Dddr-23. in Silico Drug Discovery Reveals Subtype-specific Combination Therapies With Casein Kinase 2 Inhibitor Cx-4945 in Glioblastoma
Year: 2022
Type: article
Abstract: The treatment for glioblastoma (GBM) is maximal safe resection, temozolomide chemotherapy, and radiation therapy. However, with a median survival of only 15 months, new therapies are needed. GBM tumors are highly heterogeneous and three tumor subtypes, namely classical, proneural, and mesenchymal, have been identified. On a single cell level, differences are even more granular. Casein kinase 2 (CK2), which regulates invasion and important pathways including Wnt, Shh, and Notch in GBM, may be a promising target in distinct subpopulations. The CK2 inhibitor CX-4945 (silmitasertib) is in clinical trials for several cancers, including medulloblastoma. We employed single-cell RNA sequencing and analyzed bulk RNA sequencing data of PDX tumors (Brain Tumor PDX national resource at the Mayo Clinic). We found that on the tumor level, CX-4945 may preferentially target mesenchymal subtypes, which are the most invasive. On a single-cell level, CX-4945 was predicted to target cells with Astrocyte-like and Mesenchymal-like transcriptional states, which we show to become enriched upon treatment with the pan-aurora kinase inhibitor alisertib. Thus, CX-4945 in combination with a treatment targeting tumor subtypes and cell populations that evade CK2 inhibition may achieve beneficial clinical results. We identified several promising small molecules that could complement CX-4945 treatment based on the predicted reversal of the transcriptional disease gene expression signatures, which are specific for each subtype. Among these drugs are multiple anti-cancer agents that have shown favorable tolerability and brain penetrance in patients and may be effective in combination therapies. In a next step, we will evaluate the predicted combinations with CX-4945 in vitro and in vivo, with a particular focus on how they influence invasion and migration.
Source: Neuro-Oncology
Institution: Georgetown University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4309014487