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During liver fibrogenesis, the reciprocal crosstalk among capillarized liver sinusoidal endothelial cells (LSECs), activated hepatic stellate cells (HSCs), and dysfunctional hepatocytes constructs a self-amplifying vicious cycle, greatly exacerbating the disease condition and weakening therapeutic effect. Limited by the malignant cellular interactions, the previous single-cell centric treatment approaches show unsatisfactory efficacy and fail to meet clinical demand. Herein, a vicious cycle-breaking strategy is proposed to target and repair pathological cells separately to terminate the malignant progression of liver fibrosis. Chondroitin sulfate-modified and vismodegib-loaded nanoparticles (CS-NPs/VDG) are designed to efficiently normalize the fenestrae phenotype of LSECs and restore HSCs to quiescent state by inhibiting Hedgehog signaling pathway. In addition, glycyrrhetinic acid-modified and silybin-loaded nanoparticles (GA-NPs/SIB) are prepared to restore hepatocytes function by relieving oxidative stress. The results show successful interruption of vicious cycle as well as distinct fibrosis resolution in two animal models through multiregulation of the pathological cells. This work not only highlights the significance of modulating cellular crosstalk but also provides a promising avenue for developing antifibrotic regimens., (© 2024 Wiley‐VCH GmbH.)

The long non-coding RNA HOTAIR and the Hedgehog-Gli1 signaling pathway are closely associated with tumor occurrence and drug resistance in various cancers. However, their specific roles in the development of EGFR-TKIs resistance in non-small cell carcinoma remain unclear. To address the issue of EGFR-TKIs resistance, this study utilized the electrospray method to prepare sodium alginate microspheres encapsulating HOTAIR siRNA (SA/HOTAIR siRNA) and investigated its effects on RNA interference (RNAi) in the gefitinib-resistant cell line PC9/GR. Furthermore, the study explored whether HOTAIR could modulate EGFR-TKIs resistance through the Hedgehog-GLi1 signaling pathway. The experimental results showed that sodium alginate (SA) microspheres demonstrated excellent biocompatibility with high encapsulation efficiency and drug-loading capacity, effectively enhancing the silencing efficiency of siRNA. HOTAIR siRNA significantly inhibited the proliferation, migration, and invasion abilities of PC9/GR cells while promoting apoptosis. Additionally, HOTAIR siRNA effectively suppressed tumor growth and downregulated the Hedgehog-GLi1 pathway and anti-apoptotic proteins, which were confirmed in animal experiments. Moreover, SA/HOTAIR siRNA exhibited superior inhibition of cellular and tumor functions compared to using HOTAIR siRNA alone. Clinical research findings indicated that monitoring the expression level of HOTAIR in the serum and urine samples of NSCLC patients before and after receiving EGFR-TKIs treatment can predict the efficacy of EGFR-TKIs to a certain extent. This study provided evidence that HOTAIR siRNA effectively mitigated the development of acquired resistance to EGFR-TKIs by inhibiting the Hedgehog-GLi1 pathway. Furthermore, it introduced a reliable and long-lasting drug delivery system for combating acquired resistance to EGFR-TKIs., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs., Methods: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO 2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3)., Results: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure., Conclusion: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions., (© 2024 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.)

Sonic Hedgehog (SHH) subgroup of medulloblastoma (MB) accounts for about 25% of all subgroups of MB. Tumor microenvironment (TME) may play a key role in the tumor progression and therapeutic resistance. Tumor-associated astrocytes (TAAs) are reshaped to drive tumor progression through multiple paracrine signals. However, the mechanism by which TAAs modulate MB cells remains elusive. Here, we illuminated that TAAs showed a specific and dynamic pattern during SHH-MB development. Most TAAs gathered to the tumor margin during the tumor progression, rather than evenly distributed in the early-stage tumors. We further demonstrated that lipocalin-2 (LCN2) secreted by TAAs could promote the tumor growth and was correlated with the poor prognosis of MB patients. Knocking down LCN2 in TAAs in vitro impeded the proliferation and migration abilities of MB cells. In addition, we identified that TAAs accelerated the tumor growth by secreting LCN2 via STAT3 signaling pathway. Accordingly, blockade of STAT3 signaling by its inhibitor WP1066 and AAV-Lcn2 shRNA, respectively, in TAAs abrogated the effects of LCN2 on tumor progression in vitro and in vivo. In summary, we for the first time clarified that LCN2, secreted by TAAs, could promote MB tumor progression via STAT3 pathway and has potential prognostic value. Our findings unveiled a new sight in reprogramming the TME of SHH-MB and provided a potential therapeutic strategy targeting TAAs., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Purpose: Periocular locally advanced basal cell carcinoma (POLA-BCC) is characterized by orbital involvement and/or extensive invasion of periocular structures. Hedgehog pathway inhibitors have been used for POLA-BCC with promising outcomes., Methods: The authors reviewed 11 articles published in English literature from January 2012 to July 2022 and reported the outcomes of patients with POLA-BCC who were treated with vismodegib., Results: A total of 384 patients were treated with vismodegib. The mean age was 72 years, and the median treatment duration was 9 months. The overall response rate was 75% with a median follow-up time of 14.4 months. Following vismodegib treatment, the median number of patients who required adjuvant surgery was 43% with a median time to surgery of 6.5 months. The exenteration rate was 6% (overall 8 patients). In total 93.7% of patients experienced grade I adverse events, 26.7% to 37.5% grade II, 8.8% to 10% grade III-IV, and 0.8% to 4.8% grade V. Major side effects included dysgeusia (30-100%), muscle spasm (15-100%), alopecia (47-75%), weight loss (23-83%), and decreased appetite (19-42%). The median percentage of patients who discontinued treatment due to toxicity was 29% with a median interval of 5 months before the development of side effects. The median recurrence rate following discontinuation of vismodegib was 7.8% with a median recurrence duration of 20 months., Conclusions: In patients with POLA-BCC, vismodegib, a hedgehog pathway inhibitor, provided high rates of orbital preservation, reducing exenteration rates to 6%. Neoadjuvant therapy with vismodegib can also be suggested for patients with POLA-BCC. While extremely effective, side effects lead to temporary or permanent discontinuation of vismodegib in small numbers of patients., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2023 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC., Materials and Methods: This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling., Results: A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS., Conclusion: NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

The self-renewing cancer stem cells (CSCs) represent one of the distinct cell populations occurring in a tumour that can differentiate into multiple lineages. This group of sparsely abundant cells play a vital role in tumour survival and resistance to different treatments during cancer. The lack of exclusive markers associated with CSCs makes diagnosis and prognosis in cancer patients extremely difficult. This calls for the identification of unique regulators and markers for CSCs. Various signalling pathways like the Wnt/β-catenin pathway, Hedgehog pathway, Notch pathway, and TGFβ/BMP play a major role in the regulation and maintenance of CSCs. Epigenetic regulatory mechanisms add another layer of complexity to control these signalling pathways. In this chapter, we discuss about the role of epigenetic mechanisms in regulating the cellular signalling pathways in CSCs. The epigenetic regulatory mechanisms such as DNA methylation, histone modification and microRNAs can modulate the diverse effectors of signalling pathways and consequently the growth, differentiation and tumorigenicity of CSCs. In the end, we briefly discuss the therapeutic potential of targeting these epigenetic regulators and their target genes in CSCs., (Copyright © 2024. Published by Elsevier Inc.)

Therapeutic antibodies have shown little efficacy in the treatment of pancreatic ductal adenocarcinomas (PDAC). Tumor desmoplasia, hypovascularity, and poor perfusion result in insufficient tumor cell exposure, contributing to treatment failure. Smoothened inhibitors of hedgehog signaling (sHHi) increase PDAC tumor permeability, perfusion, and drug delivery, and provide a tool to develop a quantitative, mechanistic understanding as to how the temporal dynamics of tumor priming can impact intratumor distribution of monoclonal antibodies (mAb). A linked pharmacokinetic (PK)/pharmacodynamic (PD) model was developed to integrate the plasma and tumor PK of a sHHi priming agent with its effects upon downstream stromal biomarkers Gli1, hyaluronic acid, and interstitial fluid pressure in PDAC patient-derived xenograft (PDX) tumors. In parallel, in situ tumor concentrations of cetuximab (CTX: anti-epidermal growth factor receptor; EGFR) were quantified as a marker for tumor delivery of mAb or antibody-drug conjugates. A minimal, physiologically-based pharmacokinetic (mPBPK) model was constructed to link sHHi effects upon mechanistic effectors of tumor barrier compromise with the intratumor distribution of CTX, and CTX occupancy of EGFR in tumors. Integration of the mPBPK model of mAb deposition and intratumor distribution with the PK/PD model of tumor responses to priming not only identified physiological parameters that are critical for tumor antibody distribution, but also provides insight into dosing regimens that could achieve maximal tumor disposition of therapeutic antibodies under conditions of transient PDAC tumor permeability barrier compromise that mechanistically-diverse tumor priming strategies may achieve., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Rheumatoid arthritis (RA) displays very similar characteristics to those of tumor cells, platycodin D (PD) is a triterpenoid saponin abundant in Platycodon grandiflorum (PG), plays an important role in the inhibition of tumor growth. Our previous experiments confirmed that PD inhibited MH7A cell proliferation and migration, but it's possible mechanism remain unclear. This study aimed to reveal the mechanism of PD on RA, based on network pharmacology analysis. Rat of CIA was treated with the different doses PD. The arthritis score and paw volume were evaluated, ankle imaging changes were observed via myosseous ultrasound, all rats were anaesthetized by intraperitoneal injection of 25% urethane (1 mL/100 g), and ankle histopathology was observed using hematoxylin and eosin (HE) staining. Cell (MH7A) Counting Kit 8 (CCK8) was used to measure cell activity, and JC-1 assay kit and flow cytometry were employed to examine the cell mitochondrial membrane potential and apoptosis. The expression levels of Sonic hedgehog (Shh) signaling pathway-related proteins were observed by Western blotting. Cell inflammation levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 being determined via enzyme-linked immunoassay ELISA and q-PCR. In total, the saponin PD significantly improves joint synovium inflammation and apoptosis in CIA rats. The activity of administered MH7A was significantly inhibited, the mitochondrial membrane potential decreased, the expression level of the Shh signaling pathway-related protein SuFu increased, the expression levels of SHh and Gli decreased, and cell serum levels of TNF-a and IL-6 decreased significantly. Therefore, PD exhibits therapeutic potential for synovial hyperplasia in RA.

Basal cell carcinoma (BCC) is the most common form of cancer, with a high impact on the public health burden and social costs. Despite the overall prognosis for patients with BCC being excellent, if lesions are allowed to progress, or in a small subset of cases harboring an intrinsically aggressive biological behavior, it can result in local spread and significant morbidity, and conventional treatments (surgery and radiotherapy) may be challenging. When a BCC is not amenable to either surgery or radiotherapy with a reasonable curative intent, or when metastatic spread occurs, systemic treatments with Hedgehog inhibitors are available. These guidelines were developed, applying the GRADE approach, on behalf of the Italian Association of Medical Oncologists (AIOM) to assist clinicians in treating patients with BCC. They contain recommendations with regard to the diagnosis, treatment and follow-up, from primitive tumors to those locally advanced or metastatic, addressing the aspects of BCC management considered as priorities by a panel of experts selected by AIOM and other national scientific societies. The use of these guidelines in everyday clinical practice should improve patient care., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Natural products (NPs) are highly profitable pharmacological tools due to their chemical diversity and ability to modulate biological systems. Accessing new chemical entities while retaining the biological relevance of natural chemotypes is a fundamental goal in the design of novel bioactive compounds. Notably, NPs have played a crucial role in understanding Hedgehog (HH) signalling and its pharmacological modulation in anticancer therapy. However, HH antagonists developed so far have shown several limitations, thus growing interest in the design of second-generation HH inhibitors. Through smart manipulation of the NPs core-scaffold, unprecedented and intriguing architectures have been achieved following different design strategies. This study reports the rational design and synthesis of a first and second generation of anthraquinone-based hybrids by combining the rhein scaffold with variously substituted piperazine nuclei that are structurally similar to the active portion of known SMO antagonists, the main transducer of the HH pathway. A thorough functional and biological investigation identified RH2_2 and RH2_6 rhein-based hybrids as valuable candidates for HH inhibition through SMO antagonism, with the consequent suppression of HH-dependent tumour growth. These findings also corroborated the successful application of the NPs-based hybrid design strategy in the development of novel NP-based SMO antagonists., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

Drug resistance underpins poor outcomes in many malignancies including refractory and relapsed acute myeloid leukemia (R/R AML). Glucuronidation is a common mechanism of drug inactivation impacting many AML therapies, e.g., cytarabine, decitabine, azacytidine and venetoclax. In AML cells, the capacity for glucuronidation arises from increased production of the UDP-glucuronosyltransferase 1A (UGT1A) enzymes. UGT1A elevation was first observed in AML patients who relapsed after response to ribavirin, a drug used to target the eukaryotic translation initiation factor eIF4E, and subsequently in patients who relapsed on cytarabine. UGT1A elevation resulted from increased expression of the sonic-hedgehog transcription factor GLI1. Vismodegib inhibited GLI1, decreased UGT1A levels, reduced glucuronidation of ribavirin and cytarabine, and re-sensitized cells to these drugs. Here, we examined if UGT1A protein levels, and thus glucuronidation activity, were targetable in humans and if this corresponded to clinical response. We conducted a phase II trial using vismodegib with ribavirin, with or without decitabine, in largely heavily pre-treated patients with high-eIF4E AML. Pre-therapy molecular assessment of patients' blasts indicated highly elevated UGT1A levels relative to healthy volunteers. Among patients with partial response, blast response or prolonged stable disease, vismodegib reduced UGT1A levels, which corresponded to effective targeting of eIF4E by ribavirin. In all, our studies are the first to demonstrate that UGT1A protein, and thus glucuronidation, are targetable in humans. These studies pave the way for the development of therapies that impair glucuronidation, one of the most common drug deactivation modalities. Clinicaltrials.gov: NCT02073838.

Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib ( n = 6) or vismodegib ( n = 4) between March 2012 and March 2022. We analyzed the activity, toxicity, and duration of the response to oral hedgehog inhibitors. The number of new tumors that developed prior to treatment or after treatment as well as the time of response and durability of responses were assessed. All patients achieved a complete remission. With a 30.7 ± 48.4-month median follow-up, the drug treatment significantly reduced the number of new basal cell cancers from a mean of 28.3 ± 24.6 prior to treatment to a mean of 1.4 ± 2.0 during treatment ( p = 0.0048). The median time to develop a new basal cell cancer was 47.3 months. Three patients eventually developed localized recurrences. After resection, ongoing treatment suppressed the development of additional lesions. One patient developed numerous new drug-resistant basal cell cancers and died of acute leukemia. Six patients required treatment modifications for toxicity. Sustained hedgehog inhibitor treatment can suppress the progression of both new and existing basal cell carcinomas for an extended period. Drug administration schedule adjustments improved tolerance without altering efficacy, potentially contributing to a prolonged response duration.

Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.

Background: Basal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment., Objective: To describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile., Methods: We conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected., Results: A total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24h and 48h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect., Conclusion: Sonidegib shows good effectiveness and acceptable safety profile in usual clinical practice., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction: Sonidegib and vismodegib are currently the only US Food and Drug Administration and European Medicines Agency-approved small-molecule Hedgehog pathway inhibitors (HHIs)for treating adults with advanced or refractory basal cell carcinoma (BCC) that is not amenable to conventional surgery or radiotherapy. At this time, there are no head-to-head clinical trials comparing these two HHIs for efficacy and safety to assist clinicians with determining which HHI may be best suited for their patients., Areas Covered: This review briefly describes the pathogenesis of BCC, provides a detailed overview of the key pharmacokinetic profile differences between sonidegib and vismodegib, explains their pharmacodynamics, and highlights the therapeutic considerations when either HHI is used to treat special patient populations., Expert Opinion: Although both HHIs act at the same molecular target in the Hedgehog pathway, there are significant differences in their pharmacokinetic profiles that may play a potential role in their efficacy and safety. Evidence-based recommendations serve to inform clinicians until direct comparative clinical trials of sonidegib versus vismodegib are conducted to determine the clinical relevance of the reported differences in their pharmacokinetic properties.

Background: Basal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment., Objective: To describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile., Methods: We conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected., Results: A total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24 h and 48 h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect., Conclusion: Sonidegib shows good effectiveness and acceptable safety profile in usual clinical practice., (Copyright © 2023 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Sex differences affect the occurrence, progression and regression of subarachnoid haemorrhage (SAH). Oestrogen plays a protective role in alleviating the vasospasm and neuronal apoptosis induced by SAH. However, whether oestrogen affects blood‒brain barrier (BBB) integrity has not been fully studied. Oestrogen has been found to regulate the sonic hedgehog (SHH) signalling pathway through the oestrogen receptor in gastric cancer and adrenal glands, and the SHH signalling pathway has an important role in maintaining the BBB by upregulating the expression of tight junction proteins. In this study, we investigated the relationship between oestrogen and the SHH signalling pathway using clinical data and established an experimental SAH model to explore whether oestrogen could ameliorate BBB damage after SAH through the SHH pathway., Methods: Correlations between oestrogen and the SHH pathway were analysed by patients' cerebrospinal fluid (CSF) samples and the Genotype-Tissue Expression database (GTEx). Then, an experimental rat SAH model was established using the endovascular perforation method and treated with oestrogen, oestrogen inhibitors and SHH signalling pathway inhibitors. Then, the effects of oestrogen on BBB damage were analysed by western blot, immunofluorescence and neurobehavioural experiments., Results: ESLIA detection and correlation analysis showed that oestrogen levels in patients' CSF were positively correlated with the SHH pathway, which was further verified by GTEx gene-correlation analysis. SHH was found to be mainly expressed in neurons and astrocytes in rats under physiological conditions and was upregulated by oestrogen pretreatment. In the SAH model, oestrogen pretreatment was found to reverse SAH-induced decreases in the SHH pathway, which were counteracted by oestrogen receptor inhibitors. Furthermore, oestrogen pretreatment reduced SAH-induced BBB damage, brain oedema and neurological dysfunction, which were eliminated by SHH pathway inhibitors., Conclusion: In conclusion, we demonstrate here that oestrogen pretreatment ameliorates brain injury after SAH, at least in part through SHH pathway-mediated BBB protection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Recently, several new therapies have emerged to address locally advanced cutaneous basal cell and squamous cell carcinomas. Given the constraints of the ocular adnexa and orbit, this review was designed to discuss the role of these modalities in this region., Methods: A PubMed search was carried out to analyze the utility of United States Food and Drug Administration-approved therapies to address these malignancies. The data presented in the identified investigations were analyzed and abstracted., Results: Multiple novel interventions may be useful in the management of periocular cutaneous basal cell and squamous cell carcinomas, including imiquimod, hedgehog inhibitors, and immunotherapy. While many of these treatments have not been specifically explored in the orbit and ocular adnexa, the literature generally shows favorable response rates. However, adverse events were common in these studies., Conclusions: Several novel treatments may address periorbital cutaneous malignancies, and these therapies may be particularly useful in patients with unresectable disease and those who are poor surgical candidates.

Purpose: To establish a model to predict treatment outcome of periocular locally advanced basal cell carcinoma (POLA BCC) based on initial response to treatment with vismodegib (Erivedge TM ), a sonic hedgehog inhibitor., Design: Subgroup analysis of data from the STEVIE study database., Methods: Analysis of medical history, treatment protocol, and treatment outcome of POLA BCC tumours in a STEVIE study population of 244 POLA BCC patients treated with ≥1 dose of vismodegib., Results: A predictive model for complete response (CR) was established based on the initial treatment response. A cutoff value of 20% reduction in tumour size at 3 months of treatment identified the patients with a high probability (82.76%) to achieve CR. A second cutoff value of 67.7% reduction in tumour size at 6 months of treatment improved the prediction to a 95.42% probability of a CR outcome., Conclusions: A treatment model was constructed based on the prediction of a CR outcome and the initial response to vismodegib treatment at 3 and 6 months. The study result provide significant new insights can facilitate decision-making on treatment management according to tumour response in patients with POLA BCC., (© 2022. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Background: Medulloblastoma (MB) is a heterogeneous disease, displaying distinct genetic profiles, with specific molecular subgroups. Various clinical, pathological and molecular variables have been associated with disease outcome and therefore utilised in risk stratification of patients., Objectives: To perform molecular classification of medulloblastoma using surrogate immunohistochemistry (IHC) and associate molecular subgroups, histopathological types, and available clinicopathological parameters with overall survival (OS) of MB patients., Results: This study included 65 medulloblastoma patients. Immunohistochemical staining, using β-catenin YAP1 and GRB2-Associated Binding Protein 1 (GAB1) antibodies was used to classify MB cases into wingless signalling (WNT) activated, sonic hedgehog (SHH) activated, and non-WNT/non-SHH molecular subgroups. The relevant statistical analysis was done using GraphPad Prism version 9.3.0. Histological patterns included classic (40 cases, 62%), desmoplastic nodular (D/N) (14 cases, 22%), large cell/anaplastic (LC/A) (9 cases, 13%), medulloblastoma with extensive nodularity (MBEN) (1 case, 1.5%) and one special subtype, i.e., medulloblastoma with myogenic and melanotic differentiation. Molecular subgroups included WNT (4 cases, 6%), SHH (34 cases, 52%), and non-WNT/non-SHH (27 cases, 42%) subgroups. Histopathological types differed significantly according to tumor location, degree of anaplasia and molecular subgroups. Molecular subgroups differed significantly in age distribution and tumor location. The probability of survival was 78% and 68% after 1 and 2 years, respectively. Infants (<3 years of age), LC/A pattern, and TP53-mutant status among SHH subgroup conferred poor prognosis in our study. At the end of the study (at 65 months of maximum follow-up period) probability of survival was 51%., Conclusions: Immunohistochemical analysis helps in molecular classification of medulloblastoma in majority of the cases as well as helps in predicting prognosis and treatment response., (Copyright © 2023 Copyright: © 2023 Journal of Cancer Research and Therapeutics.)

Background: Advanced basal cell carcinoma (aBCC) represents a complex and clinically heterogeneous group of lesions for which curative surgery and/or radiotherapy is unlikely. Systemic therapy with hedgehog pathway inhibitors (HHIs) changed the treatment landscape for this complex patient population., Objectives: The aims of the present study are to describe the clinical characteristics of a real-life Italian cohort diagnosed with aBCC and to investigate effectiveness and safety of HHI., Methods: A multicenter observational study was performed by twelve Italian centers in the period January 1, 2016 - October 15, 2022. Patients aged ≥18 years and diagnosed with aBCC (locally advanced [laBCC] and metastatic BCC [mBCC]) were eligible for the study. Methods for investigating tumor response to HHI included clinical and dermatoscopic evaluation, radiological imaging, and histopathology. For HHI safety assessment, therapy-related adverse events (AEs) were reported and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0., Results: We enrolled 178 patients under treatment with HHI: 126 (70.8%) and 52 patients (29.2%) received sonidegib and vismodegib, respectively. Comprehensive data on HHI effectiveness and disease outcome were available for 132 (74.1%) of 178 patients: 129 patients had a diagnosis of laBCC (n = 84, sonidegib; n = 45, vismodegib) and 3 patients of mBCC (n = 2, vismodegib; n = 1, sonidegib, off-label). Objective response rate was 76.7% (95% confidence interval [CI]: 82.3-68.7) and 33.3% (95% CI: 88.2-1.7) for laBCC (complete response [CR]: 43/129; PR: 56/129) and mBCC (CR: 0/3; PR: 1/3), respectively. High-risk aBCC histopathological subtypes and occurrence of &gt;2 therapy-related AEs were significantly associated with nonresponse to HHI therapy ([OR: 2.61; 95% CI: 1.09-6.05; p: 0.03] and [OR: 2.74; 95% CI: 1.03-7.9; p: 0.04]), respectively. Majority of our cohort (54.5%) developed at least 1 therapy-related AE, most of which were mild-moderate in severity., Conclusions: Our results demonstrate the effectiveness and safety profile of HHI and confirm the reproducibility of pivotal trial results in real-life clinical setting., (© 2023 S. Karger AG, Basel.)

Background: Vismodegib is a first-in-class inhibitor of the hedgehog pathway for treatment of locally advanced basal cell carcinoma (laBCC) and metastatic BCC., Objectives: The purpose of this study is to report outcomes of patients with laBCC, with basal cell carcinoma nevus syndrome (Gorlin Goltz syndrome [G-G Syn]) treated with vismodegib in routine clinical practice in Slovenia in 8.3-year period., Methods: In this retrospective cohort study, we analyzed baseline characteristics, outcomes, and treatment-related adverse events from locally advanced BCC. The patients were divided into two cohorts: 39 laBCC or multiple BCC patients and 7 patients with G-G Syn who were treated with vismodegib from November 2012 till January 2021., Results: During 100-month period, 46 patients were diagnosed with laBCC (26), multiple BCC (13), and G-G Syn (7), all inappropriate for surgery or radiotherapy. Baseline characteristics: median age was 72.8 years in laBCC + multiple BCC cohort and 47.4 years in G-G Syn cohort. The objective response rate was 80% in laBCC + multiple BCC and 86% in G-G Syn cohort. Disease control rate (DCR) was 95% in laBCC + multiple BCC and 100% in G-G Syn cohort. Median duration of treatment was 9.9 months (range: 1.5-43.1) in laBCC and multiple BCC cohort and 19.5 months (range: 3.6-94.1) in G-G Syn cohort. Majority of treatment-emergent adverse events (TEAEs) in laBCC or multiple BCC cohort were grade 1 or 2 (96%), only 4% of AEs were grade 3. Majority of TEAEs in G-G Syn cohort were also grade 1 or 2 (87%), 13% of AEs were grade 3. No grade 4 or 5 vismodegib-related AEs were reported., Conclusion: Vismodegib has shown meaningful efficacy with DCR from 95% to 100% in patients with laBCC, multiple BCC, and G-G Syn in Slovenia. TEAEs were successfully alleviated with multidisciplinary approach and early supportive care., (© 2022 The Author(s) Published by S. Karger AG, Basel.)

Advanced nonmelanoma skin cancers (NMSC) are tumors not amenable to surgery and/or radiation. Early systemic treatment attempts with cytotoxic chemotherapy demonstrated low response rates, short durations of response, and high toxicity. Over the last decade, modern therapies for advanced NMSC include targeted therapies and immunotherapies. Hedgehog pathway inhibitors and programmed death-1 inhibitors are available first-line therapies for the treatment of advanced basal cell carcinomas and squamous cell carcinomas, respectively., Competing Interests: Disclosure of interest M. R Migden has participated on advisory boards and received honoraria from Regeneron Pharmaceuticals, Inc., Sun Pharmaceuticals, and Sanofi; advisory role with Rakuten Medical. The authors have no other 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 article apart from those disclosed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by many cytogenetic and molecular alterations. Due to better knowledge of the molecular basis of AML, many targeted therapies have been introduced and registered, e.g. FMS-like tyrosine kinase 3 inhibitors, isocitrate dehydrogenase 1/2 mutation inhibitors, and Bcl-2 inhibitor. Despite that, the cure for AML remains an unmet clinical need in most patients., Areas Covered: The review aims to present new, not yet registered drugs for AML. We searched the English literature for articles concerning AML, targeted drugs, menin inhibitors, DOT1L, BET, IDH inhibitors, FLT3, hedgehog inhibitors, Polo-like kinase inhibitors, RNA splicing, and immune therapies via PubMed. Publications from January 2000 to August 2022 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles and Google search. Conference proceedings from the previous 5 years of The American Society of Hematology, the European Hematology Association, and the American Society of Clinical Oncology were searched manually. Additional relevant publications were obtained by reviewing the references., Expert Opinion: For several years, the therapeutic approach in AML has become more individualized. Novel groups of drugs give hope for greater curability. High response rates have agents that restore the activity of the p53 protein. In addition, agents that work independently of a particular mutation seem promising for AML without any known mutation.

Background: Basal cell carcinoma (BCC) is the most common human malignancy. In most cases, BCC has slow progression and can be definitively cured by surgery or radiotherapy. However, in rare cases, it can become locally advanced or, even more rarely, metastatic. The alternative recommended treatments are Sonic Hedgehog pathway inhibitors; however, the response is often short-lived., Methods: This was a phase 2 basket study (NCT03012581) evaluating the efficacy and safety of nivolumab in a cohort of 32 advanced BCC patients, enrolled after failure of Sonic Hedgehog inhibitors, including 29 laBCC (91%) and 3 mBCC (9%)., Results: Compared to previously published studies, our population consisted of severe patients with a poor prognosis because they had already received multiple lines of treatment: all patients received previous Sonic Hedgehog inhibitors, 53% of patients already had chemotherapy and 75% radiotherapy. At 12 weeks, we reported 3.1% of complete responses, 18.8% of partial responses, and 43.8% of stable diseases. The best response rate to nivolumab reached 12.5% of complete responses (four patients), 18.8% of partial responses (three patients), and 43.8% of stable diseases (14 patients). Adverse events (AE) were mostly grade 2 or 3, slightly different to the adverse events observed in the treatment of metastatic melanoma (higher rate of diabetes, no thyroid dysfunction)., Conclusion: Nivolumab is a relevant therapeutic option for patients with advanced relapsing/refractory BCC., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Caroline Gaudy Marquestre has declared payment for lectures/presentations/writings from BMS and MSD, and support for attending meetings from MSD, BMS and Jansen. Aurelien Marabelle has declared support for the present manuscript from Unicancer and Gustave Roussy Institute, grants or contract from BMS, MSD and Sanofi, consulting fees from Sanofi, payment for lectures/presentations/writings from BMS and MSD, support for attending meetings from BMS and MSD, participation on Advisory Board with MSD, have leadership role in the board of the French Immune-Therapy for Cancer scholar society. Marie Beylot-Barry has declared payment for lectures/presentations/writings from Sun Pharma. Nicole Basset-Seguin has declared consulting fees from Regeneron/Sanofi and Sun Pharma, payments for lectures/presentations/writings from Regeneron/Sanofi and Sun Pharma, support for attending meetings from Regeneron/Sanofi and Sun Pharma, and have participated on Advisory Board for Regeneron/Sanofi and Sun Pharma. Philippe Saiag has declared consulting fees from BMS outside the topic of this study. Philippe Jamme has declared consulting fees from BMS, support for attending meetings from Pierre Fabre, and have participated on Advisory Board with Pierre Fabre, BMS and Novartis. Celeste Lebbe has declared support for the present manuscript from Amgen, BMS, Merck Serono, MSD, Novartis, Pierre Fabre, Roche and Sanofi; she have declared consulting fees from Amgen, BMS, MSD, Novartis and Roche; payments for lectures/presentations/writings from Amgen, BMS, MSD, Novartis, Pfizer, Pierre Fabre, Roche; payment for expert testimony form Amgen, BMS, MSD, Novartis, Roche; support for attending meetings from BMS, MSD, Novartis, Pierre Fabre, Sanofi. Laurent Mortier has provided time for consulting and participation to scientific advisory boards of the following compagnies: Sun pharma, Novartis, Pierre Fabre and MSD, and have participated in congress with the same companies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. MB is classified into four primary molecular subgroups: wingless (WNT), sonic hedgehog (SHH), Group 3 (G3), and Group 4 (G4), and further genomic and proteomic subtypes have been reported. Subgroup heterogeneity and few actionable mutations have hindered the development of targeted therapies, especially for G3 MB, which has a particularly poor prognosis. To identify novel therapeutic targets for MB, we performed mass spectrometry-based deep expression proteomics and phosphoproteomics in 20 orthotopic patient-derived xenograft (PDX) models of MB comprising SHH, G3, and G4 subgroups. We found that the proteomic profiles of MB PDX tumors are closely aligned with those of primary human MB tumors illustrating the utility of PDX models. SHH PDXs were enriched for NFκB and p38 MAPK signaling, while G3 PDXs were characterized by MYC activity. Additionally, we found a significant association between actinomycin D sensitivity and increased abundance of MYC and MYC target genes. Our results highlight several candidate pathways that may serve as targets for new MB therapies. Mass spectrometry data are available via ProteomeXchange with identifier PXD035070.

Background: Cavernous nerve (CN) injury causes penile remodeling, including smooth muscle apoptosis and increased collagen, which results in erectile dysfunction (ED), and prevention of this remodeling is critical for novel ED therapy development., Aim: We developed 2 peptide amphiphile (PA) hydrogel delivery vehicles for Sonic hedgehog (SHH) protein to the penis and CN, which effectively suppress penile distrophic remodeling (apoptosis and fibrosis), in vivo in a rat CN injury model, and the aim of this study is to determine if SHH PA can be used to regenerate human corpora cavernosal smooth muscle deriving from multiple ED origins., Methods: Corpora cavernosal tissue was obtained from prostatectomy, diabetic, hypertension, cardiovascular disease and Peyronie's (control) patients (n = 21). Primary cultures (n = 21) were established, and corpora cavernosal cells were treated with SHH protein, MSA (control), 5E1 SHH inhibitor, and PBS (control). Growth was quantified by counting the number of cells at 3-4 days. Statistics were performed by ANOVA with Scheffe's post hoc test. Concentration of SHH protein for maximal growth was optimized, and a more active SHH protein examined., Outcomes: Cultures were characterized by immunohistochemical analysis with ACTA2, CD31, nNOS and P4HB, and smooth muscle was quantified in comparison to DAPI., Results: Cultures established were >97% smooth muscle. SHH protein increased growth of smooth muscle cells from prostatectomy, diabetic, and Peyronie's patients in a similar manner (49%-51%), and SHH inhibition decreased growth (20%-33%). There was no difference in growth using 25 ug and 10 ug SHH protein, suggesting a threshold concentration of SHH protein above which smooth muscle growth is enhanced. A more active lipid modified SHH peptide further enhanced growth (15%), indicating a more robust growth response. SHH increased growth in smooth muscle cells from hypertension (37%) and cardiovascular disease (32%) patients. SHH protein increased growth under normal and high glucose conditions, suggesting that high glucose conditions that may be present in under controlled diabetic patients would not detract from SHH regenerative capacity., Clinical Implications: SHH PA would be beneficial to enhance smooth muscle regeneration in patients with ED of multiple etiologies., Strengths and Limitations: Understanding how human corpora cavernosal tissue responds to SHH treatment is critical for clinical translation of SHH PA to ED patients., Conclusion: Corpora cavernosal smooth muscle from all ED patients responded to SHH treatment with increased growth. Stupp, SI. Sonic Hedgehog Signaling in Primary Culture of Human Corpora Cavernosal Tissue From Prostatectomy, Diabetic, and Peyronie's Patients. J Sex Med 2022;19:1228-1242., (Copyright © 2022 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

The sonic hedgehog (SHH) inhibitors vismodegib and sonidegib are the only 2 first-line systemic medications approved for the treatment of locally aggressive basal cell carcinoma (BCC). Vismodegib is the only SHH inhibitor approved for metastatic BCC. Cemiplimab, an immune checkpoint inhibitor (ICI), is now an approved second-line therapy for locally advanced or metastatic BCC. Efficacy and adverse effect profiles of vismodegib and sonidegib appear comparable, although head-to-head clinical trials have not been conducted. Despite the remarkable efficacy demonstrated by the 2 SHH inhibitors, adverse effects are common and often lead to treatment discontinuation. Alternative dosing schedules may help to manage these side effects, with recent approval of dose interruptions of up to 8 weeks. Given the high rate of recurrence and emerging concern regarding drug resistance, maintenance dosing regimens and potential synergism with other treatment modalities, such as radiotherapy or antifungal therapy, should be further explored. The use of SHH inhibitors in the neoadjuvant setting also is warranted, as it may allow for surgical management of previously inoperable cases of BCC.

In recent years, the category of hedgehog pathway inhibitor (HHI) has shown great results in patients with advanced basal cell carcinoma (aBCC), but few real-life data on efficacy and safety profile of sonidegib are available. We report our management of locally advanced BCCs (laBCCs) with sonidegib, also describing the favorable response of locally advanced basosquamous carcinomas (laBSCs) treated with this hedgehog signaling inhibitor. Sonidegib was generally well tolerated and it achieved high response rates, improving quality of life. Our single-center experience could be useful to better delineate long-term efficacy and tolerability profile demonstrated in the trials described in literature. Moreover, our cases provide preliminary evidence that sonidegib might be effective for laBSC., (© 2022 Wiley Periodicals LLC.)

It is now widely accepted that stem cells exist in various cancers, including lung cancer, which are referred to as cancer stem cells (CSCs). CSCs are defined in this context as the subset of tumor cells with the ability to form tumors in serial transplantation and cloning assays and form tumors at metastatic sites. Mouse models of lung cancer have shown that lung CSCs reside in niches that are essential for the maintenance of stemness, plasticity, enable antitumor immune evasion, and provide metastatic potential. Similar to normal lung stem cells, Notch, Wnt, and the Hedgehog signaling cascades have been recruited by the CSCs to regulate stemness and also provide therapy-driven resistance in lung cancer. Compounds targeting β-catenin and Sonic hedgehog (Shh) activity have shown promising anti-CSC activity in preclinical murine models of lung cancer. Understanding CSCs and their niches in lung cancer can answer fundamental questions pertaining to tumor maintenance and associated immune regulation and escape that appear important in the quest to develop novel lung cancer therapies and enhance sensitivity to currently approved chemo-, targeted-, and immune therapeutics., (Copyright © 2022 Cold Spring Harbor Laboratory Press; all rights reserved.)

As one of the most common malignancies, basal cell carcinoma (BCC) has evolved as a global burden with incidence annually rising, especially in the older population. Even though the condition is mostly localized, the nature of the disease is destructive and can evolve as either locally advanced BCC (laBCC) or even more rarely as metastatic BCC (mBCC). There are well-established conventional treatment options for these cases, including surgeries and radiotherapy. However, not all cases are eligible for conventional treatments. Recently, biologic treatment has gained a lot of attention and research. This has led to the development of targeted treatment involving the hedgehog pathway inhibitor (HPI), a key pathogenesis in laBCC and mBCC. There are currently two approved HPIs, vismodegib and sonidegib to treat inoperable laBCC and mBCC. This review seeks to explore the pathophysiology of hedgehog pathway behind the development of BCC, and the current update of the efficacy as well as pharmacokinetics properties of HPIs that led to the ideal treatment for laBCC or mBCC, either as monotherapy or in combination with other conventional therapies., (Copyright © 2022 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Most patients with advanced basal cell carcinomas (BCCs) may not benefit sufficiently from standard treatment comprising surgery and radiation. Vismodegib, an oral selective hedgehog pathway inhibitor, is approved for treatment of patients with locally advanced BCC inappropriate for surgery or radiotherapy, or for patients with symptomatic metastatic BCC. In order to enhance understanding of the effectiveness, safety and utilization of vismodegib in clinical practice in Germany, a non-interventional study, JONAS, was conducted. A total of 53 patients with locally advanced BCC who initiated treatment with vismodegib between 2016 and 2018 were included in the study, which was embedded in the German ADOReg skin cancer registry. Duration of response, the primary endpoint, was 12.4 months, progression-free survival 32.2 months and overall response rate 77.4%. Most adverse events were mild to moderate. Overall, results confirmed previous findings, demonstrating favourable responses and manageable safety of vismodegib in patients with locally advanced BCC in clinical practice.

The heterogeneous response of acute myeloid leukemia (AML) to current anti-leukemic therapies is only partially explained by mutational heterogeneity. We previously identified GPR56 as a surface marker associated with poor outcome across genetic groups, which characterizes two leukemia stem cell (LSC)-enriched compartments with different self-renewal capacities. How these compartments self-renew remained unclear. Here, we show that GPR56 + LSC compartments are promoted in a complex network involving epithelial-to-mesenchymal transition (EMT) regulators besides Rho, Wnt, and Hedgehog (Hh) signaling. Unexpectedly, Wnt pathway inhibition increased the more immature, slowly cycling GPR56 + CD34 + fraction and Hh/EMT gene expression, while Wnt activation caused opposite effects. Our data suggest that the crucial role of GPR56 lies in its ability to co-activate these opposing signals, thus ensuring the constant supply of both LSC subsets. We show that CDK7 inhibitors suppress both LSC-enriched subsets in vivo and synergize with the Bcl-2 inhibitor venetoclax. Our data establish reciprocal transition between LSC compartments as a novel concept underlying the poor outcome in GPR56 high AML and propose combined CDK7 and Bcl-2 inhibition as LSC-directed therapy in this disease., (©2022 The Authors. Published under the terms of the CC BY 4.0 license.)

Platinum-based chemotherapy is a widely used strategy for bladder cancer (BCa) treatment. However, its clinical efficacy is affected by chemotherapy resistance via complex molecular mechanisms. Therefore, there is an urgent need to explore new targets for BCa therapy. Here, we showed that bromodomain-4 protein (BRD4) expression is upregulated in BCa tissues and cells. Inhibition of BRD4 attenuated the migration and invasion of BCa cells, which was rescued by the Sonic hedgehog (SHH) pathway activator recombinant human Sonic hedgehog peptide (rhSHH). We further found that cisplatin (DDP) suppressed the migration and invasion of BCa cells in vitro and inhibited tumor growth in vivo. However, overexpression of BRD4 weakened the pharmacological effects of DDP. In brief, our research revealed that BRD4 promotes migration and invasion by positively regulating the SHH pathway, drives DDP resistance in BCa, and is a novel therapeutic target for the treatment of BCa.

Although the treatment of myocardial infarction (MI) has improved considerably, it is still a worldwide disease with high morbidity and high mortality. Whilst there is still a long way to go for discovering ideal treatments, therapeutic strategies committed to cardioprotection and cardiac repair following cardiac ischemia are emerging. Evidence of pathological characteristics in MI illustrates cell signaling pathways that participate in the survival, proliferation, apoptosis, autophagy of cardiomyocytes, endothelial cells, fibroblasts, monocytes, and stem cells. These signaling pathways include the key players in inflammation response, e.g., NLRP3/caspase-1 and TLR4/MyD88/NF-κB; the crucial mediators in oxidative stress and apoptosis, for instance, Notch, Hippo/YAP, RhoA/ROCK, Nrf2/HO-1, and Sonic hedgehog; the controller of myocardial fibrosis such as TGF-β/SMADs and Wnt/β-catenin; and the main regulator of angiogenesis, PI3K/Akt, MAPK, JAK/STAT, Sonic hedgehog, etc. Since signaling pathways play an important role in administering the process of MI, aiming at targeting these aberrant signaling pathways and improving the pathological manifestations in MI is indispensable and promising. Hence, drug therapy, gene therapy, protein therapy, cell therapy, and exosome therapy have been emerging and are known as novel therapies. In this review, we summarize the therapeutic strategies for MI by regulating these associated pathways, which contribute to inhibiting cardiomyocytes death, attenuating inflammation, enhancing angiogenesis, etc. so as to repair and re-functionalize damaged hearts., (© 2022. The Author(s).)

Non-melanoma skin cancers, also known as keratinocyte tumors, have an increasing incidence worldwide, with basal cell carcinoma and squamous cell carcinoma being the most represented ones. Although surgery represents the gold-standard treatment for both tumors, some cases can progress to an advanced or a metastatic state and targeted therapy is required. Hedgehog signaling pathway has an important role in the development of basal cell carcinoma, and its inhibition is the key to new treatment options available for the treatment of locally advanced and metastatic basal cell carcinoma. Cutaneous squamous cell carcinoma is the second most frequent malignant skin cancer; when presenting in advanced or metastatic stage, alternative treatments are required; cemiplimab is a human monoclonal antibody directed against programmed cell death-1 receptor that acts by blocking T-cell inactivation and is the first drug approved for the treatment of adult patients with metastatic or locally advanced cutaneous squamous cell carcinoma. Studies evaluating pembrolizumab, ipilimumab and nivolumab as alternative treatments for advanced squamous cell carcinoma are still underway. Objective of this review is to analyze and discuss the novel therapies for advanced basal cell carcinoma and squamous cell carcinoma to obtain a sharper perspective of the available treatment options., (© 2022. The Author(s).)

Background: Vismodegib is a novel Hedgehog pathway inhibitor that has revolutionized the treatment of patients with advanced basal cell carcinoma (BCC) who are poor candidates for surgery or radiation. Few studies have explored the use of vismodegib to facilitate further surgery or radiotherapy, and the optimal treatment duration to balance outcomes with adverse effects., Objectives: To characterize the disease response, progression, and recurrence outcomes of BCC patients, and to report the impact of subsequent therapies., Methods: We performed a retrospective study of 46 adult patients with advanced basal cell carcinoma (aBCC), including both locally advanced (laBCC) and metastatic (mBCC) disease, treated with vismodegib at a single center from 2012 to 2019., Results: Thirty-six had laBCC, and 10 had mBCC. Treatment was given over a mean of 21.9 months. Twenty-three (50%) had a complete response (CR), and 19 (41.3%) achieved partial response (PR). Median time to maximal response was 5.3 months. Eleven (23.9%) had resected disease at median 17.2 months, and 11 patients (23.9%) received radiotherapy. Thirty-two (69.6%) experienced progressive disease after achievement of CR or PR. Among 17 CR patients, who stopped treatment, 14 (82.3%) experienced subsequent relapse; 6 (85%) attained a repeat response. Twenty (43.5%) discontinued treatment at least once due to adverse effects., Conclusions: With a response rate of 91%, London Regional Cancer Center's (LRCP)'s experience with vismodegib supports its effectiveness in treatment of aBCC. Moreover, a significant number of patients treated with vismodegib became amenable to surgery or radiotherapy. Toxicity remained an important factor that limited treatment duration.

Basal cell carcinoma (BCC) is the most common cancer worldwide. While most BCC cases respond to surgical management, complex BCC often presents treatment challenges for patients unsuitable for, or refractory to, surgery and radiotherapy-limiting treatment options. Hedgehog pathway inhibitors (HHI) have emerged as an important treatment option for patients with complex BCC-providing a durable treatment modality and improved clinical outcomes. We present a case series of 10 patients with complex BCC treated with sonidegib, an oral HHI, at a dose of 200 mg once daily for a mean duration of 6 months and a mean follow-up of 7 months. Of these patients, sonidegib monotherapy was curative in eight cases. Of the remaining two patients, treatment with sonidegib arrested tumor progression and decreased tumor size to a point where surgical removal was straightforward. The positive treatment response we observed supports use of sonidegib as an effective treatment option for patients with complex BCC., (© 2021 The Authors. Dermatologic Therapy published by Wiley Periodicals LLC.)

Introduction: Vismodegib (Erivedge; Roche), a Hedgehog pathway inhibitor (HPI), is indicated for the treatment of symptomatic metastatic basal cell carcinoma (BCC) and locally advanced BCC inappropriate for surgery or radiotherapy. Due to the known risk of HPI teratogenicity, the Erivedge Pregnancy Prevention Program (PPP) was introduced at approval (2013) as part of the EU Risk Management Plan., Methods: Structured, quantitative Web-based surveys were conducted in 2015 (Wave 1), 2016 (Wave 2), and 2017/2018 (Wave 3) among prescribing oncologists and dermato-oncologists in Austria, France, Germany, Hungary, and the United Kingdom to assess the effectiveness of the Erivedge PPP., Results: Overall, 95%, 87%, and 91% of respondents in Waves 3 ( N  = 181), 2 ( N  = 214), and 1 ( N  = 207), respectively, were vismodegib prescribers. The surveys consistently showed a high awareness about the risk of teratogenicity associated with vismodegib (98%, Wave 3; 95%, Wave 2) and that a high proportion of prescribing physicians took appropriate precautions to minimize this risk (95%, Wave 3; 92%, Wave 2; 88%, Wave 1). Physicians were also highly aware of the Erivedge PPP (70%, Wave 3; 67%, Wave 2; 71%, Wave 1)., Conclusion: Survey data suggest that the risk of teratogenicity with vismodegib has been effectively communicated to the prescribing community.

Introduction: Basal cell carcinoma (BCC) is a cancer that arises from the basal layer of the epidermis and is most often caused by exposure to UV radiation. Most BCCs are localized and can be fully treated by surgical removal or topical treatment. In the last decade, it has been found that the hedgehog pathway, a signaling pathway that regulates embryonic development, has a pivotal role in the pathogenesis of BCC in adults. Therefore, two drugs that inhibit the hedgehog pathway have been developed. These drugs, indicated for metastatic or locally advanced BCC, may cause a rapid clinical and imaging response, but have an adverse reaction that includes muscle spasms, alopecia, dysgeusia and fatigue, and often leads to drug discontinuation. Due to the high rates of treatment discontinuation, the possibility of administering the drug intermittently was examined and, indeed, a decrease in adverse reactions together with tumor response was observed. Additionally, it seems that patients who discontinue treatment may benefit from long-term remission. These cases indicate the possibility of changing the schedule of administration of the drug. We hereby report two cases of patients who were treated with radiation therapy for ringworm in their childhood and developed BCC. The patients were treated with a hedgehog pathway inhibitor with complete tumor regression. After treatment was discontinued due to adverse reactions, no recurrence of the tumor was observed over a period of almost two years.

Background: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib., Materials and Methods: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment., Results: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months)., Conclusion: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms., Competing Interests: Disclosure EMN: Consulting or advisory role: Novartis, Pierre Fabre, Bristol-Myers Squibb, MSD. EM: Consulting or advisory role: MSD, Pierre Fabre, Novartis, Sanofi; research funding: MSD (Inst); travel, accommodations, expenses: MSD Oncology, Pierre Fabre, Novartis. NM: Consulting or advisory role or research funding: Bristol-Myers Squibb, MSD, Roche, Novartis, Pierre Fabre, Merck, Sanofi, Sun Pharmaceutical Industries. MB-B: Research funding: Roche; consulting or advisory role: Sun Pharmaceutical Industries. NB-S: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries. LM: Consulting or advisory role: Sanofi, Sun Pharmaceutical Industries, MSD Oncology, Bristol-Myers Squibb, Novartis. The remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Research has resulted in regulatory approval of nine agents for acute myeloid leukaemia indications by the US Food and Drug Administration since 2017: the Bcl-2 inhibitor, venetoclax; two FLT3 inhibitors, midostaurin and gilteritinib; two IDH inhibitors, ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor); the anti-CD33 antibody-drug conjugate, gemtuzumab ozogamicin; the oral, poorly absorbable hypomethylating agent, azacitidine; the liposomal formulation of cytarabine and daunorubicin (5:1 ratio), CPX-351; and the hedgehog signalling pathway inhibitor, glasdegib. A 100% absorbable oral formulation of the hypomethylating agent decitabine was approved for the treatment of myelodysplastic syndrome and chronic myelomonocytic leukaemia, and might be used as an alternative to parenteral hypomethylating agents. Several of the approvals are as single-agent therapies or in specific combinations for narrow indications, thus offering poor treatment value. In this Review, we discuss ongoing research into combinations containing these commercially available targeted therapies for acute myeloid leukaemia., Competing Interests: Declaration of interests HK reports research grants and honoraria from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Daiichi-Sankyo, Immunogen, Jazz Pharmaceuticals, Novartis, Pfizer, and Sanofi, and honoraria from Actinium (Advisory Board), Adaptive Biotechnologies, Aptitude Health, BioAscend, Delta Fly, Janssen Global, Oxford Biomedical, and Takeda Oncology. AW has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Celgene (Bristol Myers Squibb), Macrogenics, Agios, and Gilead Sciences, receives research funding from Novartis, AbbVie, Servier, Celgene (Bristol Myers Squibb), AstraZeneca, and Amgen, serves on speakers bureaus for AbbVie, Novartis, and Celgene, and receives royalty payments from the Walter and Eliza Hall Institute of Medical Research related to venetoclax. MT has served on advisory boards for AbbVie, Daiichi-Sankyo, Orsenix, Kahr, Delta Fly Pharma, Jazz Pharmaceuticals, Roche, Biosight, Novartis, Innate Pharmaceuticals, Kura Oncology, and Syros Pharmaceuticals, received research funding from AbbVie, Orsenix, Biosight, Glycomimetics, Rafael Pharmaceuticals, and Amgen, and received royalty from UpToDate. NJS has received consulting fees from Takeda Oncology and AstraZeneca, research funding from Takeda Oncology and Astellas Pharma, and honoraria from Amgen. ESW has served on advisory boards for AbbVie, Astellas, Celgene (Bristol Myers Squibb), Genentech, GlaxoSmithKline, Jazz Pharmaceuticals, Kite Pharmaceuticals, Kura Oncology, Novartis, Pfizer, Stemline, and Takeda, provided consulting for Mana Therapeutics, served as a speaker for Stemline, Kura Oncology, Pfizer, and Dava Oncology, and served on data safety monitoring committees for AbbVie and Rafael Pharmaceuticals. CDiN received research funding from AbbVie, Agios, Calithera, Cleave, Celgene (Bristol Myers Squibb), Daiichi-Sankyo, Forma, ImmuneOnc, and Loxo, consultancy fees from AbbVie, Agios, Aprea, Celgene/Bristol Myers Squibb, ImmuneOnc, and advisory board fees from Novartis, Aprea and Takeda. She is a scientific advisor with stock options from Notable Labs. AEP received research funding from AbbVie, Actinium Pharmaceuticals, Astellas, Daiichi-Sankyo, and FujiFilm, and received consultancy or advisory fees from AbbVie, Actinium Pharmaceuticals, Astellas, Celgene (Bristol Myers Squibb), Genentech, Daiichi-Sankyo, Loxo, Syndax, Sumitomo Dainippon, Forma, and Onconova. EMS received research funding from Agios, Celgene, Bristol Myers Squibb, Syndax, Syros, Bayer, and Biotheryx, and has served in a consulting or advisory role fees for Daiichi-Sankyo, Bristol Myers Squibb, Celgene, Agios, Novartis, AbbVie, Astellas, Genentech, Syndax, Gilead Sciences, Amgen, Foghorn, Neoleukin, Pinotbio, and Blueprint. ND has received research funding from Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Gilead Sciences, Sevier, Genentech, Astellas, AbbVie, Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen, and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead Sciences, Amgen, Shattuck Labs, and Agios. We declare no other competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Management of patients with locally advanced basal cell carcinoma (laBCC) with traditional strategies has yielded suboptimal outcomes. Targeted treatments including hedgehog inhibitor therapy (HHIT) present limitations when utilized as monotherapy. Herein, we report evidence-based outcomes from available literature on multimodality treatments adjuvant to HHIT in laBCC management. Utilizing a systematic search strategy in PubMed, we identified studies published from inception to April 15, 2020, screened for definitive inclusion/exclusion criteria, and performed individual study quality assessment and pooled analysis to assess impact of adjunctive treatment-based responses post-HHIT on clinical response and recurrence outcomes. Twenty-nine studies (n = 103) were included. Primary findings include a complete response (CR) rate of 90.5%, the median follow-up of 12 months post-HHIT completion. The recurrence rate was 10.8% with 12-month median time to recurrence. Mohs micrographic surgery (MMS) had 100% CR post-HHIT, while no difference was observed between surgery and radiation therapy (RT). MMS and surgery had comparable 2-year recurrence free rates (RFR) at 87% and 86% respectively, while RT had the lower 2-year RFR at 67%. Male gender portended a more advanced stage at diagnosis and worse outcomes. In a subset analysis, periorbital laBCCs with orbital involvement had a CR rate of 81.8% versus 100% in those without orbital involvement, with similar rates of recurrence. Limited available quantitative data and possible publication bias were limitations. Pooled analysis of observational data supports use of adjunctive therapies post-HHIT to improve treatment response in patients with laBCC. Longer-term follow-up is needed to study recurrence rates after combination therapy., (© 2021 Wiley Periodicals LLC.)

20( S )-Ginsenoside Rg3 (S-Rg3) has good antitumor activity and has been used in clinical oral antitumor therapy. However, the effect of S-Rg3 on the Hedgehog (Hh) signaling pathway has not been reported. In this study, we used CCK8, cell wound healing, Transwell, and western blotting assays as well as small interfering RNA to decrease GLI1 protein expression to investigate the effect of S-Rg3 on the Hh pathway in A549 cells. The results showed that S-Rg3 substantially inhibited the proliferation, migration, and invasion of A549 cells in a concentration-dependent manner. Furthermore, S-Rg3 had significant regulatory effects on PTCH1 and GLI1, key proteins in the Hh pathway, causing significant upregulation of PTCH1 levels and downregulation of GLI1 expression. After silencing the Hh signaling pathway, the inhibitory effect of S-Rg3 administration on the expression of epithelial mesenchymal transition-related proteins was further enhanced. Molecular dynamics simulations showed that Rg3 molecules could bind stably to PTCH1 protein through hydrophobic interactions, hydrogen bonds, and π-π stacking forces. Thus, S-Rg3 can regulate Hh signaling pathway transduction in A549 cells to inhibit lung cancer cell proliferation, migration, invasion, and epithelial mesenchymal transition.

Numerous new emerging therapies, including oral targeted chemotherapies, have recently entered the therapeutic arsenal against acute myeloid leukemia (AML). The significant shift toward the use of these novel therapeutics, administered either alone or in combination with intensive or low-intensity chemotherapy, changes the prospects for the control of this disease, especially for elderly patients. Glasdegib, an oral Hedgehog pathway inhibitor, showed satisfactory response rates associated with moderate toxicity and less early mortality than standard induction regimens in this population. It was approved in November 2018 by the FDA and in June 2020 by the EMA for use in combination with low-dose cytarabine as a treatment of newly-diagnosed AML in patients aged ≥ 75 and/or unfit for intensive induction chemotherapy. The current paper proposes an extensive, up-to-date review of the preclinical and clinical development of glasdegib. Elements of its routine clinical use and the landscape of ongoing clinical trials are also stated., (© 2022 Cyril Fersing et al., published by Sciendo.)

Sonidegib is an antagonist of the transmembrane protein Smoothened in the Hedgehog signaling pathway. It is indicated for the treatment of locally advanced basal cell carcinoma (BCC) that is not amenable to curative surgery or radiotherapy. Sonidegib's efficacy and safety were demonstrated in the phase 2 BOLT trial, where 61% (95% CI, 48-72%) of patients with locally advanced BCC treated with sonidegib 200 mg achieved an objective response to treatment with a mean time to response of 4 months. The median duration of response was 26.1 months and the median progression-free survival was 22.1 months. The most common adverse events were muscle spasms (54.4%), hair loss (49.4%), and loss of taste (44.3%); most events were grade 1 or 2. In this review, we summarize the main findings on the efficacy, safety, and tolerability of sonidegib and discuss the management of locally advanced BCC with this drug., (Copyright © 2020 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.)

Introduction : The standard anthracycline and cytarabine-based chemotherapy for acute myeloid leukemia (AML) has changed relatively little since the 1970s and produces unsatisfactory outcomes in many patients. In the past two decades, a better understanding of the pathophysiology and heterogeneity of this disease has led to promising new therapies, resulting in a flurry of new drug approvals. Areas covered : The MEDLINE database, ClinicalTrials.gov and conference proceedings were reviewed for the most salient literature concerning FDA-approved drugs for AML beyond standard chemotherapy: gemtuzumab ozogamicin, hypomethylating agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, isocitrate dehydrogenase (IDH) inhibitors, venetoclax, liposomal cytarabine and daunorubicin (CPX-351), and hedgehog pathway inhibitors. Key evidence for their efficacy is discussed. For each drug category, indications, typical usage and responses, major toxicities, and future directions for research are highlighted. Expert opinion : The treatment paradigm for AML is rapidly evolving. Promising new drugs targeting driver mutations have improved outcomes in specific AML subgroups. In parallel, advances in low-intensity therapies have allowed patients unfit for standard induction chemotherapy to achieve meaningful disease control. Further work is ongoing to identify synergistic drug combinations as well as optimal treatment selection guided by individual patient and disease features.