Hedgehog- & mTOR-targeted therapies for ... - Future Medicine

SPECIAL REPORT For reprint orders, please contact: [email protected]

Hedgehog- and mTOR-targeted therapies for advanced basal cell carcinomas Claudine Piérard-Franchimont1,2, Trinh Hermanns-Lê2, Philippe Paquet2, Michael Herfs3, Philippe Delvenne2,3,4 & Gérald E Piérard*,1

Basal cell carcinomas (BCCs) are the most frequent human cancer. Over 90% of all BCCs have a mutation in PTCH1 or smoothened, two conducting proteins of the Hedgehog pathway. They rarely progress deeply and metastasize; however, if they do, these advanced basal cell carcinoma become amenable to treatment by inhibiting the Hedgehog and the P13K–mTOR pathways. Such innovative drugs include vismodegib, cyclopamine, itraconazole, everolimus and a few other agents that are in early clinical development. In recent years, major pressure was placed on healthcare researchers to explore and improve the approaches for treating cancers. Some of the newer targets in oncology included the inhibitors of the Hedgehog (Hh) pathway, the mTOR signaling, the EGFR pathway, the TGF-β signaling, the NF-κB, Ras and a few others. Basal cell carcinoma (BCC) is the most common malignancy of the skin [1] , representing ∼70–80% of all cutaneous cancers in Europe. The prevalence differs according to ethnicity, skin complexion, gender, occupational activities, immunocontrol and geoclimatic environment. Due to the increasing segment of the older western populations, the BCC incidence has been on the rise worldwide. This slow-growing neoplasm rarely metastasizes to distant sites of the body, but it is potentially invasive causing local severe tissue destruction and considerable morbidity. In some instances, it represents an expensive cancer to manage [2,3] . In contrast to squamous cell carcinomas and melanomas of the skin, BCCs exhibit far less genetic aberrations. The nature of the BCC-initiating cell still remains a matter of debate. Speculations differ regarding its potential origin, either from the hair bulge stem cells or from resident progenitor cells present in the basal cell compartment of the interfollicular epidermis and upper infundibulum. Established and accepted treatments for BCC include surgical excision, curettage, electrocautery, cryotherapy, photodynamic therapy, Mohs surgery, radiation therapy as well as topical 5-fluorouracil and imiquimod [3] . Such treatment modalities are frequently reported to be successful, with 5-year clearance rates over 80%. However, the aforementioned treatments rely on adequate access to the neoplasm, and they can be associated with local adverse events. Invasive primary BCCs and metastatic BCCs that are not easily amenable to surgical or radiation treatments are termed often termed ‘advanced’ BCCs. Until recently, only limited treatment modalities were available for patients with advanced BCC. Of note, there is no widely adopted successful cytotoxic chemotherapy for advanced BCCs, although some cases of prolonged survival have been reported following cisplatin-based regimens.

KEYWORDS

• basal cell carcinoma • cancer stem cell • cyclopamine • cytotoxic chemotherapy • Desert Hedgehog • EGF • everolimus • Hedgehog • hereditary basal cell nevus syndrome • Indian Hedgehog • itraconazole • metastasis • NF-κB • protein kinase • PTCH1 • SMO • Sonic Hedgehog • TGF • therapy resistance • vismodegib

Laboratory of Skin Bioengineering & Imaging (LABIC), Department of Clinical Sciences, University of Liège, Belgium Department of Dermatopathology, Unilab Lg, Liège University Hospital, Liège, Belgium 3 Laboratory of Experimental Pathology, Liège University Hospital, Liège, Belgium 4 Departments of Pathology, Unilab Lg, Liège University Hospital, Liège, Belgium *Author for correspondence: [email protected] 1 2

10.2217/fon.15.181 © 2015 Future Medicine Ltd

Future Oncol. (2015) 11(22), 2997–3002

part of

ISSN 1479-6694

2997

Special Report Piérard-Franchimont, Hermanns-Lê, Paquet, Herfs, Delvenne & Piérard A series of challenges persist around BCC management. Increasing numbers of advanced primary BCCs are responsible for more patients experiencing functional impairments, overwhelming morbidity or disfigurement, particularly when BCCs encase the orbit and branches of the facial nerve. BCCs have a low propensity to metastasize, but two thirds of the reported metastatic tumours develop on BCC located on the head and neck region. Risk factors for BCC metastases include male gender, large size of the primary neoplasm, facial primary site, deep invasion and previous radiotherapy. BCC metastases most commonly invade regional lymph nodes, lungs, bones and skin. The Hh signaling pathway Embryogenesis of Drosophila melanogaster revealed the Hh signaling pathway. This discovery was awarded the Nobel Prize for physiology and medicine in 1995. The Hh pathway is conserved throughout species where it is particularly involved in embryonic growth, signaling and development. Thus, the Hh signaling pathway represents an important cascade for cell growth and differentiation during embryonic development. In humans, it is turned off in normal adult tissues, with exceptions in skin, hair and stem cells [4] . The Hh family of protein ligands consists of three members, namely the Sonic Hh, the Desert Hh and the Indian Hh [5] . In addition to the Hh ligands, two receptor proteins are involved in the cascade. They correspond to the transmembrane PTCH1 and SMO. PTCH1 is a suppressor/inhibitory protein forming an inactive complex with SMO in absence of Hh [6] . The Hh binding to PTCH1 prevents such inhibitory action, and SMO becomes activated. Activated SMO is involved in promoting some gene transcriptions. During embryonic development, these genes are responsible for cell growth and differentiation. In normal adults, the Hh signaling pathway is under inhibition, and gets activated upon the binding of Hh ligand to PTCH1. This process in turn allows SMO to transfer signals through various proteins. In adults, the Hh process is involved in tissue repair and stem cell maintenance. A dysregulated Hh signaling pathway is present in BCCs and other tumors such as medulloblastoma, and a series of gastrointestinal, brain, lung, breast, prostate and hematologic malignancies. Aberrant activation of the

2998

Future Oncol. (2015) 11(22)

Hh pathway stimulates cancer stem cells and boosts cell proliferation. In the epidermis, the imbalance between cell proliferation and cell cycle arrest is responsible for tissue hyperplasia and uncontrolled proliferation of basal cells leading to BCC. Either inactivation of PTCH1 or oncogenic activation of SMO is a common feature in most BCCs. Hence, increasing the inhibitory action of the PTCH1 and suppressing the SMO activation represent distinct targets for the treatment of BCCs and a series of other malignancies with hyperactivated Hh pathway. It has been hypothesized that the activation of cancer stem cells through abnormal Hh signaling is responsible for uncontrolled self-renewal of BCC neoplastic cells and development of metastases. Unchecked activation of the Hh pathway is recognized in over 70% of sporadic BCCs [7] . The vast majority of sporadic human BCCs exhibit altered PTCH1 function [8] , and fewer BCCs present an SMO mutation [9,10] . The functional loss of PTCH1, corresponding to a tumor suppressor gene located on 9q22 results in a failure of SMO inhibition [11] . When SMO is rid of its inhibition, the glioma-associated protein (GLI-1) enters cells and stimulates cell proliferation. In murine models, loss of PTCH1 function, gain in SMO function or over expression of GLI-1 lead to BCC generation [12] . The translation of such advances in the molecular understanding to the clinic has resulted in the development of a series of targeted therapies for both sporadic BCCs and congenital BCC syndromes. The P13K–mTOR pathway The protein kinase cascade plays a key role in signal transduction involves the P13K. Such a process activates other kinases boosting cell proliferation. The downstream effector of P13K is the mTOR, which plays a key regulatory role in protein translation by modulating the phosphorylation of other kinases [13] . Some growth factors and oncogenic proteins activate P13K and lead, via mTOR, to the phosphorylation and activation of a number of protein kinases, promoting cancer cell survival and proliferation. Inhibiting mTOR activity blocks such signaling cascade and interferes with tumor cell proliferation. In addition, endothelial cell proliferation and angiogenesis are under the control of VEGF acting, at least in part, through the P13K–mTOR signaling pathway.

future science group

Hedgehog- & mTOR-targeted therapies for advanced basal cell carcinomas ●●BCC-targeted treatment modalities

In recent years, new targeted drugs have improved treatment modalities for specific neoplasms, in particular BCCs. Vismodegib and a few other Hh inhibitors presently appear as new promising treatment options for advanced primary and metastatic BCCs. Furthermore, the proliferation signal inhibitor everolimus targeting mTOR showed some activity against multiple BCCs. In addition, the monoclonal antibody cetuximab against EGFR has been proposed as another treatment option for recurrent and advanced BCCs. Vismodegib therapy Vismodegib (2-chloro-N-(4-chloro-3-(pyridin2-yl)phenyl)-4-(methylsufonyl)benzamide) targets the Hh pathway activated in most BCCs. In the clinical trials, the drug was administered at a 150 mg oral dosage once daily in adults with primary advanced and metastatic BCCs. Efficacy of oral vismodegib therapy has been established in these conditions, and also in Gorlin–Goltz syndrome also knows as hereditary basal cell nevus syndrome (HBCNS) [6,14] . The promising treatment results were observed in Phase II trials [12,15] . A recent report showed an about one-third response rate for metastatic BCCs, and one-half response rate on average for advanced primary BCCs [15] . The median survival reached was about 8 months for metastatic BCCs and 9.5 months for advanced primary BCCs. A histopathological study reported the absence of residual BCC nests in about 80% of the treated cases [8] . Nevertheless, in the clinical trials reported so far, only a limited number of BCCs resolved completely following vismodegib administration. Indeed, the neoplastic progression persisted in a number of cases. Additional genotypic and phenotypic stratifications of BCCs would probably help in identifying the BCCs most likely to respond to Hh inhibitors versus those that may respond better to other classes of chemotherapeutic agents. It remains to be established whether complete regression of BCCs occurs during treatment with vismodegib, or whether resistant neoplastic cells to Hh inhibitors are normally scattered within BCCs. Adverse events following vismodegib intake are frequent and considerable [3] . They were reported in about 25% of the treated patients [15] . Indeed, long-term vismodegib use induced severe discomfort and alterations in the quality of life caused by the combination of distinct adverse effects. These include myalgia,


Special Report

muscle spasms, dysgeusia, alopecia, weight loss, hyponatremia and fatigue. Such adverse events stem directly from inhibition of the intended molecular target corresponding to the so-called ‘class effect’. They are unlikely circumvented by modifying the molecular structure of the therapeutic agent. These side effects induce a high rate of treatment withdrawal. Ongoing research is investigating means for possibly circumventing these adverse events. There was no significant risk of drug–drug interactions, when vismodegib was concomitantly administered with other drugs. Additional data are required for assessing the long-term benefits of, and the nature of resistance to, this class of Hh inhibitors. Vismodegib corresponds to a category D drug and carries a boxed warning stating that the drug possible cause fetal death or severe birth defects. Hence pregnancy needs to be ruled out at least 7 days before starting treatment. Advice has to be given about the need for contraception in female patients, and the potential risk for v ismodegib exposure through semen in male patients. The vismodegib administration in lactating mothers should be considered after assessing both the patient’s disease status and the risk–benefit ratio. The drug should not be prescribed in children as its safety and effectiveness have not been established in this group of population. In addition, patients should be advised not to donate blood products while receiving vismodegib, and for at least 7 months after the last dose. The capsule should not be handled by pregnant women and should not be opened because the power can aerosolize and put women carrying a fetus at risk. The development of vismodegib provides a great therapeutic option for patients with advanced BCCs. However, in patients with advanced primary BCCs (metastases and HBCNS) about 5% of the neoplasms keep growing during vismodegib treatment. In some cases, the rapid initial response to the drug is not sustained over time. This suggests a possible genotypic and phenotypic BCC heterogeneity regarding the Hh pathway, as well as a primary drug resistance when BCCs fail to respond adequately to vismodegib. Some BCCs exhibit acquired resistance following initial neoplastic regression, or persistence of growth at the site of and in the vicinity to the initial tumor. These issues possibly follow acquired SMO mutations decreasing the drug binding or a compensatory

www.futuremedicine.com

2999

Special Report Piérard-Franchimont, Hermanns-Lê, Paquet, Herfs, Delvenne & Piérard increase in SMO gene downstream. Moreover, the BCC growth following treatment discontinuation is potentially due to cells developing resistance to Hh inhibitors. It remains to be established whether resistance to this class of drug, or any rebound following cessation, preclude its utility as monotherapy in the long-term management of advanced BCCs and HBCNS. Cyclopamine therapy Cyclopamine is an endogenous steroidal plant alkaloid derived from the plant Veratium californicum. It represented the initial targeted therapy of the Hh pathway. This compound was initially found to bind to the SMO receptor resulting in blockade of the downstream Hh signaling pathway transduction. Topical applications of cyclopamine in a few BCC patients were reported to improve the skin condition by induction of apoptosis in the skin neoplasms [16] . This discovery led to a variety of more potent and selective SMO/Hh antagonists for the treatment of a variety of cancer types, including advanced BCC. Itraconazole therapy Itraconazole was initially introduced as an antifungal triazole. Recently, it was further recognized as a SMO antagonist leading to the inhibition of Hh signaling pathway and BCC regression [17] . Over 40.000 BCC patients have been treated with oral itraconazole 200 or 400 mg/day. A 1-month treatment showed a 23% reduction in BCC size, a 45% reduction in neoplastic proliferation and a reduction to 65% in Hh pathway activity. Other SMO/Hh inhibitors Various other SMO inhibitors including LDE225, saridegib, BMS 833923, LEQ 506, PF-04449913 and TAK-441 are presently in clinical development. These agents were evaluated, or are presently undergoing Phase I and II clinical trials. Everolimus therapy Everolimus is an immunosuppressive agent and it targets mTOR. This proliferation signal inhibitor exhibits substantial anti-neoplastic activity, in particular against BCCs. Everolimus at a 1.5–3 mg oral dosage daily for 12 months or longer induces partial to complete BCC regression. Such therapeutic effect results from a number of different mechanisms [18] . A good tolerance was reported in the few reported

3000


cases in elderly people. Controlled trials are required to assess the effect of everolimus in the management of BCCs. Resistance to SMO inhibition & GLI inhibition There is considerable cross talk between the Hh pathway and other molecules and pathways including p53, Wnt, P13K/aKT/mTOR and retinoic acid. Such interactions create a complex network providing a variety of pathways for developing resistance to drugs targeting this pathway. Although BCC treatment using vismodegib and similar agents has resulted in some dramatic responses, resistance to SMO/Hh inhibitors occasionally leads to the development of new primary BCCs, and to growth of BCCs that had responded partially to SMO/Hh inhibitors in the past. The mechanisms of vismodegib resistance have shed some light into the complex nature of the process [19] . The development of new agents exhibiting a broader SMO inhibitory profile is probably a key for unlocking more durable benefits. Additionally, inhibition of downstream molecules, such as GLI, could benefit in the cure of SMO inhibitor refractory BCCs or as vertical inhibition combination strategies with SMO inhibitors. Current GLI inhibitors in development include GANT 58 and GANT 61. Their efficacy remains to be assessed in controlled clinical trials [20] . Conclusion & future perspective In recent developments of BCC therapies, several molecular pathways were identified as potential targets. Some targets corresponded to the SMO/Hh and mTOR pathways providing novel options for the treatment of advanced primary or metastatic BCCs. They represent an advance in dermato-oncology since prior to these targeted therapies no other effective treatment options were available. Targeting the Hh pathway appears to be a promising strategy in cancer chemotherapy. In particular, several SMO/Hh inhibitors including cyclopamine, vismodegib and itraconazole have been successfully tested, inducing apoptosis in aggressive and advanced BCCs. There are obvious clinical benefits of systemic therapies for patients with HBCNS and advanced primary and metastatic BCCs. In Phase II trials, the number of cured patients only encompassed a limited proportion of the overall BCC population; however, this is still


Hedgehog- & mTOR-targeted therapies for advanced basal cell carcinomas a significant improvement compared with the past. Based on the recently reported promising partial response rates, SMO/Hh inhibitors represent valuable drugs that need to be further tested both as single agents, as neoadjuvant drugs, as part of combination therapy and in conjunction with surgery. It would be important to compare them with chemotherapy in advanced BCCs, and explore topical strategies in patients with multiple BCCs. The peculiar spectrum of adverse vismodegib effects represent a challenge especially in the BCC patients of advanced age that often present with various other comorbidities. Since Hh signaling is also essential for the viability of various normal stem cells like bone marrow and skin, the concerns of major toxicity need to be considered and continued intensive monitoring of these patients would thus seem prudent. A number of systemic and topical agents from the emerging classes of anti-BCC agents will probably become available soon. Hh inhibitors will likely prove to be valuable drugs for

Special Report

the dermato-oncologist. The increased clinical experience with these agents, the determination of the long-term safety, efficacy and economic data should become available following quantitative analyses of their impact upon patients’ quality of life. The long-term safety and efficacy in larger populations need to be confirmed using well-designed robust Phase II clinical trials. Follow-up data of patients using Hh inhibitors and P13K–mTOR inhibitors will likewise bring information about the impact of these drugs as curative or primarily palliative compounds. Financial & competing interests disclosure 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.

EXECUTIVE SUMMARY ●●

S ome of the newer targets in oncology include the inhibitors of the Hedgehog (Hh) pathway, the mTOR signaling, the EGFR pathway, the TGF-β signaling and the NF-κB, Ras.

●●

T he Hh family of protein ligands consists of three members, namely the Sonic Hh, the Desert Hh and the Indian Hh. Two receptor proteins correspond to the transmembrane PTCH1 and SMO.

●●

L ong-term vismodegib use induce severe discomfort and alterations in the quality of life caused by the combination of distinct adverse effects.

●●

T he rapid initial response to vismodegib is not always sustained over time suggesting a possible genotypic and phenotypic BCC heterogeneity regarding the Hh pathway, as well as a primary drug resistance.

●●

esistance to SMO/Hh inhibitors occasionally leads to the development of new primary BCCs, and to growth of BCCs R that had previously responded partially to SMO/Hh inhibitors.

References 1

2

3

4

5

Uhoda I, Quatresooz P, Fumal I et al. Updating trends in cutaneous cancers in south-east Belgium. Oncol. Rep. 12, 111–114 (2004). Dummer R, Karpova MB, Barysch MJ. Basal cell carcinomas: molecular abnormalities and molecularly targeted therapies. Expert Rev. Dermatol. 4, 355–369 (2009). Dreier J, Felderer L, Barysch M et al. Basal cell carcinoma: a paradigm for targeted therapies. Expert Opin. Pharmacother. 14, 1307–1318 (2013). Tang JY, Marghoob AA. Emerging treatments and signalling pathway inhibitors. Semin. Cutan. Med. Surg. 30, S14–S18 (2011).


6

Kakanj P, Reuter K, Séquaris G et al. Indian Hedgehog controls proliferation and differentiation in skin tumorigenesis and protects against malignant progression. Cell Rep. 4, 340–351 (2013). Dubey AK, Dubey S, Handu SS et al. Vismodegib: the first drug approved for advanced and metastatic basal cell carcinoma. J. Postgrad. Med. 59, 48–50 (2013).

7

Xie J. Molecular biology of basal and squamous cell carcinomas. Adv. Exp. Med. Biol. 624, 241–251 (2008).

8

Hahn H, Wicking C, Zaphiropoulous PG et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

9

Epstein EH. Basal cell carcinomas: attack of the Hedgehog. Nat. Rev. Cancer 8, 743–754 (2008).

10 Xie J, Murone M, Luoh SM et al. Activating

smoothened mutations in sporadic basal-cell carcinoma. Nature 391, 90–92 (1998). 11 Aszterbaum M, Rothman A, Johnson RL

et al. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J. Invest. Dermatol. 110, 885–888 (1998). 12 Tang JY, Mackay-Wiggan JM, Aszterbaum

M et al. Inhibiting the Hedgehog pathway in patients with the basal-cell nevus syndrome. N. Engl. J. Med. 366, 2180–2188 (2012).

www.futuremedicine.com

3001

Special Report Piérard-Franchimont, Hermanns-Lê, Paquet, Herfs, Delvenne & Piérard 13 Piérard GE, Piérard-Franchimont C, Léonard

B, Delvenne P. The MAP kinase cascade. A key target for treatments in skin cancerology. Rev. Med. Liège 68, 650–654 (2013). 14 Poggi L, Kolesar JM. Vismodegib for the

treatment of basal cell skin cancer. Am. J. Health Syst. Pharm. 70, 1033–1038 (2013). 15 Sekulic A. Efficacy and safety of vismodegib

in advanced basal cell carcinoma. N. Engl. J. Med. 366, 2171–2179 (2012).

3002

16 Tabs S, Avci O. Induction of the

differentiation and apoptosis of tumor cells in vivo with efficiency and selectivity. Eur. J. Dermatol. 14, 96–102 (2004). 17 Kim J, Tang JY, Gong R et al. Itraconazole, a

commonly used antifungal that inhibits Hedgehog pathway activity and cancer growth. Cancer Cell 17, 388–399 (2010). 18 Eibenschutz L, Colomba MD, Catricalà C.

Everolimus for compassionate use in multiple


basal cell carcinomas. Case Report Dermatol. Med. 2013, 604301 (2013). 19 Chang AL, Oro AE. Initial assessment of

tumor regrowth after vismodegib in advanced basal cell carcinoma. Arch. Dermatol. 148, 1324–1325 (2012). 20 Lauth M, Bergstrom A, Shimokawa T et al.

Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc. Natl Acad. Sci. USA 104, 8455–8460 (2007).
