Rodney Hicks, MD University of Melbourne, Melbourne, Australia
General DescriptionThis four-year Accelerator Project will include both laboratory tests and clinical trials aimed at improving the clinical benefits of PRRT. While some patients respond well to PRRT, others are resistant to this type of therapy. By understanding what drives this resistance, investigators hope to improve durable response, and therefore widen the pool of patients who benefit from PRRT. Hicks and colleagues will evaluate the impact of PRRT on tumor cells’ ability to recognize and repair radiation damage. To prevent cancer cell repair, the investigators will combine PRRT with therapies that block DNA-repair mechanisms. Laboratory studies will identify which targeted therapies “turn off” cellular repair mechanisms. Then, a pilot clinical trial will test the targeted therapies in combination with PRRT in patients.
This complex research project that extended from genomic characterization through preclinical studies using relevant animal models to clinical studies has demonstrated the importance of DNA-repair mechanisms to sensitivity of NET to the internal radiation delivered to neuroendocrine tumor deposits through peptide receptor radionuclide radionuclide therapy (PRRT). Intrinsic resistance the PRRT was demonstrated in several relevant cell lines used in the study of NET biology and we were also able to develop radioresistance in initially sensitive cell lines in preclinical animal models through repeated application of PRRT, recapitulating clinical experience which suggests decreasing efficacy of PRRT in the retreatment setting. Genomic analysis has indicated that there isn’t a consistent mechanism within these radioresistant cell lines. However, our research has demonstrated further that modification DNA-repair genes through either suppressing their expression at genomic level or through pharmaceutical intervention can increase sensitivity to PRRT both in cell culture and in animal models. In particular, we demonstrated the utility of drugs that target the repair of both single-strand and double-strand DNA breaks induced by radiation in increasing the sensitivity to PRRT. One of these classes of drugs has been translated into an ongoing clinical trial. The other agent shows even greater promise for clinical translation.
Finally, we applied whole genome and whole exome sequencing to interrogate 53 pancreatic NET tumors from 41 patients who had demonstrated good response to PRRT. The genomic profile of these tumors was broadly consistent with the known spectrum of mutations previously reported in pancreatic NETs. A strong predictive biomarker of PRRT response was unfortunately not evident from mutation data. Therefore, an expansion of the number of patient cases analysed may be required to increase the statistical power for analysis. Alternatively, the analysis of RNA transcription and DNA methylation in tumor samples may be required as an alternative biomarker type. However, serendipitously, we identified a novel recurrent gene-fusion involving the gene PSIP1 in PNETs and have successfully generated a cell line model from a patient’s tumor. Future work will involve characterising the function of this fusion and its importance to PNET tumorigenesis.
- State: International
- Grant Duration: 4 years
- Awards: Accelerator Grant
- Sponsor: Margie & Robert E. Petersen Foundation
NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.