Melanoma is among the most common malignant neoplasms in the United States, with 91 270 cases estimated to be diagnosed in 2018.¹ For cases of invasive melanoma without nodal or extralymphatic metastasis, current national guidelines recommend treatment with wide margin excision (WME) and consideration of sentinel lymph node biopsy, depending on patient preference and comorbidities.² Although not currently espoused by guidelines for this indication, use of Mohs micrographic surgery (MMS) has increased as an alternative to WME.³ Some controversy remains as to the potential effects of the 2 surgical techniques on patient survival, with proponents of MMS pointing to its complete margin evaluation and critics of MMS concerned about residual disease in tumors without contiguous growth patterns.^4,5

The presence and degree of peripheral blood involvement in patients with cutaneous T-cell lymphoma (CTCL) portend a worse clinical outcome. Available systemic therapies for CTCL may variably decrease tumor burden and improve quality of life, but offer limited effects on survival; thus, novel approaches to the treatment of advanced stages of this non-Hodgkin lymphoma are clearly warranted. Mutational analyses of CTCL patient peripheral blood malignant cell samples suggested the antiapoptotic mediator B-cell lymphoma 2 (BCL2) as a potential therapeutic target. To test this, we developed a screening assay for evaluating the sensitivity of CTCL cells to targeted molecular agents, and compared a novel BCL2 inhibitor, venetoclax, alone and in combination with a histone deacetylase (HDAC) inhibitor, vorinostat or romidepsin. Peripheral blood CTCL malignant cells were isolated from 25 patients and exposed ex vivo to the 3 drugs alone and in combination, and comparisons were made to 4 CTCL cell lines (Hut78, Sez4, HH, MyLa). The majority of CTCL patient samples were sensitive to venetoclax, and BCL2 expression levels were negatively correlated (r = −0.52; P = .018) to 50% inhibitory concentration values. Furthermore, this anti-BCL2 effect was markedly potentiated by concurrent HDAC inhibition with 93% of samples treated with venetoclax and vorinostat and 73% of samples treated with venetoclax and romidepsin showing synergistic effects. These data strongly suggest that concurrent BCL2 and HDAC inhibition may offer synergy in the treatment of patients with advanced CTCL. By using combination therapies and correlating response to gene expression in this way, we hope to achieve more effective and personalized treatments for CTCL. Key Points The antiapoptotic protein BCL2 is a promising potential target in the treatment of CTCL. Combination inhibition of BCL2 and HDACs leads to efficient killing of CTCL cells due to the synergistic activation of apoptosis.

Significance: One in five individuals in the United States will develop skin cancer over the course of a lifetime, and nonsurgical options are limited. To address this, we developed a bioadhesive nanoparticle (BNP) treatment for long-lasting local drug delivery. Incorporation of the topoisomerase inhibitor camptothecin (CPT) into BNPs enhanced tumor cell uptake, bioadhesion within the tumor microenvironment, and prolonged intratumoral drug retention. Therefore, we investigated BNPs encapsulating CPT as a local, nonsurgical treatment for nodular squamous cell carcinoma (SCC) skin cancers in a mouse model. BNP-CPT treatment facilitated tumor destruction and resolution, and was compatible with local immunotherapy. These findings suggest that BNP delivery of antitumor agents may provide opportunities for nonsurgical treatment of nodular skin cancers like SCC.

Oncotarget | https://doi.org/10.18632/oncotarget.25670 Sa Rang Kim, Julia M. Lewis, Benoit M. Cyrenne, Patrick F. Monico, Fatima N. Mirza, Kacie R. Carlson, Francine M. Foss, Michael Girardi BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition