Images in Immunotherapy and Precision Oncology: Advanced Basal Cell Carcinoma.

A 62-year-old man presented with a slowly growing, painless lesion on his face. This eventually led to a progressive left-eye vision lesion, and the patient was subsequently diagnosed with advanced basal cell carcinoma (BCC). Of note, BCC involving cranial nerves is extremely rare, making this case unique and important to highlight. Standard treatment options for BCC involve surgery, radiation, or platinum-based chemotherapy. However, targeted therapies such as sonidegib and vismodegib - sonic hedgehog pathway inhibitors - have emerged that have been approved for treating BCC, as have anti-PD1 immunotherapies, such as cemiplimab, with their success likely based on the high tumor mutational burden seen in some of these tumors. Epidermal growth factor receptor (EGFR) inhibitors also serve a role in treating this condition as well. Molecular studies on metastatic/advanced BCC and other rare malignancies may inform treatment therapeutic decisions.

A case of basal cell carcinoma of skin with bone metastasis: a case report.

BACKGROUND: Basal cell carcinoma is the most prevalent skin cancer, most characterized by local aggressiveness but with low metastatic potential, and bone metastasis is quite heterogeneous, thus the incidence profile is variable size from 0.0028% to 0.5%. We have this patient with an unusual example of basal cell carcinoma with bone metastases to add to the scarce report on this matter. CASE DESCRIPTION: Here we document a 48-year-old Persian man with a background of being exposed to the sun for a long time. He was diagnosed with an ulcer on the cheek, which was clinically characterized and further confirmed by biopsy as morpheaform basal cell carcinoma. Following the first round of excision, multiple relapses eventually metastasized to the bone. The latter was found on follow-up radiologic scans. This case is characterized by the aggressive nature of the disease and the heterogeneity of basal cell carcinoma growth, thus challenging the conventional view of basal cell carcinoma behavior. Treatment included surgical excision of the primary lesion, which was treated with radiotherapy afterward. However, the skeleton improved slowly during follow-up, and palliative care was eventually pursued to control symptoms and improve quality of life. CONCLUSIONS: This was a rare case of basal cell carcinoma metastasis to non-bone organs, which reminded us to consider basal cell carcinoma metastasis, especially in the case of atypical basal cell carcinoma. Therefore, risk-aware patient management is essential. Moreover, these findings highlight the role of further research into the mechanisms of basal cell carcinoma metastasis, leading to improved therapeutic strategies that may lead to potential improvements in patient outcomes.

Oral smoothened inhibitors for Gorlin syndrome: A clinical review.

Although smoothened inhibitors (SMOi) have demonstrated efficacy in the management of basal cell carcinoma, no guidelines are available on how to utilize SMOi in the treatment of Gorlin syndrome (GS). This review's objective is to assess the clinical response to SMOi in GS, provide practical guidance for clinicians, and identify areas for future research. Through comprehensive searches of previous publications and expert opinion, this review demonstrates that intermittent dosing of SMOi and daily dosing have similar efficacy. While the adverse events of SMOi may result in their discontinuation during treatment of GS, intermittent dosing may improve compliance.

Oral Hedgehog Inhibitor, Vismodegib, for Locally Advanced Periorbital and Orbital Basal Cell Carcinoma: A Report by the American Academy of Ophthalmology.

PURPOSE: To review the efficacy and safety of oral vismodegib (Erivedge; Genentech) in the management of locally advanced orbital and periorbital basal cell carcinoma (BCC). METHODS: A literature search was conducted last in September 2023 in the PubMed database for English language original research that evaluated the effect of oral vismodegib on orbital and periorbital BCC. Sixty articles were identified and 16 met the inclusion criteria. RESULTS: Most studies demonstrated high response rates, with up to 100% of patients responding to the medication in individual studies and initial complete regression occurring in up to 88% of patients. Vismodegib treatment resulted in significant reductions in tumor volume, resulting in globe preservation for most patients. However, in 12% of patients, the response was partial. Recurrences also occurred with substantial frequency, even after an initial complete response. As such, up to 79.4% of patients required surgical intervention, and up to 23% of patients still required exenteration. Use of these agents resulted in reductions in tumor volume that may delay or prevent the need for exenteration in some, but not all, patients. Importantly, molecular analysis of tissue excised after vismodegib therapy revealed persistent tumor in all patients, with frequent accumulation of mutations that may confer resistance to further hedgehog inhibitor therapy. Although most adverse events were rated as level I or II, side effects were common, with up to 100% of patients in studies experiencing at least 1 event. Muscle cramps, alopecia, weight loss, fatigue, and dysgeusia were the most common adverse events, and several patients discontinued therapy because of them. Furthermore, 1 patient died of sepsis that may have resulted from the therapy. CONCLUSIONS: Although level I and II evidence are lacking, most studies indicate a benefit from the use of oral vismodegib to treat orbital and periorbital BCC tumor volume. However, patients should be cautioned about the adverse side effects of treatment and the persistence of tumor cells with mutations that may cause long-term resistance. Use of vismodegib as short-term neoadjuvant therapy may be effective in shrinking tumor volume to reduce surgical morbidity while reducing the frequency and severity of side effects. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Concurrent Basal Cell Carcinoma Masquerading As Osteomyelitis of the Acromioclavicular Joint: A Rare Presentation.

Basal cell carcinoma (BCC) ranks as the most common form of skin cancer in the United States, and its prevalence continues to increase. Regular self-examinations of the skin can significantly enhance treatment outcomes. This report investigates a rare instance of BCC initially misdiagnosed as osteomyelitis, stemming from a longstanding wound on the patient's left shoulder. A 66-year-old male with a history of working in construction presented with a non-healing wound on his left shoulder, which he initially sustained from a metallic rod injury. Despite self-treatment, the wound deteriorated, revealing subcutaneous fat and producing foul-smelling drainage. Imaging suggested osteomyelitis, but the persistent and worsening nature of the wound over two years, previously concealed from his family and healthcare providers, prompted further investigation. A biopsy confirmed infiltrative BCC. The patient was referred to a tertiary care facility for comprehensive treatment, including long-term antibiotics for osteomyelitis and systemic therapy with vismodegib for BCC. Basal cell carcinoma commonly appears as a pink or flesh-colored papule or nodule, often with surface features that aid in early identification and treatment. Yet, infiltrative BCC, like the case described here, can pose diagnostic challenges because of its subtle yet aggressive characteristics. The complex causes of BCC highlight the necessity of preventive actions, particularly for those with prolonged exposure to ultraviolet (UV) radiation. Treatment approaches primarily aim at removing the tumor and may incorporate targeted therapies for more advanced instances. This case underscores the importance of regular skin self-examinations and prompt medical attention for lingering wounds, particularly among those at higher risk. Successfully addressing BCC demands a comprehensive strategy involving surgery, targeted chemotherapy, and preventive actions against potential future skin malignancies. Maintaining long-term surveillance is crucial for individuals with prior BCC diagnoses to detect any potential recurrence and address any enduring consequences of treatment.

Advanced and Metastatic Non-Melanoma Skin Cancer: Epidemiology, Risk Factors, Clinical Features, and Treatment Options.

Non-melanoma skin cancers (NMSC) form the majority of skin cancers, with basal cell carcinoma (BCC) being the most common and cutaneous squamous cell carcinoma (cSCC) being second. Prolonged ultraviolet (UV) exposure, aging, male gender, and immunosuppression represent most of the causes of this category of diseases. BCCs and cSCCs both include different types of skin cancers, such as nodular or morpheaform BCC or flat cSCC. Locally advanced and metastatic NMSCs cannot be treated surgically; thus, systemic therapy (TKI and Immunotherapy) is needed. Interestingly, NMSCs are frequently linked to abnormal Hedgehog (HH) signaling which most systemic immunotherapies for these cancers are based upon. Of note, the first line therapies of BCC, sonidegib and vismodegib, are HH inhibitors. Programmed death receptor 1 antibody (PD-1) inhibitors such as cemiplimab, pembrolizumab, and nivolumab have been approved for the treatment of cSCC. Thus, this paper reviews the epidemiology, risk factors, clinical features, and treatment options for both BCC and cSCC.

A novel indole derivative, 2-{3-[1-(benzylsulfonyl)piperidin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone, suppresses hedgehog signaling and drug-resistant tumor growth.

The Hedgehog (Hh) signaling pathway plays important roles in various physiological functions. Several malignancies, such as basal cell carcinoma (BCC) and medulloblastoma (MB), have been linked to the aberrant activation of Hh signaling. Although therapeutic drugs have been developed to inhibit Hh pathway-dependent cancer growth, drug resistance remains a major obstacle in cancer treatment. Here, we show that the newly identified, 2-{3-[1-(benzylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl]-2-methyl-1H-indol-1-yl}-1-(pyrrolidin-1-yl)ethenone analog (LKD1214) exhibits comparable potency to vismodegib in suppressing the Hh pathway activation. LKD1214 represses Smoothened (SMO) activity by blocking its ciliary translocation. Interestingly, we also identified that it has a distinctive binding interface with SMO compared with other SMO-regulating chemicals. Notably, it maintains an inhibitory activity against the SmoD477H mutant, as observed in a patient with vismodegib-resistant BCC. Furthermore, LKD1214 inhibits tumor growth in the mouse model of MB. Collectively, these findings suggest that LKD1214 has the therapeutic potential to overcome drug-resistance in Hh-dependent cancers.

Development of a molecularly imprinted polymer-based electrochemical sensor with metal-organic frameworks for monitoring the antineoplastic drug vismodegib.

A novel and robust electrochemical sensing tool for the determination of vismodegib (VIS), an anticancer drug, has been developed by integrating the selective recognition capabilities of molecularly imprinted polymer (MIP) and the sensitivity enhancement capability of metal-organic framework (MOF). Prior to this step, the electrochemical behavior of VIS was investigated using a bare glassy carbon electrode (GCE). It was observed that in 0.5 M H2SO4 solution as electrolyte, VIS has an oxidation peak around 1.3 V and the oxidation mechanism is diffusion controlled. The determination of VIS in a standard solution using a bare GCE showed a linear response in the concentration range from 2.5 µM to 100 µM, with a limit of detection (LOD) of 0.75 µM. Since sufficient sensitivity and selectivity could not be achieved with bare GCE, a MIP sensor was developed in the next step of the study. For this purpose, the GCE surface was first modified by drop casting with as-synthesized Co-MOF. Subsequently, a MIP network was synthesized via a thermal polymerization approach using 2-acrylamido-2-methylpropanesulfonic acid (AMPS) as monomer and VIS as template. MOFs are ideal electrode materials due to their controllable and diverse morphologies and modifiable surface properties. These characteristics enable the development of MIPs with more homogeneous binding sites and high affinity for target molecules. Integrating MOFs could help the performance of sensors with the desired stability and reproducibility. Electrochemical analysis revealed an observable enhancement of the output signal by the incorporation of MOF molecules, which is consistent with the sensitivity-enhancing role of MOF by providing more anchoring sites for the attachment of the polymer texture to the electrode surface. This MOF-MIP sensor exhibited impressive linear dynamic ranges ranging from 0.1 to 1.0 pM for VIS, with detection limits in the low picomolar range. In addition, the MOF-MIP sensor offers high accuracy, selectivity and precision for the determination of VIS, with no interference observed from complex media of serum samples. Additionally, in this study, Analytical GREEnness metric (AGREE), Analytical GREEnness preparation (AGREEprep) and Blue Applicability Grade Index (BAGI) were used to calculate the green profile score.

Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway. The use of hedgehog pathway inhibitors-vismodegib and sonidegib-has emerged as a promising therapeutic strategy for managing BCCs in individuals with GS. In a retrospective study conducted between March 2012 and January 2024, a cohort of 16 Gorlin syndrome patients who received treatment with either sonidegib or vismodegib were analyzed. The primary objectives of the study were to evaluate the efficacy, safety profile, and duration of response to oral hedgehog inhibitors in this patient population. The study assessed various parameters, including the number of new BCCs that developed before and after treatment initiation, the duration and sustainability of treatment responses, as well as the incidence of adverse effects associated with hedgehog inhibitor therapy. The findings of the study revealed that sustained treatment with hedgehog inhibitors could effectively suppress the progression of both new and existing BCCs. Furthermore, the results indicated that sonidegib exhibited superior efficacy and safety compared to vismodegib in the treatment of BCCs in individuals with GS. Notably, adjustments to the administration schedule of sonidegib were found to improve tolerability without compromising therapeutic efficacy, potentially leading to prolonged durations of treatment response and disease control.

Vismodegib in Gorlin-Goltz syndrome: A systematic review.

Treatment with Hedgehog Inhibitors in Gorlin-Goltz syndrome (GGS) yields favourable objective clinical responses, yet secondary resistance and class-related toxicity restrict treatment duration. This study aims to review current data on GGS patients undergoing vismodegib therapy, focusing on treatment duration, clinical outcomes and schedule modifications. A systematic search of the PubMed database was conducted for English articles from 1993 to 2023, identifying 31 papers suitable for inclusion. A total of 351 patients, with a mean age of 52 years, were analysed. The average treatment duration was 9.3 months for patients who discontinued treatment, and 25.1 months for those who continued vismodegib at the time this study was published. Vismodegib achieved a complete response rate of 44%. Treatment interruption predominantly occurred due to side effects (69.1%) and secondary resistance (9.1%). The use of alternative regimens, although not compromising efficacy, may enhance treatment compliance. Further investigations are warranted to ascertain the optimal treatment regimen and timeline for GGS patients. Schedule modifications offer promise in ameliorating side effects and facilitating long-term treatment.

Vismodegib as an adjuvant treatment for periorbital basal cell carcinoma: a case report and review of literature.

Background: Basal cell carcinoma (BCC) is the most common cancer type worldwide. Although there are several treatment options for the treatment of BCC, selecting the best treatment option for periorbital BCC is challenging and it varies case by case. More than half of periocular BCC cases initially occur on the inner angle and lower lid. The treatment options for BCC include radical surgical excision using Mohs micrographic technique, radiotherapy, neoadjuvant vismodegib, imiquimod, and combination therapy followed by reconstruction for functionality and aesthetic outcome. Selection of each treatment varies based on the severity and extension of BCC. Case Description: We report a case of periorbital BCC invading the left lower eyelid in a 50-year-old Caucasian male which was initially excised a few years ago, and, following recurrence, the patient underwent Mohs micrographic surgery. Due to a recurrence after Mohs micrographic surgery, treatment with oral vismodegib was started, which led to near-total tumor shrinkage. To determine the outcome of periorbital BCC treated with vismodegib, we reviewed the literature on the periorbital BCC treated with vismodegib, their follow-up period, outcome, and whether they were metastatic or had recurrence. Conclusions: Neoadjuvant vismodegib, followed by surgery excision, such as Mohs micrographic surgery, has shown a promising clinical and aesthetic outcome in the treatment of periorbital BCC.

SHH induces macrophage oxidative phosphorylation and efferocytosis to promote scar formation.

Excessive scar formation such as hypertrophic scars and keloids, resulting from trauma or surgical procedures, present a widespread concern for causing disfigurement, discomfort, and functional limitations. Macrophages play pivotal roles in maintaining tissue homeostasis, orchestrating tissue development, repair, and immune responses, and its transition of function and phenotype plays a critical role in regulating the balance between inflammation and tissue regeneration, which is central to cutaneous scar formation. Recent evidence suggests the involvement of Sonic Hedgehog (SHH) in the induction of anti-inflammatory M2-like macrophage phenotypes within tumor microenvironments. In our study, we observed increased SHH expression in human hypertrophic scars, prompting an investigation into its influence on macrophage polarization, efferocytosis, and cutaneous scar formation. Our findings reveal that SHH can enhance oxidative phosphorylation (OXPHOS) in macrophages, augment macrophage efferocytosis, and promote M2 polarization, finally contributing to the progression of cutaneous scar formation. Notably, targeting SHH signaling with vismodegib exhibited promising potential in mitigating scar formation by reversing the effects of enhanced OXPHOS and M2 polarization in macrophages. In conclusion, this study underscores the critical roles of macrophage metabolism, particularly OXPHOS, efferocytosis and SHH signaling in cutaneous scar formation. Understanding these mechanisms provides new avenues for potential interventions and scar prevention strategies.

Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is a common cancer with several accepted treatments, such as chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and immune checkpoint inhibitors. Nevertheless, NSCLC cells often become insensitive to these treatments, and therapeutic resistance is a major reason NSCLC still has a high mortality rate. The induction of therapeutic resistance in NSCLC often involves hedgehog, and suppression of hedgehog can increase NSCLC cell sensitivity to several conventional therapies. In our previous work, we demonstrated that the marine antimicrobial peptide tilapia piscidin 4 (TP4) exhibits potent anti-NSCLC activity in both EGFR-WT and EGFR-mutant NSCLC cells. Here, we sought to further explore whether hedgehog might influence the sensitivity of NSCLC cells to TP4. Our results showed that hedgehog was activated by TP4 in both WT and EGFR-mutant NSCLC cells and that pharmacological inhibition of hedgehog by vismodegib, a Food and Drug Administration-approved hedgehog inhibitor, potentiated TP4-induced cytotoxicity. Mechanistically, vismodegib acted by enhancing TP4-mediated increases in mitochondrial membrane potential and intracellular reactive oxygen species (ROS). MitoTempo, a specific mitochondrial ROS scavenger, abolished vismodegib/TP4 cytotoxicity. The combination of vismodegib with TP4 also reduced the levels of the antioxidant proteins catalase and superoxide dismutase, and it diminished the levels of chemoresistance-related proteins, Bcl-2 and p21. Thus, we conclude that hedgehog regulates the cytotoxic sensitivity of NSCLC cells to TP4 by protecting against mitochondrial dysfunction and suppressing oxidative stress. These findings suggest that combined treatment of vismodegib and TP4 may be a promising therapeutic strategy for NSCLC.

A Multidisciplinary approach to metastatic giant basal cell carcinoma-A case report.

We present a case of a 49-year-old man with a giant basal cell carcinoma of the back, with metastases in the lungs, liver, mediastinum and both adrenal glands. Neoadjuvant vismodegib was administered, after which wide local resection of the tumour was performed. There have been no signs of local recurrence.

The importance of caregivers for patients with advanced basal cell carcinoma treated with hedgehog-pathway inhibitors: an observational prospective study.

Oral targeted therapy with hedgehog pathway inhibitors has revolutionized the standard of care for patients with advanced basal cell carcinoma (BCC). These patients are frail and elderly, have various comorbidities, and receive pharmacological polytherapy. Moreover, adverse events may have a significant impact on therapeutic adherence, which must be managed by the clinician. We evaluated the impact of caregivers on the treatment of patients with advanced BCC in terms of continuation of therapy over time. All patients included in this observational prospective study had histologically confirmed metastatic or locally advanced BCC (LaBCC) and were treated with hedgehog pathway inhibitors from January 2016 to December 2021 at the Department of Dermatology at the University of Florence, Italy. The collected patient data included: age, sex, BCC site and area of spread; number of cycles, dose, duration and tolerability of therapy; marital status (single, divorced, married/living with a partner, widow/widower); and information such as living with someone, and the presence of any caregivers. Of the 34 patients included, 33 had LaBCC and one metastatic BCC. There were 11 females (32.4%) and 23 males (67.6%). Patients who were married or living with a caregiver -tolerated therapy better than single patients who lived alone. Indeed, patients with married/live-in caregivers and/or those with an adequate caregiver experienced greater therapeutic adherence and tolerance of adverse events. Given the greater therapeutic adherence of patients with live-in caregivers as partners, it is essential to consider patients' marital status. It is advisable to involve the caregiver early on, and there should be a training discussion on the various possible adverse events and the best way to mitigate them. Therapeutic success is linked not only to patients being informed but also to training of caregivers.

Beyond cyclopamine: Targeting Hedgehog signaling for cancer intervention.

Hedgehog (Hh) signaling plays a significant role in embryogenesis and several physiological processes, such as wound healing and organ homeostasis. In a pathological setting, it is associated with oncogenesis and is responsible for disease progression and poor clinical outcomes. Hedgehog signaling mediates downstream actions via Glioma Associated Oncogene Homolog (GLI) transcription factors. Inhibiting Hh signaling is an important oncological strategy in which inhibitors of the ligands SMO or GLI have been looked at. This review briefly narrates the Hh ligands, signal transduction, the target genes involved and comprehensively describes the numerous inhibitors that have been evaluated for use in various neoplastic settings.

Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib.

Adult medulloblastoma (MB) is a rare disease affecting 0.6 persons per million adults over 19 years of age. The SHH-activated/TP53-wild type is the most common subtype, accounting for 60% of adult MBs, being characterized by mutations in PTCH1, SMO, or the TERT promoter. Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. Like other oncogene-addicted solid tumors, detection of the corresponding drivers through liquid biopsy could aid in the molecular diagnosis and monitoring of the disease through less invasive procedures. However, most studies have only evaluated cerebrospinal fluid as the ctDNA reservoir, and very limited evidence exists on the role of liquid biopsy in plasma in patients with primary central nervous system tumors, including MB. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.

A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened.

The hedgehog (Hh) signaling pathway has long been a hotspot for anti-cancer drug development due to its important role in cell proliferation and tumorigenesis. However, most clinically available Hh pathway inhibitors target the seven-transmembrane region (7TM) of smoothened (SMO), and the acquired drug resistance is an urgent problem in SMO inhibitory therapy. Here, we identify a sterol analog Q29 and show that it can inhibit the Hh pathway through binding to the cysteine-rich domain (CRD) of SMO and blocking its cholesterylation. Q29 suppresses Hh signaling-dependent cell proliferation and arrests Hh-dependent medulloblastoma growth. Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.

Photobiomodulation Recovers the Submandibular Gland in Vismodegib-Treated Rats.

Objective: The submandibular gland (SMG) produces the most saliva, and factors such as aging and chemotherapy can affect its structure and function. However, there are only temporary treatments available for salivary hypofunction. This study aimed to evaluate the effects of photobiomodulation (PBM) on the function of SMG by using a rat animal model and vismodegib, an antagonist of the sonic hedgehog (SHH) pathway. Methods: Vismodegib (10 mg/kg) drug was gavaged orally for 14 days in rats to significantly decrease the SHH signaling proteins [SHH, protein patched homolog 1 (PTCH1), smoothened protein (SMO), glioma-associated oncogene homolog 1 (GLI1)], induce damage in SMG tissue, and affect salivary functional markers AQP5 and Keratin5. After that, in conjunction with vismodegib administration, PBM was performed using an 850 nm high-power light-emitting diode (LED) device treated daily for 6 days at varying total energy densities of 60, 120, and 180 J/cm2 in at least 3 rats per group. The test results were confirmed by Western blot, immunofluorescence staining, and hematoxylin and eosin staining, and the statistics were t-test or one-way analysis of variance (ANOVA) with Tukey's multiple comparisons tests. Results: Significant decreases in the expression of SHH-related proteins (PTCH1, SMO, GLI1, p < 0.05) with damage of SMG ductal cells were observed with vismodegib administration. However, a significant increase in the expression levels of SHH-related proteins (SHH, SMO, GLI1, p < 0.05) and recovery of SMG ductal cells damaged after vismodegib administration were observed for PBM-treated groups. Salivary functional marker AQP5 also showed the same increase or decrease. Conclusions: This study found that vismodegib damages SMG ductal cells and decreases SHH-related proteins and associated salivary functional markers. Also, 850 nm high-power LED recovered the damaged structure of SMG and increased SHH-related proteins and salivary functional markers. The study results suggest that PBM can restore SMG structure and function through SHH signaling.

Ablative fractional laser treatment reduces hedgehog pathway gene expression in murine basal cell carcinomas.

This study aimed to investigate the impact of ablative fractional laser (AFL) on hedgehog pathway gene expression in murine microscopic basal cell carcinomas (BCCs) and compare these results to the effect of topical treatment with vismodegib, an FDA-approved hedgehog inhibitor. In 25 mice, 1 cm2 skin test sites (n = 44) containing microscopic BCCs were exposed to one of three interventions: a single CO2 AFL treatment (1 pulse, 40 mJ/microbeam, wavelength 10.6 µm, 5% density, pulse rate 250 Hz, n = 12), eight topical vismodegib treatments (3.8 mg/mL, n = 8), or combination of AFL and vismodegib treatments (n = 9). Untreated controls were included for comparison (n = 15). After 4 days, skin samples were analyzed for hedgehog gene expression (Gli1, Gli2, and Ptch1) by qPCR and vismodegib concentrations by liquid chromatography mass spectrometry (data analyzed with two-tailed t-tests and linear regression). A single treatment with AFL monotherapy significantly reduced hedgehog gene expression compared to untreated controls (Gli1 72.4% reduction, p = 0.003; Gli2 55.2%, p = 0.010; Ptch1 70.9%, p < 0.001). Vismodegib treatment also reduced hedgehog gene expression (Gli1 91.6%; Gli2 83.3%; Ptch1 83.0%), significantly surpassing AFL monotherapy for two out of three genes (Gli1, p = 0.017; Gli2, p = 0.007; Ptch1, p = 0.15). AFL and vismodegib combination mirrored the effects of vismodegib monotherapy (Gli1, p = 0.424; Gli2, p = 0.289; Ptch1, p = 0.593), possibly due to comparable cutaneous vismodegib concentrations (mean ± SD, vismodegib monotherapy 850 ± 475 µmol/L; combination 1036 ± 824 µmol/L; p = 0.573). In conclusion, a single AFL treatment significantly reduced hedgehog gene expression in murine BCCs mimicking the effects of eight topical applications of vismodegib. Further studies are needed to assess whether AFL can be utilized for BCC treatment, either as monotherapy or in combination with other drugs.