Date of Award

3-2023

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Pharmaceutical Sciences

Track

Bioanalysis

Research Advisor

Jianxiong Jiang, PhD

Committee

Hassan Almoazen, PhD; Wei Li, PhD; Udai P. Singh, PhD; Jun Yang, PhD

Keywords

Pediatric Cancer, Tumor Inflammation

Abstract

Prostaglandin E2 (PGE2) is a predominant proinflammatory regulator that plays pivotal roles in regulating tumor cell proliferation, migration, and invasion. It fosters an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. Neuroblastoma (NB) is a lethal pediatric malignancy. PGE2 has been reported to promote high-risk NB proliferation and progression. However, the PGE2 receptor subtype (EP1-EP4) which potentially contributed to NB growth remained elusive. In this research, at first, we demonstrated that EP2 receptor was highly correlated with NB aggressiveness, and acted as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including chromosome 11q deletion and MYCN amplification. CRISPR/Cas9 induced EP2 knockout blocked the development of NB xenografts in athymic nude mice. Additionally, EP2 conditional knockdown prevented established tumors from progressing in vivo. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 substantially suppressed the NB tumor growth in both nude mice and syngeneic immunocompetent hosts, with the observable anti-inflammatory, anti-angiogenic, and apoptotic effects. Next, based on the scaffold of TG6-129, we developed, and identified a novel robust EP2 antagonizing compound GLL-618. GLL-618 demonstrated enhanced EP2 binding potency. Meanwhile, it also showed advanced pharmacokinetic features such as prolonged plasma half-life and im-proved bioavailability. Applied as a single treatment reagent, GLL-618 could significantly inhibited high-risk NB neuro-spheres development and suppressed high-risk NB xenograft tumors growth by 50%. Subsequently, we combined GLL-618 with vincristine, a prevalently used chemotherapy drug for the treatment of high-risk NB. GLL-618 could synergistically increase the anti-tumor effect of vincristine, which was evidenced by an overall 70% tumor weight reduction at the treatment endpoint in an immunocompetent allograft model, accompanied with quenched proinflammatory signaling within the tumor microenvironment and elevated expression of apoptotic markers. In conclusion, this study suggested that the PGE2/EP2 signaling pathway might contribute to NB development and progression. EP2 inhibition with our drug-like compounds could be potentially applied as an alternative, and adjunctive treatment strategy for this deadly pediatric cancer.

Declaration of Authorship

Declaration of Authorship is included in the supplemental files.

ORCID

https://orcid.org/0000-0002-9040-8223

DOI

10.21007/etd.cghs.2023.0616

Additional Files
2023-003-Hou-DOA.pdf (168 kB)
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