Abstract 2888: Dopamine signaling and therapeutic resistance in GBM
Authors: Caragher Seamus P. , Park Cheol H. , Atashi Fatemeh , Baisiwala Shivani , Ahmed Atique U. 
Published: July 2017

Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, is characterized by aggressive recurrence after conventional treatment, which include surgery followed by radiation and chemotherapy. This recurrence reilies on GBM cells’ ability to promote therapeutic resistance. The recently developed Cancer Stem Cell (CSC) hypothesis argues that GBMs are driven by a rare subset of cells called Glioma Stem Cells (GSCs). A significant corollary of the CSC hypothesis is that GSCs have the ability to survive intensive radio- and chemotherapy and give rise to recurrent disease. Recent studies from our laboratory and others have shown a high degree of plasticity in GBM cells that indicated normal GBM cells acquire a stem-like state during anti-glioma therapy. Termed conversion, this molecular process increases the frequency of therapy resistant GSCs and promotes disease recurrence. We hypothesize that a drug capable of blocking tumor cell plasticity would prevent the generation of therapy-resistant GSCs, thereby block GBM recurrence. Based on this concept, we have developed a plasticity-based high-throughput drug screening method for GSCs. Our initial screening has identified several novel FDA-approved compounds that act as antagonists of neurotransmitter receptors. Further investigation revealed that treatment of patient-derived xenograft (PDX) GBM lines with temozolomide (TMZ) led to the formation of a population of cells that express both CD133, a marker of CSCs, and dopamine receptors 2 and 3 (DRDs) (control mean CD133+/DRD2+: 19.7%, TMZ mean: 83.8%, p=.0001). PDX lines treated with a dopamine receptor agonist exhibited increased expression of SOX2, OCT4 and c-Myc, GSC-markers. However, this treatment did not increase the expression of Ki67 in the GSC compartment, a marker for cell proliferation (mean DMSO: 63.8%, mean TMZ: 57.4%). Thus, DRD signaling may influence the plasticity driven GSC niche. Utilizing a CD133-reporter cell line, we found that two anti-psychotics, chlorprothioxene and loxapine, prevented the induction of CD133 expression caused by treatment with TMZ. Finally, we treated PDX lines with chlorpromazine, a newer version chlorprothioxene, in conjunction with TMZ, which resulted in increased therapeutic effecacy (p&lt;.0001 by MTT assay). Overall, these data suggest that dopamine receptor signaling and stress-induced cellular plasticity interact in GBM. We proposed that dopamine receptors represent a strategy by which specific molecular changes induces by canonical chemotherapeutic agents can be inhibited to prevent the induction of resistance in surviving cells.

Citation Format: Seamus P. Caragher, Cheol H. Park, Fatemeh Atashi, Shivani Baisiwala, Atique U. Ahmed. Dopamine signaling and therapeutic resistance in GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2888. doi:10.1158/1538-7445.AM2017-2888