient at a dose of 240 mg, whereas grade 3 hypophosphatemia was observed in one patient at 540 mg [62,63]. IPI-926 (Saridegib)
IPI-926 is an orally bioavailable, semisynthetic derivative of cyclopamine, which targets the Hh pathway by inhibiting Smo. Clinical activity was observed in three patients with locally advanced BCC who received IPI-926 for longer than 12 months at the time of report. In a Phase I dose escalation trial conducted by Rudin et al. IPI-926 was well tolerated up to a dose of Expert Rev. Anticancer Ther. 14(6), (2014)
Locally advanced & metastatic BCC
160 mg daily. The most common AEs were fatigue (29% total; 3% were grade 3), alanine aminotransferase elevation (20; 8% were grade 3), aspartate aminotransferase elevation (19; 4% were grade 3) and nausea (19%; none were grade 3). Dose-limiting toxicities in this study were asymptomatic grade 3 increased transaminases and/or bilirubin (one patient at 160 mg, four patients at 160 mg), all of which resolved when drug was held [64].
LDE-225 is a selective orally bioavailable inhibitor of Smo. Topical preparation of LDE-225 has been also developed and studied in patients with BCNS. In a double-blind randomized study involving eight patients with 27 BCC tumors, of 13 BCCs treated with active compound, 3 showed complete responses, 9 had partial responses, and 1 had no clinical response, in contrast to only one partial response out of 14 BCC tumors treated with the vehicle. The most frequently reported AEs were fatigue, nausea, vomiting, anorexia, muscle cramps, myalgia and dysgeusia [65].
treatment, to assess its long-term efficacy and safety and dose regimen. In relation to the established standard dose of 150 mg, there could be major problems of toxicity among those patients with lower weight, so that the dose could be a topic for discussion. Another important aspect is the development of acquired drug resistance, which is not fully understood and their understanding will enable to development of better strategies to overcome this problem; these strategies include combination with other targeted therapies or the development of second-generation Hh inhibitors. Additional studies will further elucidate vismodegib and other Smo inhibitors role in the treatment of BCC and other cancers. The recent introduction of vismodegib into daily clinical practice will provide important and necessary data on the duration and safety of treatment and a possible role as a neoadjuvant treatment to reduce the size of the tumor, in order to perform surgery or radiotherapy of the residual tumoral lesion as described in a recent publication by Chang et al. [66].
Expert commentary & five-year view
Financial & competing interests disclosure
Hh inhibitors represent an interesting option as novel anticancer therapies. However, the understanding of how this pathway affects different cancers is still under study. In the case of vismodegib, the first drug approved by FDA for the treatment of locally advanced and metastatic BCC has been used in daily clinical practice with good results; however, there are many unknowns in relation to effectiveness such as the duration of
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Key issues • Currently, we have few therapeutic tools for the treatment of locally advanced and/or metastatic basal cell carcinoma, so in recent years, it has emerged the need for finding new therapeutic targets. • The discovery of the Hedgehog pathway, when aberrant plays an important role in the development of multiple malignancies, has allowed the development of new targeted drugs. • Vismodegib is the first drug approved by US FDA for the treatment of locally advanced and metastatic basal cell carcinoma, that acts as a inhibitor of smoothened receptor, an important component of the Hh pathway, whose activation is linked with cellular and neoplasic proliferation. • The first clinical trials published show moderate efficacy of vismodegib, and we need more experience in clinical practice in order to asses their long-term effectiveness and safety. • Another important aspect is the development of acquired drug resistance, which is not fully understood and their understanding will enable to development of better strategies to overcome this problem.
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Locally advanced and metastatic basal cell carcinoma: molecular pathways, treatment options and new targeted therapies Expert Rev. Anticancer Ther. 14(6), 741–749 (2014)
Veronica Ruiz Salas*, Marta Alegre, Joan Ramo´n Garce´s and Lluis Puig Department of Dermatology, Hospital de la Santa Creu I Sant Pau, C/ Sant Antoni Maria Claret 167, 08025 Barcelona, Spain *Author for correspondence: Tel.: +34 696 197 868 Fax: +34 932 919 427 [email protected]
The hedgehog (Hh) signaling pathway has been identified as important to normal embryonic development in living organisms and it is implicated in processes including cell proliferation, differentiation and tissue patterning. Aberrant Hh pathway has been involved in the pathogenesis and chemotherapy resistance of different solid and hematologic malignancies. Basal cell carcinoma (BCC) and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Vismodegib has recently approved as the first inhibitor of one of the components of the Hh pathway (smoothened). This review attempts to provide current data on the molecular pathways involved in the development of BCC and the therapeutic options available for the treatment of locally advanced and metastatic BCC, and the new targeted therapies in development. KEYWORDS: basal cell carcinoma • hedgehog • locally advanced • metastatic • vismodegib
Basal cell carcinoma (BCC) is the most common of all human malignancies and the most common keratinocyte skin cancer in persons of Caucasian ancestry. The true incidence of this disease is unknown since it is often seen and treated in the outpatient setting, thus not being reflected in hospital statistics [1]. Certain risk factors for the disease (e.g., UV light exposure [2] and fair complexion [3]) are not constant worldwide, so the incidence of BCC varies by geographical location [2]. The precise origin of BCC is still unknown, but it seems to develop from epidermal stem cells of the outer root sheath of the hair follicle [3]. More common in men than in women, BCC usually occurs at an average age of 60 years. Predisposing factors include environmental exposure to arsenic, ionizing radiation, oral methoxsalen (psoralen), history of chronic trauma (burns, radiodermitis, wound and ulceration) and immunosuppressive therapy such as in organ transplant recipients [4]. Persons with a phototypes I and II, history of intermittent sun exposure and severe sunburn informahealthcare.com
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during childhood and patients with some genodermatoses such as albinism, xeroderma pigmentosum, rombo syndrome (RS), gorlin syndrome (GS), bazex-dupre-christol syndrome (BDCS), dugois-colomb-berthon syndrome, bloom syndrome (BS), Rothmund–Thompson syndrome (RTS), muir-torre syndrome (MTS) and linear unilateral BCC are at highest risk [5]. RS is an extremely rare condition characterized by acral and facial erythematous lesions, atrophoderma vermiculatum on the face and elbows, facial hypotrichosis, multiple vellus hair cysts with a milia-like appearance, telangiectasias on sun-exposed areas and predisposition to BCCs [6]. Although some of these features are shared with BDCS, the disease evolution and the absence of congenital manifestations in RS support their noslogical differentiation. The disease usually starts at the end of the first decade of life with skin atrophy and erythematous and, occasionally, painful skin lesions of the extremities and face. Subsequently, vellus hair cysts and telangiectasias superimposed on erythematous lesions develop.
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Multiple BCCs are the last sign to appear, usually after the age of 35 years [7]. RS has been reported in only three families [6–8] although in one of them [8], the diagnosis has been questioned. In two cases, RS occurred sporadically, while in the original report, vertical male-to-male transmission suggests an autosomal-dominant inheritance pattern. The molecular basis of RS remains unknown. BDCS or Bazex syndrome is an uncommon genodermatosis first reported in 1964 and is so far described in 90 patients [9]. Its main features include congenital hypotrichosis, generalized or facial hypohidrosis, atrophoderma follicularis on the dorsum of the hands and more rarely the elbows [10], multiple milia with histological features of follicular cysts and multiple BCCs and trichoepitheliomas, both mainly localizing on the face. Consistent ancillary features include a typical face with pinched nose [11], facial and flexural hyperpigmentation, hidradenitis suppurativa and hair shaft abnormalities [12]. BDCS displays the dual association of defective skin organogenesis (i.e., ectodermal dysplasia) and proneness to cutaneous tumors. Such a combination is shared by few other conditions, including RS, scho¨pf–schulz–passarge syndrome, generalized follicular basaloid hamartoma syndrome and, partially, GS [12]. In BDCS, skin neoplasms may appear very early with the youngest patients with BCC aged 3 years [13]. However, ectodermal defects are usually the first to appear, leading to the possible misdiagnosis of pure ectodermal dysplasia. MTS is characterized by the association of sebaceous tumors (or keratoacantomas) and visceral cancers, mainly involving the gastrointestinal tract, urinary apparatus and endometrium. MTS is inherited as an autosomal-dominant trait and is due to mutations of the mismatch repair genes such as MLH1 (3p21.3) or MSH2 (2p22–p21). The diagnosis is established by microsatellite instability and/or immunohistochemical examination of a tumor followed by molecular testing of DNA from peripheral blood [14]. In MTS, multiple BCCs, occasionally with sebaceous differentiation, have been reported. BS is a genomic instability syndrome caused by recessive mutations in RECQL3 (15q26.1), encoding for a specific human helicase. Diagnosis of BS is first performed by cytogenetic analysis, which shows tetraradial figures and increased sister chromatid exchanges, and then by molecular testing. BS is mainly characterized by the triad of short stature of prenatal onset (i.e., primordial dwarfism), photosensitivity manifesting with erythematous butterfly-like sun-sensitive skin lesions on the nose and cheeks and occasionally on the dorsum of hands and feet, multiple cafe´au-lait spots and immune dysregulation [15]. BCCs appear more commonly in BS than in the general population. Given the increased chromosome instability of BS, surveillance and management of cancer should avoid the use of ionizing radiation. RTS, or poikiloderma congenitale, is caused by recessive mutations in the gene coding for human helicase type 4, namely RECQL4 (8q24), in two of the three cases. Similar to BS, RTS is transmitted as an autosomal-recessive trait and shows proneness to various neoplasms. The most common cancers in RTS are osteosarcoma and cutaneous neoplasms, occurring in 30 and 5% of the patients, respectively. Skin cancers include SCC, BCC 742
and Bowen’s disease and appear at a mean age of 34.4 years [16]. A patient with RTS and amelanotic melanoma has recently been reported [17]. While genotype–phenotype correlation for proneness to osteosarcomas in RTS has been outlined [18], such a molecular definition is still lacking for skin neoplasms. GS, also known as basal cell nevus syndrome (BCNS) and naevoid BCC syndrome, is an autosomal-dominant genodermatosis that is characterized by a wide range of developmental defects and proneness to various cancers, mainly BCCs. GS is the best-known genetic disorder associated with BCCs. Its manifestations are highly variable including a least 100 different associated features. At present, the diagnosis of GS is clinical and based on established diagnostic criteria including major and minor features [19]. Major criteria consist of multiple (>5) and/or early-onset (2 cm, incomplete excision and perivascular involvement, metastases only occur after years of existence in 0.028–0.55% of all cases. If metastasis appear (more commonly in the regional lymph nodes, followed by bone, liver and lung), the prognosis is poor with a mean survival of 3.6 years after diagnosis [21]. A wide range of several effective therapeutic options is available for the therapy of BCC. Intended to be curative or at least locally controlling, the treatment can either be surgical or nonsurgical depending on several tumor or patient-related factors. Especially, tumor size, location, histological subtype, patient’s health and wishes, possible complications and aesthetic results should be taken into account. Curettage, electrodesiccation and cryosurgery are surgical approaches that are easily applied in low-risk lesions with nonaggressive histological features such as superficial BCC. With conventional surgery, depending on the safety margins of excision, a higher rate of residual tumor cells and thus increased recurrence rate of 4–34% is reported. With Mohs micrographic surgery, the reported 5-year recurrence rates range from 1 to 3% for primary BCC and 3–7% for recurrent tumors. Nonsurgical treatment options include radiotherapy, photodynamic therapy and topical application of imiquimod and 5-fluorouracyl [22]. Locally advanced BCC is defined as the tumor in which radiation or surgery would not be curative or surgery would be mutilating. More than 300 cases of metastatic BCC have been reported in the literature. Some patient and primary tumor characteristics that could predict for metastatic disease have been suggested, including male gender primary lesion in the headand-neck region, especially the ear and face [23], large and locally invasive (e.g., T4) lesions and recurrence following surgery and/or radiation. Also, immunosuppression, especially impairment of cell-mediated immunity (e.g., AIDS, therapeutic immunosuppression) may predispose to the development of metastatic disease [21]. The most common sites of metastatic disease in patients with BCC are regional lymph nodes. The survival of patients with hematogeneous metastases (bone, lungs, internal organs) is reported to be about 10 months [24]. If only regional node(s) are involved, then potentially curative local therapy, for example, surgery and/or radiation, is often an option, and the prognosis is better with an average survival of 3.6 years (range:10 months to 9 years) [25]. Initial evidence that BCC may respond to cytotoxic chemotherapy originated from observations in patients being treated for squamous cell carcinomas of the head and neck. The drugs used at that time for head-and-neck cancer included methotrexate, bleomycin and vincristine, which were given in various combinations for metastatic BCC without significant responses [26]. The first report of successful treatment for metastatic BCC was published in 1978, when one complete and one partial response were noted in a Phase I trial of cisplatin [27]. Woods and Stewart demonstrated a durable partial informahealthcare.com
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response (lasting >12 months) with cisplatin and cyclophosphamide in a patient who had previously failed methotrexate, vincristine and bleomycin [26]. In 1983, Wieman et al. reported another patient who had a complete response to cisplatin [28]. Guthrie et al. reported their experience using a combination of cisplatin and doxorubicin for eight patients with metastatic BCC in 1985 [29]. They noted five complete and two partial responses, suggesting that this combination was highly effective. In 1990, the same investigators reported four complete, five partial and three no responses in 12 patients with that combination [30]. Interestingly, of the eight patients who received the drugs neoadjuvantly for large primary BCC, six had a response (one CR, five PR), thereby allowing surgery or radiation, which would have been difficult otherwise. In 1996, Moeholt and colleagues reviewed the published data on cisplatin-based therapy. Of the 53 cases reported, a response rate of 83% with 17 complete (37%) and 21 partial remissions (46%) was observed. Eight patients (17%) did not respond. The median time to progression was 24 months. Based on these data, platinum-based chemotherapy emerged as the standard of care in this population [31]. In 2004, Jefford and colleagues reported a patient with a dramatic, but short-lived response to a combination of cisplatin and paclitaxel [32]. This patient developed peripheral neuropathy, so the authors hypothesized that substituting carboplatin for cisplatin might result in decreased neuropathy without necessarily decreasing efficacy. Platinum therapy shows good efficacy data but has a significant toxicity (mainly neurological, renal, otologic and myelosuppression) and may not be administered in many elderly patients, so recently there has been a need to develop noveltargeted therapies aimed to treat this type of tumors. Two signaling pathways have been described as the most relevant in the genesis of these neoplasms: EGF receptor pathway
EGFR is a member of the family of tyrosine kinase receptors whose activation results in an intracellular autophosphorylation initiate a cascade of events that lead to the progression of the cell cycle, angiogenesis, metastasis and apoptosis reduction. Is expressed normally in human cells, but has high levels of expression in multiple neoplasms like 80% of squamous carcinomas and in 57% of BCC. Strong expression of the EGF receptor (EGFR) is present in approximately 38% of BCC, and weak expression is present in a further 19% [33]. Triple expression of EGFR/HER2/HER3 is seen in approximately 30% of all BCC. This suggests a prominent role for the EGFR pathway in the pathogenesis of BCC and thereby a potential role for agents targeting this pathway in the treatment of BCC. The first report of the use of anti-EGFR therapy in BCC was by Mu¨ller et al. [34]. They reported a dramatic response in an 87-year-old male with an extensive midfacial rodent ulcer who was treated with the monoclonal anti-EGFR antibody cetuximab. Hh pathway
The Hh gene was initially discovered by C Nusslein-Volhard and EF Weischaus in 1980 in their screen for mutations that 743
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disrupt the Drosophila larval body plan. The name Hh originates from the short and ‘spiked’ phenotype of the cuticle of the Hh mutant Drosophila larvae, which resembled the spikes of a Hh [5]. The Hh family of proteins has since been recognized as key mediators of many fundamental processes in vertebrate embryonic development playing a crucial role in controlling cell fate, patterning, proliferation, survival and differentiation of many different regions. Hh signals have diverse functions in different contexts. The crucial developmental function of Hh signaling is illustrated by the dramatic consequences in human fetuses, with defects in the Hh signaling pathway resulting in fetuses with brain, facial and other midline defects such as holoprosencephaly (failure of forebrain development) or microencephaly, cyclopia, absent nose or cleft palate. In adults, the Hh pathway remains active only in hair follicles and stem cells, in which this signaling pathway drives their maintenance; in all other cells except stem cells, the pathway is no longer active and is involved in regulation of tissue homeostasis, continuous renewal and repair of adult tissues and stem cell maintenance [35]. The Hh signaling pathway has also been recognized to be one of the most important signaling pathways and a therapeutic target in cancer. In adults, mutation or deregulation of this pathway plays a key role in both proliferation and differentiation, leading to tumorigenesis or tumor growth acceleration in a wide variety of tissues. BCC and medulloblastoma are two well-recognized cancers with mutations in components of the Hh pathway. Inappropriate activation of the Hh signaling pathway has been implicated in the development of several other types of cancer including lung, prostate, breast and pancreas, colon, as well as hematological malignancies including leukemia, lymphoma and multiple myeloma as examples [36,37]. The first Hh pathway inhibitor to be identified was the naturally occurring plant alkaloid, cyclopamine. This was discovered as a teratogenic compound causing cyclopia and holoprosencephaly in lambs whose mothers had ingested corn lilies [38]. Hh proteins are secreted as signaling proteins that were first discovered in Drosophila along with many other components of their signal transduction machinery. The mechanism of Hh protein processing, secretion and signaling appears to be more or less conserved in evolution between Drosophila and higher organisms although some differences exist. Drosophila has only one Hh gene, whereas vertebrate Hh signal transduction involves three Hh homologs with different spatial and temporal distribution pattern: Shh, Indian Hh (Ihh) and Desert Hh. Shh is known to be important for the embryonic development and maintenance of the nervous system, axial skeleton, lungs, skin, hair and stem cells [39]. Indian Hh is important for bone and cartilage development; desert Hh is involved in the development of male germ cells. In mammals, one of three Hh pathway ligands (Desert, Indian and Sonic) binds to the transmembrane receptor Ptch to initiate pathway signaling [40]. When Ptch is inactive, it exerts an inhibitory effect on the signal transduced smoothened (Smo), and no downstream signaling occurs. When Hh ligand binds to Ptch, the inhibition of Smo is released and activate the downstream 744
signaling, regulating the expression of the transcription factors Gli1–3. When ligand binds and Ptch inhibition of Smo is released, Ptch moves out of the primary cilia and Smo moves in to facilitate the interaction with Glis and associated proteins [41]. They subsequently enter the nucleus and regulate expression of Hh target genes among others GLI1, PTCH1, MYC, BCL-2 and Cyclin D1. There are numerous other cellular components engaged in the activation of Hh pathway, especially in the steps regulating GLI activity downstream from Smo. These components include suppressor of fused (SUFU), KIF7, PKA, glycogen synthase kinase 3b and casein kinase 1 [42]. SUFU is a negative regulator of this pathway; it achieves this effect via several mechanisms. Physically, SUFU sequesters GLI transcription factors, whereas functionally SUFU affects GLI transcription ability [43]. The kinase protein KIF7 acts as both a positive and negative regulator of Hh pathway. It interacts with GLI proteins and inhibits GLI-dependent transcriptional activation [44]. Conversely, KIF7 may assume a positive role via its movement to cilia tip after pathway activation where it antagonizes the activity of SUFU. However, the actual functions of most of these proteins are still subject to intensive studies and not fully understood. The mechanisms by which aberrant activations of Hh signaling can lead to cancer are complex, but in general, they include activating mutations of members in the Hh pathway (ligand independent) and excessive/inappropriate expression of Hh ligands (ligand dependent). Loss-of-function mutations in Ptch1 were initially identified in patients with BCNS. Further studies also showed that Ptch1 mutations occur in sporadic cases of BCC and medulloblastoma. More than 40 different Ptch1 mutations have been reported, which mostly result in truncated protein and are scattered throughout the gene [45]. Gain-of-function mutations in Smo are also present in some cases of sporadic BCCs [46]. One mutation at base pair 1604 (G-to-T transversion) of exon 9 of the Smo gene changes codon 535 from tryptophan to leucine and has been reported in about 20% of sporadic BCCs. Genetic alterations of other components of Hh pathway, such as GLI and SUFU mutations, have also been observed. Germline mutations of SUFU have been reported in 3% of sporadic and -10% of desmoplastic medulloblastomas [47]. Aberrant activation of the Hh signaling pathway in cancers may also be ligand dependent and has been reported in several malignancies [48]. Ligand-dependent activation of the Hh pathway was initially described to occur in autocrine mode, but there is an increasing understanding that paracrine or reverse paracrine modes may also occur. In the autocrine mode, tumor cells selfsecrete Hh ligands to which they subsequently respond and culminate in activation of the signaling pathway; that occurs in tumors like prostate lung, glioblastoma, breast, leukemia and gastrointestinal tract. In the paracrine mode, Hh ligands are secreted by tumor cells and induce activity within infiltrating stromal cells like in prostate, pancreas and colorectal cancer. This in turn results in the production of unknown factors within the tumor environment, which ultimately support tumor growth. Reverse paracrine stimulation occurs when Hh Expert Rev. Anticancer Ther. 14(6), (2014)
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ligands produced by surrounding stromal cells activate the tumoral cell Hh pathway like in leukemia and non-Hodgkin lymphoma [41]. BCC carcinogenesis probably constitutes a mechanism of interactions between various signaling pathways and mutated genes that regulate pigmentation, the DNA repair and apoptosis. We know that the fox family proteins are overexpressed in BCC compared with normal keratinocytes. A relationship with ras/raf pathway is less defined. Also Wnt pathway would be involved; this is a cell signaling pathway highly conserved along the phylogenetic scale. It is not exclusive of bone but is involved in other processes such as embryogenesis and tumorigenesis. The high incidence of BCC in elderly people may be a consequence of a decrease in the DNA repair, and mutations in specific genes have been associated with development of BCC like XRCC1, XRCC3, SPA and XPD [5]. Hh inhibition & cancer stem cell theory
According to the cancer stem cell (CSC) theory, tumors contain two distinct populations of cells: a majoritary of population differentiated tumor cells that phenotypically characterize the disease; and a second population of CSC or tumorinitiating cells, with properties of self-renewal and differentiation responsible for disease maintenance and relapse [49]. CSC theory tries to explain the complete response to initial chemotherapy followed by relapsed disease propagated by a small population of residual cancer cells that were undetectable following initial therapy. For many cancers, conventional chemotherapy is effective against the differentiated tumor cells. For this reason, we need novel strategies targeting the residual CSCs responsible for disease recurrence to prolong remissions, eradicate the tumor-initiating cells and result in long-term cure. Hh signaling has been identified as a potential CSC-specific target in various cancers [41]. Preclinical data have suggested a possible regulatory role of Hh pathway in CSCs across a number of malignancies such as glioblastoma, breast cancer, pancreatic adenocarcinoma and hematological malignancies [50]. CSC theory remains controversial due to the varying techniques for identification and the discrepancies in CSC numbers identified in primary samples and required to recreate tumors in mice by different researchers with varying techniques. Regardless of the exact criteria for identifying CSC, the clinical observation holds that rare populations of cancer cells persist following initial therapy and play a role in disease recurrence, and novel strategies to target these resistant, persistent cells are needed [41]. Vismodegib
Vismodegib is a potent orally bioavailable small molecule inhibitor of the Hh pathway that acts by binding and inhibiting Smo [51]. It is the first drug approved by US FDA for the treatment of locally advanced and metastatic BCC (Erivedge, Genentech, January 2012). Antitumor activity of this drug was initially shown in preclinical models of medulloblastoma, colon and pancreatic tumors. A Phase I clinical trial of this agent informahealthcare.com
Review
involved 68 patients with refractory, locally advanced or metastatic solid tumors; it demonstrated an acceptable safety profile with no dose-limiting toxicity. The most frequently reported adverse events (AEs) have been muscle spasms, dysgeusia, fatigue, alopecia and nausea. Seven grade 4 AEs (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma and paranoia with hyperglycemia) were reported in six patients (9%). Grade 3 AEs were observed in 28% of patients; they most commonly included hyponatremia (10%), abdominal pain (7%) and fatigue (6%). The Phase I clinical trial of vismodegib has shown significant clinical activity in tumors with driver mutations of the Hh pathway. The overall response rate (defined as both complete and partial responses) in advanced BCC was achieved in 19 out of 33 patients (58%). Complete response was achieved in two patients. The authors reported a median response duration of 12.8 months (range: 3.7–26.4 months) among evaluable patients [52,53]. The clinical benefit of vismodegib has also been reported in medulloblastoma. Treatment of a patient with refractory widespread metastatic medulloblastoma with a somatic mutation in Ptch1 (Ptch1-W844C) and loss of heterozygosity resulted in a rapid, although transient, regression of disease at all tumor sites and improvement of symptoms [54]. As the maximum-tolerated dose was not reached, the recommended Phase II dose was chosen as 150 mg orally daily based on the pharmacokinetic data showing saturable plasma concentrations of vismodegib. An attempt was made to reduce the frequency to 150 mg three-times per week or once weekly following a loading dose of 150 mg daily for 11 days, but this maneuver failed to achieve unbound plasma concentration associated with efficacy in patients with BCC and medulloblastoma. Two published clinical trials have further demonstrated the remarkable clinical benefit of this agent in BCC. In a study by Sekulic et al. vismodegib at a dose of 150 mg daily was associated with objective response rates of 30 and 43% in patients with locally advanced and metastatic BCC, respectively. In the group of locally advanced BCC, 13 out of 63 patients (21%) had a complete response. Median duration of response for both groups was 7.6 months [55]. In addition, vismodegib had promising results in a randomized placebo-controlled trial in patients with BCNS developed by Tang et al. [56]. They tested the antiBCC efficacy of vismodegib in a randomized, double-blind, placebo-controlled trial in patients with the BCNS at three clinical centers from September 2009 through January 2011. The primary endpoint was reduction in the incidence of new BCCs that were eligible for surgical resection (surgically eligible) with vismodegib versus placebo after 3 months; secondary endpoints included reduction in the size of existing BCCs. In 41 patients followed for a mean of 8 months (range: 1–15) after enrollment, the per patient rate of new surgically eligible BCCs was lower with vismodegib than with placebo (2 vs 29 cases per group per year, p < 0.001), at a daily dose of vismodegib of 150 mg as was the size (percent change from baseline in the sum of the longest diameter) of existing clinically significant BCCs (-65 vs -11%; p = 0.003). In some patients, 745
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all BCCs clinically regressed. No tumors progressed during treatment with vismodegib. Patients receiving vismodegib routinely had grade 1 or 2 AEs of loss of taste, muscle cramps, hair loss and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to AEs. At 1 month, vismodegib use had reduced the Hh target gene expression by BCC by 90% (p < 0.001) and diminished tumor cell proliferation, but apoptosis was not affected. No residual BCC was detectable in 83% of biopsy samples taken from sites of clinically regressed BCCs. Although no tumors progressed during treatment with vismodegib, BCCs and palmar plantar pits associated with BCNS both recurred after stopping the treatment. Both studies reported notable drugrelated toxicity profiles. Muscle spasms, alopecia, dysgeusia, nausea, decreased appetite, diarrhea, fatigue and weight loss were the most commonly reported AEs. Although most of these toxicities were low grade in nature, they led to treatment discontinuation in 54% of patients in the BCNS study. Furthermore, in the study by Sekulic et al. seven fatal events were reported [55]. Although all seven patients had coexisting conditions at baseline, it is relevant to note that three of the deaths were due to unknown causes. Resistance to Hh inhibitors antagonizing Smo
Acquired resistance to kinase inhibitors is especially frequent and relevant. The recent introduction of vismodegib as an inhibitor of the Hh pathway has prompted the first reports of resistance to targeted therapies and has highlighted the phenomenon of acquired resistance to drugs targeted against molecules related with the G protein receptor. Rudin et al. [54] reported the first case of medulloblastoma treated with vismodegib; the patient had an impressive clinical and radiological response at 2 months but relapsed at 3 months after treatment initiation. Analysis of the patient’s primary and metastatic tumors taken prior to treatment revealed a somatic mutation in Ptch1 (Ptch1–W844C), as well as upregulated expression of Hh target genes, supporting the premise that the disease was driven by hyperactivation of the Hh pathway. To explore the mechanisms of acquired resistance to vismodegib, Yauch and colleagues [57] analyzed a sample from a progressing lesion taken from the medulloblastoma patient to assess the status of known components of the Hh pathway. Sequencing of Ptch1 confirmed the presence of the previously detected Ptch1-W844C mutation, which was accompanied by loss of heterozygosity. Intriguingly, in addition to the Ptch1 mutation, they identified a Smo mutation, a heterozygous G-toC missense mutation at position 1697 that is predicted to change codon 473 from Asp to His (D473H). Smo-D473H was not detected in the pretreatment biopsies although it is possible that the mutation was present at a frequency below detection levels. Alternatively, it may have arisen at a tumor site different from the one initially biopsied and reseeded all of the metastatic sites following the initial response to vismodegib. Dijkgraaf et al. performed further investigations into mechanisms of resistance to vismodegib and determined that E518 is an important residue in vismodegib activity on Smo and its mutation conferred complete 746
resistance to vismodegib [58]. Amplifications of Gli2 transcription factor and Hh target gene Cyclin D1 have been identified as alternative mechanisms for the development of resistance to Hh inhibitors [58]. Compensatory upregulation of the IGF-1R/PI3K pathway may also play a role in resistance development to Smo antagonists. This is based on the observation of increased upregultion of the IGF-1R/PI3K pathway in LDE-225-resistant tumor samples [59]. An effort to identify second-generation Smo antagonists that display activity in vismodegib-resistant tumors revealed that HhAntag (a benzimidazole) exhibited a similar degree of efficacy in its inhibition of Smo-WT and Smo-D473H [60]. In addition, a member of the bisamide class of Smo inhibitors (compound 5) showed activity against vismodegib-resistant Smo in both cell-based assays and a vismodegib-resistant mouse model (described below), supporting the possibility of developing secondgeneration inhibitors of mutant Smo [58]. An attractive alternative is the use of antagonists with a mechanism of action clearly distinct from that of vismodegib. Itraconazole, a systemic azole antifungal agent that targets cytochrome P450, was recently shown to inhibit Hh signaling, although it is significantly less potent than the pathway inhibitors currently in clinical development [61]. Itraconazole acts on Smo by a mechanism distinct from that of cyclopamine although exactly how it functions remains to be determined. Considering this distinct mode of binding, it is possible that itraconazole will retain its efficacy against vismodegib-resistant Smo mutants. The use of antagonists that target the Hh pathway downstream of Smo, such as GANT61, which blocks GLI function, is likewise an appealing therapeutic strategy in the context of resistance driven by SMO mutations. Additional molecules in development, antagonizing Smo, for treatment of locally advanced & metastatic BCC BMS-833923 (XL139)
BMS-833923 is another potent, oral, small molecule antagonist of Smo. A Phase I trial of BMS-833923 has shown good clinical tolerance at doses up to 360 mg. In this study, one patient with BCNS achieved complete response, one patient with nonsmall-cell lung cancer had a partial response and 21% (6 of 28 patients) remained on treatment longer than 100 days at the time of report. Combination regimens of BMS-833923 with chemotherapy in several tumor types are currently underway. The most common AEs include dysgeusia (44%), muscle spasms (44%), alopecia (15%), diarrhea (11%), myalgia (11%), dry mouth (11%) and nausea (11%). Grade 2 pancreatitis and lipase elevation occurred in one patient at a dose of 240 mg, whereas grade 3 hypophosphatemia was observed in one patient at 540 mg [62,63]. IPI-926 (Saridegib)
IPI-926 is an orally bioavailable, semisynthetic derivative of cyclopamine, which targets the Hh pathway by inhibiting Smo. Clinical activity was observed in three patients with locally advanced BCC who received IPI-926 for longer than 12 months at the time of report. In a Phase I dose escalation trial conducted by Rudin et al. IPI-926 was well tolerated up to a dose of Expert Rev. Anticancer Ther. 14(6), (2014)
Locally advanced & metastatic BCC
160 mg daily. The most common AEs were fatigue (29% total; 3% were grade 3), alanine aminotransferase elevation (20; 8% were grade 3), aspartate aminotransferase elevation (19; 4% were grade 3) and nausea (19%; none were grade 3). Dose-limiting toxicities in this study were asymptomatic grade 3 increased transaminases and/or bilirubin (one patient at 160 mg, four patients at 160 mg), all of which resolved when drug was held [64].
LDE-225 is a selective orally bioavailable inhibitor of Smo. Topical preparation of LDE-225 has been also developed and studied in patients with BCNS. In a double-blind randomized study involving eight patients with 27 BCC tumors, of 13 BCCs treated with active compound, 3 showed complete responses, 9 had partial responses, and 1 had no clinical response, in contrast to only one partial response out of 14 BCC tumors treated with the vehicle. The most frequently reported AEs were fatigue, nausea, vomiting, anorexia, muscle cramps, myalgia and dysgeusia [65].
treatment, to assess its long-term efficacy and safety and dose regimen. In relation to the established standard dose of 150 mg, there could be major problems of toxicity among those patients with lower weight, so that the dose could be a topic for discussion. Another important aspect is the development of acquired drug resistance, which is not fully understood and their understanding will enable to development of better strategies to overcome this problem; these strategies include combination with other targeted therapies or the development of second-generation Hh inhibitors. Additional studies will further elucidate vismodegib and other Smo inhibitors role in the treatment of BCC and other cancers. The recent introduction of vismodegib into daily clinical practice will provide important and necessary data on the duration and safety of treatment and a possible role as a neoadjuvant treatment to reduce the size of the tumor, in order to perform surgery or radiotherapy of the residual tumoral lesion as described in a recent publication by Chang et al. [66].
Expert commentary & five-year view
Financial & competing interests disclosure
Hh inhibitors represent an interesting option as novel anticancer therapies. However, the understanding of how this pathway affects different cancers is still under study. In the case of vismodegib, the first drug approved by FDA for the treatment of locally advanced and metastatic BCC has been used in daily clinical practice with good results; however, there are many unknowns in relation to effectiveness such as the duration of
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Key issues • Currently, we have few therapeutic tools for the treatment of locally advanced and/or metastatic basal cell carcinoma, so in recent years, it has emerged the need for finding new therapeutic targets. • The discovery of the Hedgehog pathway, when aberrant plays an important role in the development of multiple malignancies, has allowed the development of new targeted drugs. • Vismodegib is the first drug approved by US FDA for the treatment of locally advanced and metastatic basal cell carcinoma, that acts as a inhibitor of smoothened receptor, an important component of the Hh pathway, whose activation is linked with cellular and neoplasic proliferation. • The first clinical trials published show moderate efficacy of vismodegib, and we need more experience in clinical practice in order to asses their long-term effectiveness and safety. • Another important aspect is the development of acquired drug resistance, which is not fully understood and their understanding will enable to development of better strategies to overcome this problem.
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