Identifying therapeutic targets in small cell carcinoma of the ovary-hypercalcemic type (SCCOHT)
Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare, highly malignant form of ovarian cancer affecting young females, as young as 14 months and with an average onset of 24 years of age. SCCOHT patients face extremely poor survival rates. Due to the rarity of the cancer and ambiguity of the symptoms, this cancer often goes undiagnosed until stages III and IV. Survival at these stages is 4-12 months, despite treatments of surgical debulking, chemotherapy, and high-dose radiation. SCCOHT is characterized by mutations in SMARCA4; the ATPase subunit of the SWI/SNF chromatin remodeling complex, a complex known to be necessary for cell survival. Over 95% of SCCOHT patients have a mutation in SMARCA4 that renders this complex dysfunctional. This raises the question of how these cancer cells are surviving. One possibility is that another family of chromatin remodelers is compensating for loss of SWI/SNF. Another is that the loss of SWI/SNF causes an increase in oncogenic expression due to an increase in super-enhancer activity. These two theories are not mutually exclusive. Based on these ideas, nine candidate genes were selected for testing their necessity in the growth and viability of SCCOHT. Using siRNA knockdown, each of these candidate genes were silenced individually and growth and viability of SCCOHT cells was measured. Our results demonstrate SCCOHT’s dependency on super-enhancer associated oncogenes as well as chromodomain helicase DNA-binding remodelers. Cells with MLLT10 knockdown exhibited approximately 82% repression of growth compared to 91% in HRPT positive control, while growth of cells with knockdown of CHD2 were repressed in growth by approximately 89%. Although further testing and experimentation is needed, these results may be the first step in improving treatment options and patient outcomes in individuals suffering from SCCOHT.
