IMPACCT · Improved Patient Care by Combinatorial Treatment

Targeted precision medicine combined with companion diagnostics will provide the basis for future more effective more economic patient care. Recent advances in breast cancer treatment combining inhibitors of poly-ADP-ribose polymerase (PARP1) in conjunction with other targets are at the forefront of this new advance both at the level of basic research and pharmaceutical interest, due to its pivotal role in gene expression, chromatin and repair. We have discovered a key enzyme downstream of PARP1 which generates ATP locally in the nucleus; NUDIX5. This enzyme is overexpressed in cancer and correlates with poor prognosis, as the activity of this enzyme is essential for changes within the 3D chromatin structure, gene regulation and the proliferation of cancer cells. We have developed inhibitors of NUDIX5 in addition to a companion diagnostic, and propose to prove using a multi-disciplinary, international collaborative effort that they can be used to determine not only patient risk and treatment options but also provide an exciting new avenue for the combinatorial treatment of breast and (we hope) other cancer patients.