The Sonic Hedgehog Pathway

Transcription

1 To Print: Click your browser's PRINT button. NOTE: To view the article with Web enhancements, go to: Conference Report Highlights of the Combined Annual Meeting of the American Society for Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology Brent R. Moody, MD Medscape Dermatology. 2006;7(1) 2006 Medscape Posted 02/07/2006 The 2005 Combined Annual Meeting of the American Society for Dermatologic Surgery (ASDS) and American College of Mohs Micrographic Surgery and Cutaneous Oncology (ACMMSCO) featured state-of-the-art dermatologic, oncologic, and cosmetic surgery courses, and attendance exceeded past records. The Sonic Hedgehog Pathway David Kouba, MD, PhD, University of Maryland, Baltimore, reported on his ASDS-funded research into the Gli pathway, its interaction with Sonic hedgehog (SHH), and basal cell carcinoma. [1] Considerable insight into the fundamental pathways controlling normal development as well as dysregulation of the normal state have been made in the recent past. A number of these discoveries bear directly on the development of the skin, hair, nails, teeth, and skin appendage structures and are important to dermatology. Several entities warrant review. Smoothened (SMO) is a transmembrane protein, and increases in SMO signaling may result in cancer. Patched (PTC) is also a transmembrane protein that inhibits the action of SMO, thus acting as a tumor suppressor. SMO can be activated (ie, cancer-promoting) in a number of ways. A mutation can render PTC inactive, thus freeing SMO to be a tumor promoter. A mutation in SMO can lead to its activation. Finally, SHH can inactivate PTC. Current evidence indicates that dysregulation in the SHH pathway plays an important role in basal cell carcinoma (BCC) development through its relationship with PTC. Because BCC is extremely common, an understanding of these pathways and the identification of therapeutic targets is germane to dermatology. Moreover, many of these entities play significant roles in normal development and other malignancies. SHH is 1 of 3 vertebrate hedgehog homologs that play roles in the development of nearly every organ system. SHH is involved in the normal development of hair follicles, sebaceous glands, and teeth. Table 1 lists the disease states known to be associated with abnormal SHH pathway expression. The interaction between SHH and Gli proteins is the focus of Dr. Kouba's research. Gli proteins are the last step in the SHH signaling pathway. Three Gli proteins have been identified: Gli1 and Gli2 appear to be transcription activators, while Gli3 serves as a suppressor. While previous work has primarily looked at the individual Gli proteins, Dr. Kouba is investigating dynamic and synergistic relationships between the Gli proteins. He is specifically studying the interaction between wild-type Gli1 and a highly active form of a Gli2 mutant. Photodynamic Therapy Nathalie Zeitouni, MD, CM, FRPC, Roswell Park Cancer Institute, Buffalo, New York, and Mitchell Goldman, MD, University of California, San Diego, led an informative session entitled "Latest Advances in Photodynamic Therapy." [2] Photodynamic therapy (PDT) is being increasingly used for the treatment of premalignant lesions, malignant lesions, acne, and photorejuvenation. Dermatology has a long history of employing chemicals and light or ultraviolet irradiation for therapeutic effect. Photochemotherapy with psoralens and ultraviolet light is well established for the management of psoriasis, vitiligo, and cutaneous lymphomas. Phototherapy alone is commonly used for psoriasis and occasionally for pruritus. The term photodynamic therapy most commonly refers to the use Page 1 sur 5

2 of a photosensitizer in the porphyrin metabolic pathway followed by activation of the agent with visible light. A number of exogenous porphyrins have been used, and these agents can be administered systemically or applied topically. For most dermatologic applications, topical administration is the most practical approach. 5-aminolevulinic acid (ALA) is commercially available in a convenient single-dose stick (Levulan Kerastick) that is approved by the US Food and Drug Administration. ALA is a natural precursor to protoporphyrin IX (PpIX), an efficient photosensitizer. Methyl aminolevulinate is another topical photosensitizer (Metvixia). The panelists at the session focused their reports on the use of topical ALA. The basic precept of PDT is that activation of the photosensitizer induces destruction in the target tissue. The exact mechanism of this destruction is not entirely clear, but evidence suggests that multiple mechanisms contribute to the clinical efficacy of PDT. Direct cellular damage occurs via the generation of radical oxygen species and lipid peroxidation. Vascular changes resulting from PDT lead to nutritional deprivation of the target cells. A number of sources for ALA activation are available. The panelists said that they tend to use 1 of 3 sources: a blue visible light source, intense pulsed light (IPL), or the pulsed dye laser (V-Beam; Candela Corporation; Wayland, Massachusetts). PpIX has well-defined absorption peaks. A significant absorption peak occurs at the visible blue light wavelength, which explains the common practice of using visible blue light as the PDT activator. The Blu-U unit (DUSA Pharmaceuticals; Wilmington, Massachusetts) generates a 417-nm wavelength. Sufficient drug activation occurs with the 595-nm pulsed dye laser and IPL to make these sources clinically effective. The selection of the activation source is primarily based on availability and the intended clinical effect of the treatment. In many dermatology practices, the broadest application of PDT is the management of actinic keratoses (AK). Initially, the Levulan ALA protocol for AK was logistically challenging. An 18-hour incubation of the Levulan followed by activation with visible light in the blue spectrum necessitated 2 office visits and could be marked by significant patient discomfort. The efficacy of the treatment led to alternative treatment protocols that focused on shorter drug incubation times to allow for a single-day treatment. Studies have demonstrated clinical efficacy for AK with a so-called short incubation protocol. For AK, the conference panelists (and this author) typically use short incubation of the ALA; 1 hour of ALA contact time appears sufficient. Peter Lee, MD, PhD, University of Minnesota, Minneapolis, presented his protocol (which this author also has found successful): Clean target area with acetone. Apply ALA to all palpable/visible lesions. If a broader area of treatment is desired, the entire area is coated. Once the medicine has dried, a second coat can be applied to visible/palpable lesions. Occlusion with plastic wrap may enhance absorption. Wait a minimum of 1 hour. (I will usually wait 2-plus hours for the scalp or extremities.) 4. Treat with activator. For the primarily medical indication of AK, use Blu-U for 16 minutes, 40 seconds. 5. Wash area with mild soap and water; apply sunscreen if treated area will be exposed to light. Avoid excess light exposure for the next 24 hours. Dr. Lee has used the above protocol in an efficacious manner with his solid organ transplant recipient (SOTR) patients. SOTR patients have a greatly increased risk of developing cutaneous SCC and precursor AK. A subset of these patients exhibit progressive disease. A number of strategies have emerged for dealing with AK and SCC in this population. For multiple or high-risk invasive SCC, systemic retinoids or alteration in immunosuppression may be required. Dr. Lee has observed a marked decrease in SCC development in SOTR patients treated with cyclical PDT. Using the 1-hour ALA contact time protocol, he treats affected areas every 6-8 weeks for 24 months. Patient acceptance for this approach was reported as good, and a small study published by Dragieva and colleagues [3] reported acceptable results for AK in SOTR patients. A cautionary note should be sounded about the treatment of hyperkeratotic AK lesions with PDT. One advantage of PDT is its ability to treat large areas of actinic damage, but hyperkeratotic lesions may not be treated sufficiently with a single modality. Various strategies are available to deal with these lesions; some investigators have removed hyperkeratotic lesions with curettage or acid prior to PDT. My strategy is to treat hyperkeratotic lesions with cryosurgery and use PDT to treat the thinner lesions as well as the entire field. Hyperkeratotic lesions can be treated on the front end -- prior to PDT -- or after residual lesions are identified after PDT. Page 2 sur 5

3 Actinic cheilitis is a therapeutic challenge to the clinician because most treatment modalities have unacceptably high recurrence rates. Macrene Alexiades-Armenakas, MD, PhD, [4] New York, NY, described her protocol for actinic cheilitis using ALA and the pulsed dye laser: ALA contact for 2-3 hours. Treat with the pulsed dye laser (V-Beam). Wavelength of 595 nm, 7.5 J/cm 2, 10-ms pulse width, 10-mm spot size, and cooling settings or 30 ms spray and 30 ms delay. Treat 1-3 times at 1-month intervals based on clinical assessment of response. Dr. Alexiades-Armenakas advised herpes simplex virus prophylaxis in patients with a history of oral herpes labialis. In her original series, patients with erosive disease were noted to develop secondary bacterial infection, and antibacterial prophylaxis was also advised in those cases. As PDT has gained acceptance for the management of AK and as physician experience with the modality has increased, the technique has expanded into other indications. Two additional areas that have generated enthusiasm are the management of acne vulgaris and photoaging. The panelists all agreed that ALA-PDT plays an important role in the management of these conditions. For acne vulgaris, ALA is the common thread in PDT, while the activation source varied among clinicians. Sources used to activate the ALA include blue light, red light, pulsed dye laser, and broadband or IPL. While each light source has advantages and disadvantages, they all appear to be efficacious. The ALA incubation time for acne is shorter than that for AK. Contact times as short as 15 minutes have been reported, although more typically a longer incubation (30-45 minutes) may be required. It is interesting to note that blue light alone (without exogenous ALA) has been used for acne vulgaris. This approach uses the endogenous porphyrins produced by Propionibacterium acnes. [5] ALA-PDT has generated interest in the treatment of diffuse photoaging beyond frank AK. Patients with generalized photodamage may benefit from what is being termed photodynamic photorejuvenation. Incubation time can be as short as 30 minutes to 1 hour. Again, any number of devices have been described as the ALA activator. IPL may be particularly useful, because IPL alone can have a rejuvenation effect. A previously published split-face study by Tina Alster, MD, and colleagues [6] indicated that ALA-PDT with an IPL device is superior to IPL alone. The panelists thought that the addition of ALA to IPL would ultimately decrease the number of treatments required to reach the desired clinical endpoint. Finally, the panelists reviewed their experience with PDT and a number of other conditions. Michael Gold, MD, [7] Nashville, Tennessee, described his experience with ALA-PDT and hidradenitis suppurativa. He reported good results with 30 minutes of ALA contact and activation with the ClearLight blue light system (Lumenis; Santa Clara, California). Patients required multiple treatments but did achieve what was described as 75% clearance. From Dr. Gold's original report, it appears that the cases were on the milder end of the disease spectrum. In a report by Strauss and colleagues, [8] less favorable results were reported in their open-label trial of ALA-PDT in hidradenitis suppurativa, with patients achieving partial short-term improvement at best. The severity of disease in this report is difficult to discern. Differences in results between the 2 investigators cannot be fully reconciled, but both studies were small and there were differences in the treatment protocols. Sebaceous hyperplasia is a common patient concern. Myriad treatment options exist, but none is entirely satisfactory. ALA-PDT can be added to the therapeutic options. Incubation times range form 30 minutes to 1 hour. Again, activation sources such as vascular laser, blue light, and IPL have been reported. Improvement was in the 50% to 70% range, and multiple treatments may be needed. [9] Clearly, PDT will have a growing role in the management of many dermatologic conditions. Indeed, sufficient optimism regarding this modality exists to justify the creation of the American Society for Photodynamic Therapy. Table Disease States Known to Be Associated With Dysregulation of the Hedgehog Pathway Page 3 sur 5

4 Congenital Diseases/Syndromes Acquired Diseases Holoprosencephaly (incomplete forebrain cleavage) Basal cell carcinoma Bradydactyly Medulloblastoma Partial gonadal dysgenesis Rhabdomyosarcoma Gorlin syndrome (nevoid basal cell carcinoma) Prostate cancer Limb malformation Rubenstein-Taybi Hereditary multiple exostoses Simpson-Golabi-Behmel References Opening General Session. Program and abstracts of the Combined Annual Meeting of the American Society for Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology; October 27-30, 2005; Atlanta, Georgia. Latest Advances in Photodynamic Therapy. Program and abstracts of the Combined Annual Meeting of the American Society for Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology; October 27-30, 2005; Atlanta, Georgia. Dragieva G, Hafner J, Drummer R, et al. Topical photodynamic therapy in the treatment of actinic keratoses and Bowen's disease in transplant recipients. Transplantation. 2004;77: Abstract 4. Alexiadas-Armenkas MR, Geronemus RG. Laser-mediated photodynamic therapy of actinic cheilitis. J Drugs Dermatol. 2004;3: Abstract 5. Ashkenazi H, Malik Z, Harth Y, Nitzan Y. Eradication of Propionibacterum acnes by its endogenic porphyrins after illumination with high intensity blue light. FEMS Immunol Med Microbiol. 2002;35: Alster TS, Tanzi EL, Welsh EC. Photorejuvenation of facial skin with topical 20% 5-aminolevulinic acid and intense pulsed light treatment: a split-face comparison study. J Drugs Dermatol. 2005;4: Abstract 7. Gold MH. ALA-PDT and blue light therapy for hidradenitis suppurativa. J Drug Dermatol. 2004;3:S32-S Strauss RM, Pollock B, Stables GI, Goulden V, Cunliffe WJ. Photodynamic therapy using aminolevulinic acid does not lead to clinical improvement in hidradenitis suppurativa. Brit J Dermatol. 2005;152: Gold MH, Bradshaw VL, Boring MM, Bridges TM, Biron JL, Lewis TL. Treatment of sebaceous gland hyperplasia by photodynamic therapy with 5-aminolevulinic acid and a blue light source or intense pulsed light source. J Drugs Dermatol. 2004;3:S6-S9. Abstract Suggested Readings Altaba AR. Gli proteins and Hedgehog signaling: development and cancer. Trends Genet. 1999;15: Altaba AR. The works of Gli and power of Hedgehog. Nature Cell Biol 1999;1: Aszterbaum M, Rothman A, Johnson RL, et al. Identification of mutations in human PATCHED gene in sporadic basal cell carcinoma and in patients with the basal cell nevus syndrome. J Invest Dermatol. 1998;110: Babilas P, Karrer S, Sidoroff A, Landthaler M, Szeimies RM. Photodynamic therapy in dermatology -- an update. Photodermatol Photoimmunol Photomed. 2005;21: Bonifas JM, Pennypacker S, Chuang PT, et al. Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol. 2001;116: Coburne MT, Miletich I, Sharpe PT. Restriction of sonic hedgehog signaling during early tooth development. Development. 2004;131: Goldman MP, Boyce SM. A single-center study of aminolevulinic acid and 417 nm photodynamic therapy in Page 4 sur 5

5 the treatment of moderate to severe acne vulgaris. J Drugs Dermatol. 2003;2: Hongcharu W. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol. 2000;115: Kalka K, Merk H, Mukhtar H. Photodynamic therapy in dermatology. J Am Acad Dermatol. 2000;42: Kormeili T, Yamauchi PS, Lowe NJ. Topical photodynamic therapy in clinical dermatology. Brit J Dermatol. 2004;150: Nieuwenhuis E, Hui C. Hedgehog signaling and congenital malformations. Clin Genet. 2004;67: Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest BA. A trial of short incubation, broad-area photodynamic therapy for facial actinic keratoses and diffuse photodamage. Arch Dermatol. 2004;140: Tsao H. Genetics of nonmelanoma skin cancer. Arch Dermatol. 2001;137: Brent R. Moody, MD, Assistant Professor, Dermatology, Vanderbilt University, Nashville, Tennessee; Director of Cosmetic Dermatologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee Disclosure: Brent R. Moody, MD, has disclosed no relevant financial relationships. Page 5 sur 5