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By MedGenome Scientific Affairs
Skin cancer is the most common type of cancer in the US. One in five Americans have the likelihood of developing skin cancer by the age of 70. Some common manifestations of skin cancer include basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and melanoma. Research suggests over 5 million cases of skin cancer occur annually in the US alone. Non-melanoma skin cancers (BCC and SCC) are the most common, followed by melanoma, the more aggressive form. Other types of skin cancer include Merkel cell cancer, cutaneous T-cell lymphoma, Kaposi sarcoma, skin adnexal tumors and sarcomas.
Understanding skin cancer risks: Several factors are associated with risk of developing skin cancer, including chronic exposure to UV light, number and size of moles on the skin, fair skin, and light hair color. In addition, a familial history of skin cancer increases the likelihood of developing the disease due to genetic predisposition. Other risk factors include sunburn history, light complexion, eye color, and hair color, as well as certain skin conditions such as chronic inflammation, immune suppression, and environmental exposures like arsenic exposure and radiation1.
Genetic insights into melanoma’s aggressive nature
While non-melanoma skin cancer has a negligible impact on cancer mortality, melanoma accounts for most skin cancer-related deaths1.
Malignant melanoma arises from unchecked growth or damage to melanocytes. It is characterized by significant genetic heterogeneity, with tumors showcasing numerous genetic alterations and mutations. This complexity fuels the aggressiveness of melanoma, driving tumor progression, metastasis, and resistance to treatment. A study featured in Nature Cell Biology delved into the role of LAP1 protein in melanoma advancement. Elevated LAP1 levels in metastatic cells hint at its crucial role in cancer spread, as demonstrated in this research2, highlighting LAP1 as a pivotal regulator of melanoma’s aggressiveness. Targeting LAP1 emerges as a promising strategy to curb melanoma spread. Conducted by researchers from the Francis Crick Institute, Queen Mary University of London, and King’s College London, the study suggests classifying LAP1 as a potential prognostic marker in melanoma patients. Higher LAP1 levels at the perimeter of primary tumors correlate with increased melanoma aggressiveness and poorer outcomes.
Genetic factors and syndromic associations in skin cancer pathogenesis
Skin cancer occurrence is significantly influenced by hereditary genetic predisposition. For example:
- Melanoma: Hereditary melanoma arises from mutations in two key genes, cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4), both major tumor suppressor genes. These mutations notably elevate melanoma risk, with CDKN2A mutations alone accounting for 35-40% of familial melanomas. Other implicated genes include BAP1, BRAF, CDK4, KIT, MITF, NF1, NRAS, PTEN, TERT, and TP53, affecting crucial pathways such as the phosphoinositide 3-kinase (PI3K)/AKT pathway and the RAS/RAF/MEK/ERK signaling cascade.
- Basal cell carcinoma: Mutations in PTCH1 and PTCH2 genes underlie Basal Cell Nevus Syndrome, increasing the risk of BCC.
- Squamous cell carcinoma: Certain syndromes like oculocutaneous albinism, epidermolysis bullosa, and Fanconi anemia are associated with higher susceptibility to SCC.
Current strategies for prevention and treatment of skin cancers:
Preventing skin cancer involves several key strategies aimed at reducing exposure to harmful UV radiation and minimizing other risk factors. These include using sunscreen, avoiding artificial sources of UV exposure like tanning beds and sunlamps, and regularly performing skin self-exams. By adopting these preventive measures, individuals can reduce their risk of developing skin cancer and promote overall skin health.
Early diagnosis is critical for skin cancer, as survival rates plummet with advanced disease stages. While surgery offers a cure for localized cases, advanced stages like metastatic melanoma have significantly worse outcomes, with 3-year overall survival ranging from a mere 4.7% to 26.4%. Fortunately, promising new avenues like immunotherapy and targeted therapies are providing renewed hope. BRAF/MEK inhibitors, anti-PD1 therapy, and combinations like nivolumab and ipilimumab have shown promising results in melanoma (Table 1). For advanced BCC, vismodegib and sonidegib target the Hedgehog pathway, while cemiplimab serves as a second-line therapy. Similarly, anti-PD1 agents like cemiplimab, pembrolizumab, and cosibelimab have yielded significant responses in locally advanced or metastatic SCC. PD-1/PD-L1 inhibitors and locoregional approaches are also under investigation for Merkel cell carcinoma3.
Additionally, Tumor mutation burden (TMB) analysis, facilitated by genomic techniques, is increasingly recognized as a pivotal determinant of treatment response, particularly in immunotherapy. High TMB correlates with heightened responsiveness to immunotherapeutic interventions, offering a promising avenue for personalized treatment strategies.
| Sl. No. | Therapeutic drug | Mode of action |
|---|---|---|
| Targeted therapy | ||
| 1 | Vemurafenib | BRAF inhibitor |
| 2 | Cobimetinib + Vemurafenib | MEK inhibitor + BRAF inhibitor |
| 3 | Binimetinib + Encorafenib | MEK inhibitor + BRAF Inhibitor |
| 4 | Dabrafenib + Trametinib | BRAF inhibitor + MEK inhibitor |
| Immunotherapy | ||
| 5 | Ipilimumab | Antibody against CTLA-4 |
| 6 | Nivolumab | Antibody against PD-1 |
| 7 | Pembrolizumab | Antibody against PD-1 |
| 8 | Talimogene Laherparepvec (T-VEC) | Oncolytic virus |
| 9 | Ipilimumab + Nivolumab | Antibody against CTLA-4 + antibody against PD-1 |
| 10 | Tebentafusptebn | T-cell receptor-bispecific molecule that targets both glycoprotein 100 and CD3 |
| 11 | Nivolumab + Relatlimab | Antibody against PD-1 + antibody against LAG-3 |
| Combined (Immunotherapy + Targeted therapy) | ||
| 12 | Atezolizumab + Cobimetinib + Vemurafenib | Antibody against PD-L1 + MEK inhibitor + BRAF inhibitor |
| Cellular therapy | ||
| 13 | Lifileucel | Tumor-derived autologous T-cell immunotherapy |
Numerous clinical trials are exploring pharmacological treatments for melanoma, BCC and SCC. Preclinical research has identified potential future targets such as CD126, CSPG4, tandem CD70 and B7-H3, and αvβ3 integrin for targeted melanoma therapy. In addition, novel approaches like oncolytic virus therapy and interventions to enhance immunotherapy effectiveness are being investigated. Despite the success of immunotherapy in some cases, its efficacy varies among patients, with only about 50% experiencing long-term survival. Consequently, current research aims to identify predictors of immunotherapy response and develop strategies for better prognosis in refractory patients. These ongoing investigations aim to develop more effective and personalized treatment options, ultimately improving patient outcomes and survival rates5.
FDA has recently approved the first cancer tumor-infiltrating lymphocytes (TIL) therapy lifileucel (Amtagvi) for treatment of advanced melanoma. TIL (tumor-infiltrating lymphocyte) therapy, entails augmenting the population of immune cells within tumors, leveraging their potency to combat cancer6.
Genomics in skin cancer: In recent decades, advancements in skin cancer treatment, including targeted agents and immunotherapy, have significantly improved patient outcomes. Despite these strides, challenges persist, including limited efficacy, therapy resistance, and adverse effects. For example, while immunotherapy shows promise, it benefits only a subset of patients and can trigger adverse reactions. Combining therapies can enhance effectiveness but often leads to heightened side effects. Therefore, ongoing research aims to explore new targets, refine existing therapies, mitigate side effects, and comprehend resistance mechanisms. Genomic technologies, like next-generation sequencing (NGS), play a pivotal role in this pursuit. NGS panels have transformed skin cancer treatment by enabling precise molecular characterization. By analyzing individual patient tumor profiles, specific genetic alterations can be identified for targeted personalized therapies. This approach holds significant promise for enhancing treatment efficacy, minimizing side effects, and ultimately improving the prognosis for skin cancer patients.
Conclusions
The significant burden of skin cancer necessitates continued research efforts to improve prevention, early detection, and treatment strategies. This includes public health initiatives to promote sun protection and early detection measures, alongside advancements in personalized medicine through leveraging genetic insights. By tailoring treatment approaches based on individual patient characteristics and tumor profiles, we can strive for a future with more effective and less toxic therapies, ultimately reducing the morbidity and mortality associated with skin cancer.
MedGenome’s advanced solutions for skin cancer
MedGenome offers comprehensive tumor microenvironment solutions supported by a targeted sequencing approach, facilitating the identification of immune-oncology biomarkers such as microsatellite instability (MSI) and tumor mutational burden (TMB). Our optimized NGS assays enable the detection of low-prevalence pathogenic variants and epigenetic regulators relevant to various skin cancers. As pioneers in advanced genomic technologies and certified 10x service provider, we support your research journey from design to publication. Our expertise ensures the selection of optimal workflows, precise sample processing, and timely result delivery. We augment your research with custom visualizations, tailored analysis workflows, and seamless integration of external data, ensuring readiness for publication.
Feel free to contact our expert scientific team at research@medgenome.com for any questions or further information.
To know more about our advanced genomics solutions and services please click on the following links: Spatial Transcriptomics, Single cell sequencing, RNA Sequencing, Immune profiling, Whole genome and whole exome sequencing, and Epigenetic profiling
References
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- https://www.cancer.gov/types/skin/hp/skin-genetics-pdq#_38
- Jung-Garcia, Y., Maiques, O., Monger, J. et al. LAP1 supports nuclear adaptability during constrained melanoma cell migration and invasion. Nat Cell Biol 25, 108–119 (2023).
- Rubatto M, Sciamarrelli N, Borriello S, Pala V, Mastorino L, Tonella L, Ribero S, Quaglino P. Classic and new strategies for the treatment of advanced melanoma and non-melanoma skin cancer (2023). Front Med (Lausanne)., 9:959289.
- Fateeva A, Eddy K, Chen S. Current State of Melanoma Therapy and Next Steps: Battling Therapeutic Resistance (2024). Cancers (Basel). 16(8):1571.
- Natarelli N, Aleman SJ, Mark IM, Tran JT, Kwak S, Botto E, Aflatooni S, Diaz MJ, Lipner SR. A Review of Current and Pipeline Drugs for Treatment of Melanoma (2024). Pharmaceuticals (Basel). 17(2):214.
- https://www.cancer.gov/news-events/cancer-currents-blog/2024/fda-amtagvi-til-therapy-melanoma#:~:text=In%20an%20event%20more%20than,%2Dinfiltrating%20lymphocytes%2C%20or%20TILs.
#Skin cancer, #Basal cell carcinoma, #Squamous cell carcinoma, #Melanoma, #UV radiation, #Melanocytes, #Mutations, #Treatment resistance, #Immunotherapy, #Targeted therapy, #Cellular therapy, #Clinical trials, #Genomics, #Skin cancer treatment
