1. Tissue regeneration after radiation damage

More than half of cancer patients are treated with ionizing radiation. Therapeutic effect of IR is due to its ability to induce apoptosis. Surviving cells could, however, proliferate and regenerate the tumor leading to treatment failure. We have been using Drosophila melanogaster to identify and study mechanism by which cells survive radiation exposure and regenerate in the context of multicellular animals. We uncovered a mechanism for cell death in the absence of p53 that relies on E2F proteins (Wichmann et al., PNAS, 2006; Wichmann et al., Dev Bio, 2010). We found that surviving cells in the larval wing disc receive ‘do not die’ signals from dying cells (Bilak et al., PLoS Genetics, 2014). This signal also operates to protect Germline Stem Cells (Xing et al., Nat Comm, 2015). We identified a subset of columnar epithelial cells in the larval wing disc that relinquish their original fate to behave like stem cells after X-ray damage (Verghese and Su, PLoS Biology, 2016). We identified mechanisms that ensure that only one wing disc is regenerated, no more and no less (Verghese and Su, PLoS Genetics, 2017).

 

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.