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Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism.

Al's Comment:

I have written a lot about this drug (Onc-201) lately - I am excited about it and we (the Musella Foundation) have a special interest in it because we gave grants to help them get this far!  This study shows that it may also be good to treat many other types of tumors that overexpress the target!  Right now for brain tumors it is in clinical trials for DIPG and high grade gliomas that have the H3 K27M mutation - which usually occurs in younger people with tumors in the midline of the brain.

Posted on: 12/19/2018

Clin Cancer Res. 2018 Dec 17. pii: clincanres.2572.2018. doi: 10.1158/1078-0432.CCR-18-2572. [Epub ahead of print]

Dopamine Receptor D5 is a Modulator of Tumor Response to Dopamine Receptor D2 Antagonism.

Prabhu VV1, Madhukar NS2, Gilvary C2, Kline CLB3 , Oster S4, El-Deiry WS3, Elemento O5, Doherty FC6, VanEngelenburg A7, Durrant J8, Tarapore RS9, Deacon S10, Charter N10, Jung J11, Park DM12, Gilbert MR11, Rusert JM13, Wechsler-Reya RJ14, Arrillaga-Romany I15, Batchelor TT15, Wen PY16, Oster W9 , Allen JE17.
Author information:
1. R&D, Oncoceutics Inc.
2. Weill Cornell Medical College.
3. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center.
4. Fox Chase Cancer Center.
5. Institute for Computational Biomedicine, Weill Cornell Medical College.
6. Immunohistochemistry, HistoTox Labs, Inc.
7. HistoTox Labs, Inc.
8. Pathology, HistoTox Labs, Inc.
9. Oncoceutics Inc.
10. Eurofins DiscoverX Corporation.
11. Center for Cancer Research, National Cancer Institute.
12. Neurology, University of Chicago.
13. Tumor Initiation & Maintenance Program, Sanford Burnham-Prebys Medical Discovery Institute.
14. Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute.
15. Massachusettes General Hospital.
16. Dana Farber Cancer Institute.
17. R&D, Oncoceutics Inc.
Dopamine receptor D2 (DRD2) is a G protein-coupled receptor antagonized by ONC201, an anti-cancer small molecule in clinical trials for high grade gliomas and other malignancies. DRD5 is a dopamine receptor family member that oppose DRD2 signaling. We investigated the expression of these dopamine receptors in cancer and their influence on tumor cell sensitivity to ONC201.
The Cancer Genome Atlas was used to determine DRD2/DRD5 expression broadly across human cancers. Cell viability assays were performed with ONC201 in >1,000 Genomic of Drug Sensitivity in Cancer and NCI60 cell lines. Immunohistochemistry staining of DRD2/DRD5 was performed in tissue microarrays and archival tumor tissues of glioblastoma patients treated with ONC201. Whole exome sequencing was performed in RKO cells with and without acquired ONC201 resistance. Wild-type and mutant DRD5 constructs were generated for overexpression studies.
DRD2 overexpression broadly occurs across tumor types and is associated with a poor prognosis. Whole exome sequencing of cancer cells with acquired resistance to ONC201 revealed a de novo Q366R mutation in the DRD5 gene. Expression of Q366R DRD5 was sufficient to induce tumor cell apoptosis, consistent with a gain-of-function. DRD5 overexpression in glioblastoma cells enhanced DRD2/DRD5 heterodimers and DRD5 expression was inversely correlated with innate tumor cell sensitivity to ONC201. Investigation of archival tumor samples from recurrent glioblastoma patients treated with ONC201 revealed that low DRD5 expression was associated with relatively superior clinical outcomes.
These results implicate DRD5 as a negative regulator of DRD2 signaling and tumor sensitivity to ONC201 DRD2 antagonism.


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