Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cohen, Leah S.; Tsai, Kenneth Y.

doi:10.1002/mc.23042

Cited by 5 publications

(13 citation statements)

References 99 publications

(178 reference statements)

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“…A number of potential MCC targets and pathways including PI3K/mTOR/AKT, receptor tyrosine kinases and downstream signaling, DNA repair, survivin, BCL-2 family, HDACs, heat shock proteins, MDM2, etc. have been suggested in the literature (see 1 , 3 for recent reviews). Many of the compounds identified in this screen have been reported to directly or indirectly affect one or more of these pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine carcinoma of the skin 1 – 3 . MCC has histological properties that led to the initial belief that this cancer started in Merkel cells; however it is currently debated from which cell type this cancer originates 2 , 3 .…”

Section: Introductionmentioning

confidence: 99%

“…Due to the highly aggressive nature of the tumors, reoccurrence is typically observed 6 . Immunotherapies have shown promise as a monotherapy for MCC 1 , 6 but more effective treatments are still needed.…”

Section: Introductionmentioning

confidence: 99%

“…The remaining 20% of MCC tumors are virus negative (VN-MCC) and are associated with UV induced DNA damage leading to a high mutational burden 3 . Inactivation of tumor suppressor genes and activation of protooncogenes lead to possible treatable targets in major pathways involved in tumorigenesis 1 . Some alterations are shared between both tumor types, while others are only seen in VN-MCC tumors.…”

Section: Introductionmentioning

confidence: 99%

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Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Smith

Hill

Gelb

et al. 2021

Sci Rep

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Merkel cell carcinoma (MCC) is a rare, but aggressive skin cancer the incidence of which has increased significantly in recent years. The majority of MCCs have incorporated Merkel cell polyomavirus (VP-MCC) while the remainder are virus-negative (VN-MCC). Although a variety of therapeutic options have shown promise in treating MCC, there remains a need for additional therapeutics as well as probes for better understanding MCC. A high-throughput screening campaign was used to assess the ability of > 25,000 synthetic and natural product compounds as well as > 20,000 natural product extracts to affect growth and survival of VN-MCC and VP-MCC cell lines. Sixteen active compounds were identified that have mechanisms of action reported in the literature along with a number of compounds with unknown mechanisms. Screening results with pure compounds suggest a range of potential targets for MCC including DNA damage, inhibition of DNA or protein synthesis, reactive oxygen species, and proteasome inhibition as well as NFκB inhibition while also suggesting the importance of zinc and/or copper binding. Many of the active compounds, particularly some of the natural products, have multiple reported targets suggesting that this strategy might be a particularly fruitful approach. Processing of several active natural product extracts resulted in the identification of additional MCC-active compounds. Based on these results, further investigations focused on natural products sources, particularly of fungal origin, are expected to yield further potentially useful modulators of MCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Smith

Hill

Gelb

et al. 2021

Sci Rep

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“…Adjuvant radiotherapy therapy (RT) has been shown to decrease local and regional relapses by 80% and 70%, respectively, when compared to surgery alone, in addition to increasing overall survival (OS) and disease‐free survival with the greatest benefit for intermediate stage MCC. Adjuvant radiation has not been shown to prevent distant metastases 7–11 . The extent of surgery, and in particular sentinel lymph node (SLN) biopsy, is controversial.…”

Section: Introductionmentioning

confidence: 99%

Effect of Sentinel Lymph Node Biopsy and LVI on Merkel Cell Carcinoma Prognosis and Treatment

et al. 2020

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Objective Prognostic factors and optimal treatment approaches for Merkel cell carcinoma (MCC) remain uncertain. This study evaluated the influences of sentinel lymph node (SLN) biopsy and lymphovascular invasion (LVI) on treatment planning and prognosis. Study Design Retrospective cohort study. Methods Stage 1 to 3 MCC patients treated 2005 to 2018. Predictors of nodal radiation were tested using logistic regression. Predictors of recurrence‐free, disease‐specific, and overall survival were tested in Cox proportional hazard models. Results Of 122 patients, 99 were without clinically apparent nodal metastases. Of these, 76 (77%) underwent excision and SLN biopsy; 29% had metastasis in SLNs, including 20% of MCCs 1 cm or less. Primary tumor diameter, site, patient age, gender, and immunosuppressed status were not significantly associated with an involved SLN. Among patients who underwent SLN biopsy, 13 of 21 (62%) MCCs with LVI had cancer in SLNs compared with 14 of 44 (25.5%) without LVI (P = .003). Although local radiation was common, nodal radiation was infrequently employed in SLN negative (pathologic N0) patients (21.8% vs. 76.2% for patients with SLN metastases, P = .0001). Survival of patients with positive SLNs was unfavorable, regardless of completion lymphadenectomy and/or adjuvant radiation. After accounting for tumor (T) and node (N) classification, age, immunosuppression, and primary site, a positive SLN and LVI were independently associated with worse survival (LVI/recurrence‐free survival [RFS]: hazard ratio [HR] 2.3 (1.04–5, P = .04; LVI/disease‐specific survival [DSS]: HR 5.2 (1.8–15, P = .007); N1a vs. pN0/RFS HR 3.6 (1.42–9.3, P = .007); DSS HR5.0 (1.3–19, P = .17). Conclusion SLN biopsy assists in risk stratification and radiation treatment planning in MCC. LVI and disease in SLNs, independently associated with worse survival, constitute markers of high‐risk disease warranting consideration for investigational studies. Level of Evidence III Laryngoscope, 131:E828–E835, 2021

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Molecular and immune targets in cutaneous squamous cell carcinoma

Galambus

Tsai

2022

Molecular Carcinogenesis

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Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and often confers a good prognosis. Though surgery is the gold standard of treatment, unresectable or metastatic disease can necessitate systemic therapy. Of systemic agents, there is increasing interest in the use of immunotherapies and targeted therapy. Further study into the driver mutations in cSCC has identified opportunities for targeted therapy. In this review, we discuss both current and investigational immune and molecular targets of therapy for cSCC.

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Molecular and immune targets for Merkel cell carcinoma therapy and prevention

Cited by 5 publications

References 99 publications

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Identification of natural product modulators of Merkel cell carcinoma cell growth and survival

Effect of Sentinel Lymph Node Biopsy and LVI on Merkel Cell Carcinoma Prognosis and Treatment

Molecular and immune targets in cutaneous squamous cell carcinoma

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