Utveckling av en ny cancerterapi riktad mot en av de vanligaste genetiska defekterna i barncancer

In the 0-14 years old age group, there are approximately 300 children that are diagnosed with cancer each year in Sweden. The prognosis for most tumors is generally good with an approximately 10-year survival of 80 percent. Still, one out of five children with cancer dies from the tumor, making cancer the most common cause of death among children in Sweden. In addition, despite the improved survival rate many of the treated children suffer of multiple side-effects that can adversely affect their future lives.

We are developing a novel therapy for children with cancer aiming to be more effective, and with fewer side-effects, than current standard of care by selectively killing cells that carry one of the most common defects in cancer patients, i.e., an impaired tumor suppressor Retinoblastoma 1 (RB1) signal pathway.

This proposal addresses the many side effects that cancer treatment causes in children treated with anti-proliferative chemotherapy. These agents are prescribed for a broad range of malignancies and target tumor growth by impairing processes such as genome homeostasis or the activities of microtubules. In this context, we found that a cell compensates the lack of RB1 activity with an increased expression of gamma-tubulin 1 (TUBG1), and in tumor cells with an impaired RB1 signal pathway, disruption of the activity of TUBG1 kills those sick cells without affecting healthy cells. Thus, the RB1-TUBG1 signal network can be used as a strategy for targeted chemotherapy of RB1-deficient tumors. Impairment of the RB1 signal pathway is one of the mechanisms behind the development of childhood malignancies, such as, retinoblastoma, osteosarcoma, neuroblastoma, and lymphoblastic leukemia. Thus, by exploring and optimizing a lead candidate, L12 (a TUBG inhibitor), we hope to develop personalized anti-cancer therapies that specifically target cancer cells with non-unfavorable side effects in treated children.