Our laboratory performs translational research mainly in onco-dermatology with an emphasis on cutaneous T-cell lymphoma (CTCL). We work in tight collaboration with dermatologists from Rabin Medical Center, with access to samples from human subjects. CTCL is a heterogeneous group of malignancies derived from skin-homing T-cells. The most common types are mycosis fungoides (MF) and its leukemic form, Sezary syndrome. The aim of our research is to gain further insight into the genetics, epigenetics, cell biology, immunology and the tumor microenvironment underlying the development and progression of CTCL in order to promote the development of novel drugs and therapeutic modalities, including a search for potent cannabis extracts and new immune blockade. Recently, we have extended our work to non-melanoma skin cancers such as cutaneous squamous cell carcinoma (cSCC) and actinic keratosis (AK).
Genomics and epigenomics of CTCL
- Identification of inherited pathogenetic mutations in familial MF. We are analyzing genomic DNA of 30 families with familial MF by using whole exome sequencing and whole genome sequencing.
- Involvement of miR-155 in MF progression. We detected up-regulation of miR-155 in advanced-stage MF vs early-stage biopsies. We demonstrated that miR-155 contributes to the cancerous phenotype of MF cells in-vitro and in mice model. Currently, miRagen (USA) is launching phase II clinical trials with miR-155 inhibitor in patients with MF.
- Overexpression of miR-17~92 in the tumor microenvironment of MF. We discovered that compared to multifocal MF, unifocal MF is characterized by high expression of the miR-17~92, Th1 skewing with suppression of Th2 to promote anti-cancer immune response.
Tumor microenvironment (TME) and intercellular communication in MF
New drugs and treatments for CTCL
- The role of cancer-associated fibroblasts (CAFs) in MF lesions.We showed that activated and proliferated CAFs are abundant in MF biopsies. CAFs protect MF cells from doxorubicin-induced cell death and promote their migration through secretion of high levels of CXCL12, the ligand of CXCR4 (known to be overexpressed in MF cells). Indeed, interfering with CXCL12-CXCR4 axis leads to chemo-sensitization of MF cells, with a reduction in their motility and growth.
- The role of MF-derived exosomes in intercellular communication and their potential as biomarkers. Exosomal miR-155 and miR-1246 were highly expressed and delivered from high grade to low grade MF cell lines, protected them from doxorubicin-induced cell death, and enhanced cell motility. A high expression of cell-free miR-155 and miR-1246 was detected in plasma samples of patients with MF and are analyzed now as potential biomarkers. Further studies are being done on exosomal immune-checkpoint proteins and their role in the anti-tumor immune response.
- Cytotoxic activity of cannabinoid extracts (in collaboration with Hinanit Koltai, Volcani Center). We identified active cannabis compounds extracted from Cannabis sativa that exert high cytotoxic activity against CTCL cell lines and PBMCs from Sezary patients. A synergistic apoptotic mixture was determined with selective apoptotic effect on the malignant Sezary PBMCs. Soon we will conduct clinical trial with ointment based on our synergistically active phytocannabinoid compounds for CTCL.
- Diagnostic and treatment potential of mAb14 antibody (in collaboration with Angel Porgador, Ben Gurion University). Fraction of PCNA was found to localize to the membrane of cancer cells, termed as cell-surface PCNA (csPCNA). csPCNA serves as immune checkpoint protein helping cancer cells escape NK-cell-mediated immune attack. mAb14 is a monoclonal antibody which binds to csPCNA, thereby preventing its binding to NK cells and restoring the cytotoxic activity of NK cells against cancer. We are studying the use of mAb14 antibody for the detection of malignant cells in Sezary blood samples and its potential as immune therapy treatment.