SCIENTIFIC BACKGROUND We are working with the hypoxia-tolerant (down to 3% O2), long-lived (>20 years) subterranean blind mole-rat, Spalax, which shows an outstanding cancer-resistance and anti-cancer capabilities. Observations of thousands of individuals at our Institute have never noticed a spontaneous malignant tumor. Furthermore, we have found in Spalax different structure and function of major genes related to cancer (p53, heparanase, genes of antioxidant defense and DNA-repair genes). Assessment of Spalax transcriptome assembly and expression data has revealed enrichment of genes that overlap cancer resistance, apoptosis, angiogenesis, and hypoxia-tolerance and elicits much wider and stronger expression in Spalax than in rat (Malik et al, 2012, BMC genomics, 13, 615). Moreover, Spalax has shown extremely high cancer-resistance to chemical carcinogens that induced cancer in 100% of mice and rats. Most intriguing, fibroblast cells only from Spalax, but not from other species, inhibit growth and kill cancer cells, but not normal cells, from various tissues and species, most importantly a wide range of human cancer cells. This is exhibited in both co-culture system or by exposure to factors secreted into conditioned media harvested from Spalax fibroblasts. Decreased cancer cell viability and proliferation, reduced colony formation in soft agar, disturbed cell cycle progression, chromatin condensation, nuclei deformation and mitochondrial fragmentation were reproducibly observed (Manov et al., 2013, BMC biology 11, 91). Our present objectives is to identify and isolate the substances secreted by Spalax cells, resolve with which components they interact that are active only on cancer cells, in order to unravel the biological mechanisms and pathways that evolved in Spalax cell machinery and ultimately lead to the death of cancer-cells. Bioinformatics objectives are a major part of this. The study could attest to be a breakthrough in cancer research, using the long lived, hypoxia- and cancer-tolerant Spalax as a significant biological resource for biomedical research that hopefully could open new horizons in treatment and prevention of cancer in humans.