Acral Lentiginous Melanoma (ALM) is one of the most aggressive forms of melanoma, notoriously difficult to treat and linked to a grim prognosis, largely because of late-stage diagnosis and distinct biological features. Protheragen is at the forefront of preclinical research and therapeutic development for ALM, focusing on unique molecular disease mechanisms to accelerate innovative concepts into clinical practice.
ALM remains the most prevalent melanoma subspecies among people with darker skin and manifests on non-sun exposed skin like the palms, soles, and nail beds. Different from most melanoma forms, ALM does not have a strong correlation with UV exposure. Rather, it masquerades as a large and often advanced lesion. The combination of advanced stage at diagnosis, aggressive cells, and rapid spread to other parts of the body considerably reduce the survival rate compared to other forms of melanoma. The distinct biological features that underlie the molecular pathology of ALM render standard therapies for melanoma often futile.
Fig.1 Tumor genetics. Genes that are more frequently implicated in acral melanomas are highlighted in purple. (Thakker et al., 2025)
Unlike UV-related melanomas, acral lentiginous melanoma (ALM) melanoma's pathogenesis is rooted in distinct genomic changes. While other types of melanoma are often marked by BRAF and NRAS mutations, ALM is more often marked by mutations in KIT, NF1, and some chromosomal copy number changes. These alterations are associated with the activation of the critical signaling pathways, such as MAPK and PI3K/AKT pathways, which promote abnormal cell growth, survival, and resistance to programmed cell death. The distinct genomic landscape of ALM underscores the importance of personalized medicine and specific therapies designed to counter its unique molecular pathways.
Fig.1 Microenvironment. Key cell types and receptors which mediate the acral melanoma tumor microenvironment. (Thakker et al., 2025)
| Drug Name | Target | Key Findings / Rationale | Development Stage |
| Imatinib / Nilotinib / Dasatinib | c-KIT | Induces cell cycle arrest and apoptosis in c-KIT-mutant ALM; higher mutation prevalence in ALM vs. cutaneous melanoma | Phase II |
| Entrectinib | ROS1 / ALK / NTRK | Durable responses in ROS1-fusion ALM cases; supports genotype-directed therapy | Phase II |
| Palbociclib / Ribociclib | CDK4 / CDK6 | Targets frequent CDK4/6-CCND1 amplifications in ALM; promising strategy for BRAF/NRAS wild-type tumors | Phase I/II |
| Selumetinib / Pimasertib | MEK1 / MEK2 | Explores MEK inhibition in MAPK-activated ALM, including BRAF wild-type cases | Phase I/II |
| Alpelisib / Dactolisib | PI3K | Targets PI3K-AKT pathway activation; evaluated as monotherapy or combinations | Phase I/II |
| EZH2 Inhibitors | EZH2 | Suppresses tumorigenesis via histone methylation modulation; demonstrates preclinical anti-tumor activity | Preclinical |
| MDM2 Inhibitors | MDM2-p53 interaction | Reactivates p53 tumor-suppressor function in wild-type p53 ALM | Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Protheragen offers a complete suite of services to accelerate therapeutic development for acral lentiginous melanoma. Our team of specialists, including scientists, dermatologists, and geneticists, formulates therapeutic and disease model to support all phases of your research project.
Protheragen excels in developing custom 2D cell models, 3D skin models and animal models that accurately mimic ALM's etiology, characterized by specific genomic alterations, high metastatic potential, and resistance to conventional therapies. These models are invaluable for therapeutic testing and validation.
Protheragen's DMPK and drug safety evaluation services provide critical insights into how your drug is absorbed, distributed, metabolized, and excreted. Our services help to predict in vivo behavior and optimize dosing strategies for ALM therapies, with an emphasis on systemic exposure and efficacy.
In Vivo Pharmacokinetics Services
Protheragen specializes in cutting-edge preclinical research services. Utilizing our integrated discovery platforms, we accelerate therapeutic development for rare cutaneous disorders like acral lentiginous melanoma. Our innovative proprietary disease models, alongside comprehensive drug safety evaluation and DMPK services, facilitate a seamless progression from target validation to IND-enabling studies.
If you are interested in our services, please feel free to contact us.
References
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