A Novel Target for Neuroblastoma Treatment

Background

We speculated that agents targeting the protein-protein interaction mediated through the interconnector domain loop of the protein caPCNA may be selectively and preferentially toxic to neuroblastoma (NB) cells while sparing normal cells. To test this premise, we designed a cell permeable peptide containing the target sequence of PCNA (R9-caPep). We found that this peptide selectively kills NB cells while exhibiting little effect on non-malignant cells. Surprisingly, NB cells with MYCN amplification were uniformly more sensitive to R9-caPep than NB cell lines without MYCN amplification. In addition, R9-caPep was observed to significantly suppress NB cell growth in a mouse xenograft model. To leverage the biological and structural insight derived from studying caPCNA and R9-caPep and move these encouraging findings towards the clinic, we designed and tested a series of small molecule agents through multiple rounds of analysis and functional testing.

Project Goal

As a result of the work, we identified the potent PCNA inhibitor AOH1160, which selectively kills NB cells at sub-micromolar concentrations and sensitizes NB cells to cisplatin treatment. Mechanistically, AOH1160 blocks homologous recombination (HR) mediated DNA repair and causes accumulation of unrepaired DNA damage, G2 cell cycle arrest, and apoptosis in cancer cells. The compound is orally available to animals and suppresses tumor growth without causing significant weight loss in mice. In summary, the pharmacologic and therapeutic properties of AOH1160 are extremely favorable. This application proposes studies to advance the compound to the stage of clinical evaluation and meet FDA investigational new drug (ING) requirements.