1. Non-autonomous protective effect of dying cells

Earlier this year, we reported a phenomenon wherein induction of apoptosis by a variety of means in wing imaginal discs of Drosophila larvae resulted in the activation of an anti-apoptotic microRNA, bantam. Cells in the vicinity of apoptotic cells also become harder to kill by ionizing radiation (IR)-induced apoptosis. The protective effect spanned as much as 100 microns away from dying cells. Both ban activation and increased protection from IR required receptor tyrosine kinase Tie, which we identified in a genetic screen for modifiers of ban. Apoptotic cells showed increased expression of transcriptional reporters for Pvf1 and Pvf2, putative ligands for Tie. We proposed that apoptotic cells activate ban in surviving cells through Tie to make the latter cells harder to kill, thereby preserving tissues and ensuring organism survival.

 

2. Chemical modulators of radiation sensitivity

Drosophila larvae have an amazing capacity to regenerate. Even after half of the cells in larval organ precursors have been killed with X-rays, the remaining cells can regenerate to produce a healthy, fertile adult. We are using this system to screen for small chemical molecules that inhibit regeneration after radiation damage, thereby enhancing the killing effect of radiation. We have screened through several public and commercial chemical libraries. Some of the hits enhance the effect of radiation in both Drosophila and human cancer models in proof-of-concept studies. We are focusing on a family of molecules that act by blocking the elongation step of protein synthesis. Translation elongation remains under-utilized as a drug target in oncology despite emerging evidence that it is highly relevant to cancer and recovery after radiation damage (e.g. Kruiswijk et al., Science Signaling, 2012). We hope to exploit this space to develop new ways to improve the treatment of cancers such as head and neck cancers and glioblastoma where radiation remains a key therapy choice.