Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma

Fischer, Stefanie; Ali, Omar Hasan; Jochum, Wolfram; Kluckert, Thomas; Flatz, Lukas; Siano, Marco

doi:10.1159/000487084

Cited by 41 publications

(32 citation statements)

References 20 publications

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“…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

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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.

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Section: Discussionmentioning

confidence: 99%

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Peer

Tesanovic

Aberger

2019

Cancers

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“…To treat hedgehog inhibitor resistant tumours, immunotherapy is currently under investigation. There have been several case reports showing remarkable and sustained antitumour response with PD-1/PD-L1 blockade regardless of PD-L1 expression in vismodegib resistant BCC tumours 18 19…”

Section: Discussionmentioning

confidence: 99%

Rare basal cell metastasis of a basal-squamous skin collision tumour to the lung and axillary lymph node

Lee

Huang

et al. 2019

BMJ Case Rep

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We report a case of a 60-year-old man who was a former cigar smoker with a slow-growing, large exophytic left shoulder mass (15 cm in diameter) and later found to have left axillary lymphadenopathy. Fine needle aspirate biopsy of the left shoulder mass revealed squamous cell carcinoma (SCC). However, pathology of the enlarged left axillary lymph node was reported as metastatic adenocarcinoma. The patient underwent surgical resection of the shoulder mass which comprised of SCC (>95%) and adenoid basal cell carcinoma (BCC) as a second component of the tumour. The BCC had identical histology as the metastatic carcinoma in the left axillary lymph node. Therefore, diagnosis was revised as cutaneous collision tumour with metastatic BCC. Six months later following adjuvant radiation therapy, the patient was diagnosed with metastatic BCC in the right lung. Stereotactic body radiation therapy (SBRT) and a selective hedgehog pathway inhibitor vismodegib were given with only limited efficacy. Clinical trial registration number NCT03132636.

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“…Moreover, secondary resistance has been reported to be an HPI class-related effect, and a study in nine patients with advanced BCC resistant to vismodegib reported similar resistance with subsequent sonidegib treatment [31]. Off-label anti-programmed cell death protein 1 (PD-1) therapy showed promising results in case reports of patients with metastatic BCC that progressed or were resistant to previous HPI treatment [32,33], and anti-PD-1 agents (pebrolizumab, nivolumab, REGN2810) are currently under study for advanced BCC in clinical trials (NCT02690948, NCT03521830, NCT03132636). Recurrence after HPI discontinuation may occur, and in our clinical practice, we follow patients with response that discontinue HPI because of adverse events or personal reasons, every 3 months.…”

Section: Rechallenge With Hpimentioning

confidence: 99%

A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors

et al. 2019

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The Hedgehog pathway inhibitors (HPIs), vismodegib and sonidegib, are increasingly employed in the treatment of patients with advanced basal cell carcinoma (BCC). The aim of this review is to create a synthesis of available information in the literature regarding the follow‐up of patients with advanced BCC treated with HPIs and to provide the treating physician with a structured practical guide to standardize clinical practice. Several challenges during treatment are addressed: to optimally evaluate tumor responses, to differentiate between resistance (HPI rechallenge not possible) and recurrence (HPI rechallenge may be possible) in case of BCC regrowth, to readily assess for toxicity and tolerability issues, to provide patients with practical ways and behaviors to effectively cope with adverse events, and to improve patient adherence and quality of life. Implications for Practice This is a practical guide for clinical practice regarding the monitoring and follow‐up of patients with advanced basal cell carcinoma (BCC) during treatment with the Hedgehog pathway inhibitors (HPIs) vismodegib and sonidegib. This review aims to bridge the gap in knowledge of assessing tumor response for BCC with both an externally visible component and an infiltrating component measurable with imaging. Furthermore, it addresses the follow‐up for adverse events as a challenging multistep process involving practices aiming to readily assess new‐onset symptoms of HPI toxicity, perform total‐body skin examination, and improve patient adherence and quality of life.

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Anti-PD-1 Therapy Leads to Near-Complete Remission in a Patient with Metastatic Basal Cell Carcinoma

Cited by 41 publications

References 20 publications

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Next-Generation Hedgehog/GLI Pathway Inhibitors for Cancer Therapy

Rare basal cell metastasis of a basal-squamous skin collision tumour to the lung and axillary lymph node

A Practical Guide for the Follow-Up of Patients with Advanced Basal Cell Carcinoma During Treatment with Hedgehog Pathway Inhibitors

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