Effective anti-programmed death-1 therapy in a<i>SUFU</i>-mutated patient with Gorlin-Goltz syndrome

Moreira, Álvaro; Kirchberger, Michael C.; Toussaint, Frédéric; Erdmann, Michael; Heinzerling, Lucie

doi:10.1111/bjd.16607

Cited by 27 publications

(13 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given the immunosuppressive function of HH/GLI, HH antagonists may synergize with immune checkpoint blockers such as anti-PD-1 antibodies in fighting cancer. Notably, single case studies with BCC patients receiving nivolumab or pembrolizumab (two clinically approved anti-PD-1 antibodies) have already yielded promising results, suggesting that the use of immune checkpoint inhibitors can provide a therapeutic benefit in HH/GLI-driven non-melanoma skin cancer [74, 76, 89, 90]. The outcome of recent and ongoing clinical trials with immune checkpoint inhibitors for the treatment of metastatic or unresectable BCC alone or in combination with HH/SMO inhibitors will inform about whether immunotherapy or combinatorial treatments can increase the efficacy and durability of the response of BCC patients (see https://www.clinicaltrials.gov/ trials identifiers: NCT03132636; NCT03521830; NCT02690948).…”

Section: Discussionmentioning

confidence: 99%

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

2019

View full text Add to dashboard Cite

Uncontrolled activation of the Hedgehog/Glioma-associated oncogene (HH/GLI) pathway is a potent oncogenic driver signal promoting numerous cancer hallmarks such as proliferation, survival, angiogenesis, metastasis and metabolic rewiring. Several HH pathway inhibitors have already been approved for medical therapy of advanced and metastatic basal cell carcinoma and acute myeloid leukemia with partially impressive therapeutic activity. However, de novo and acquired resistance as well as severe side effects and unexplained lack of therapeutic efficacy are major challenges that urgently call for improved treatment options with more durable responses. The recent breakthroughs in cancer immunotherapy have changed our current understanding of targeted therapy and opened up promising therapeutic opportunities including combinations of selective cancer pathway and immune checkpoint inhibitors. Although HH/GLI signaling has been intensely studied with respect to the classical hallmarks of cancer, its role in the modulation of the anti-tumoral immune response has only become evident in recent studies. These have uncovered HH/GLI regulated immunosuppressive mechanisms such as enhanced regulatory T-cell formation and production of immunosuppressive cytokines. In light of these exciting novel data on oncogenic HH/GLI signaling in immune cross-talk and modulation, we summarize and connect in this review the existing knowledge from different HH-related cancers and chronic inflammatory diseases. This is to provide a basis for the investigation and evaluation of novel treatments combining immunotherapeutic strategies with approved as well as next-generation HH/GLI inhibitors. Further, we also critically discuss recent studies demonstrating a possible negative impact of current HH/GLI pathway inhibitors on the anti-tumoral immune response, which may explain some of the disappointing results of several oncological trials with anti-HH drugs.

show abstract

Section: Discussionmentioning

confidence: 99%

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

2019

View full text Add to dashboard Cite

show abstract

“…Although not directly compared due to the non-randomized design of the study, the authors concluded combination therapy was not superior to monotherapy. The use of pembrolizumab in BCC has also been noted in 5 case reports with complete [30,33] and partial [29,34,35] responses achieved, as well as a report of progressive disease of metastatic BCC bony lesions [30] on therapy. Nivolumab [28,36] and cemiplimab [27] have also shown efficacy against advanced BCC.…”

Section: Basal Cell Carcinomamentioning

confidence: 86%

Immunotherapy for Non-melanoma Skin Cancer

et al. 2021

View full text Add to dashboard Cite

Purpose of ReviewThe therapeutic landscape for non-melanoma skin cancer (NMSC) has recently expanded with the development of effective and targeted immunotherapy. Here, we provide an overview of the role of immunotherapy in the management of advanced cutaneous carcinomas. Recent Findings Several agents were recently U.S. Food and Drug Administration (FDA)-approved for the treatment of locally advanced and metastatic cutaneous squamous cell carcinoma, Merkel cell carcinoma, and basal cell carcinoma. However, recent approvals in tissue-agnostic indications may also benefit other NMSCs including cutaneous adnexal solid tumors with high tumor mutation burdens or microsatellite instability. Furthermore, while FDA-approved indications will likely continue to expand, continued studies are needed to support the role of immunotherapy in the neoadjuvant, adjuvant, and refractory settings. Summary Immunotherapy is emerging as the standard of care for several advanced NMSCs not amenable to surgery and radiation. Ongoing evaluation of the clinical trial landscape is needed to optimize enrollment and ensure continued innovation.

show abstract

“…Finally, we also envision that HH/GLI pathway blockers in combination with drugs targeting immune evasion mechanisms, such as immune checkpoint inhibitors, are likely to provide further therapeutic benefit. Although our present knowledge about the impact of HH/GLI on tumor immune evasion is fairly limited, first evidence from preclinical and clinical observations suggests that next-generation HH/GLI inhibitors together with strategies reactivating the antitumoral immune response may represent the next leap for anti-HH/GLI therapy of cancers [154,155,156,157,158].…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Peer

Tesanovic

Aberger

2019

Cancers

View full text Add to dashboard Cite

The Hedgehog/Glioma-associated oncogene homolog (HH/GLI) signaling pathway regulates self-renewal of rare and highly malignant cancer stem cells (CSC), which have been shown to account for the initiation and maintenance of tumor growth as well as for drug resistance, metastatic spread and relapse. Efficacious therapeutic approaches targeting CSC pathways, such as HH/GLI signaling in combination with chemo, radiation or immunotherapy are, therefore, of high medical need. Pharmacological inhibition of HH/GLI pathway activity represents a promising approach to eliminate malignant CSC. Clinically approved HH/GLI pathway inhibitors target the essential pathway effector Smoothened (SMO) with striking therapeutic efficacy in skin and brain cancer patients. However, multiple genetic and molecular mechanisms resulting in de novo and acquired resistance to SMO inhibitors pose major limitations to anti-HH/GLI therapies and, thus, the eradication of CSC. In this review, we summarize reasons for clinical failure of SMO inhibitors, including mechanisms caused by genetic alterations in HH pathway effectors or triggered by additional oncogenic signals activating GLI transcription factors in a noncanonical manner. We then discuss emerging novel and rationale-based approaches to overcome SMO-inhibitor resistance, focusing on pharmacological perturbations of enzymatic modifiers of GLI activity and on compounds either directly targeting oncogenic GLI factors or interfering with synergistic crosstalk signals known to boost the oncogenicity of HH/GLI signaling.

show abstract

Effective anti-programmed death-1 therapy in aSUFU-mutated patient with Gorlin-Goltz syndrome

Cited by 27 publications

References 10 publications

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

Immunotherapy for Non-melanoma Skin Cancer

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Contact Info

Product

Resources

About