Abstract
Purpose: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models. Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients. To deliver personalized RNA-based-therapy targeting oncogenic miRNAs that form part of this common PDAC miRNA over-expression signature, we packaged antimiR oligonucleotides against one of these miRNAs in tumor-penetrating nanocomplexes (TPN) targeting cell surface proteins on PDAC tumors. Results: As a validation for our pre-clinical strategy, the therapeutic potential of one of our nano-drugs, TPN-21, was first shown to decrease tumor cell growth and survival in PDO avatars for individual patients, then in their PDX avatars. Conclusions: This general approach appears suitable for co-clinical validation of personalized RNA medicine and paves the way to prospectively identify patients with eligible miRNA profiles for personalized RNA-based therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 1734-1747 |
| Number of pages | 14 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2018 |
Bibliographical note
Publisher Copyright:© 2018 American Association for Cancer Research.
Funding
We thank Heather Fleming and Teddy Jégu for critical reading of this manuscript, Omar Gandarilla Cuellar and Dipikaa Ashinthala for providing PDO and reagents required for PDO growth, and Nelson Moreira for providing normal pancreatic tissue samples. This work was supported by a grant to F.J. Slack and S.N. Bhatia by the Harvard Medical School Initiative for RNA Medicine and to F.J. Slack, S.K. Muthuswamy, and M. Hidalgo from the BIDMC CAO Pilot Award. We thank Heather Fleming and Teddy Jegu for critical reading of this manuscript, Omar Gandarilla Cuellar and Dipikaa Ashinthala for providing PDO and reagents required for PDO growth, and Nelson Moreira for providing normal pancreatic tissue samples. This work was supported by a grant to F.J. Slack and S.N. Bhatia by the Harvard Medical School Initiative for RNA Medicine and to F.J. Slack, S.K. Muthuswamy, and M. Hidalgo from the BIDMC CAO Pilot Award.
| Funders | Funder number |
|---|---|
| Beth Israel Deaconess Medical Center | |
| Harvard Medical School |
ASJC Scopus subject areas
- General Medicine
