PLK inhibitors come of age in pediatric brain tumors Free

Medulloblastoma is the most common embryonal tumor of early childhood.¹ These tumors exhibit considerable heterogeneity in their response to treatment.² Profiling studies have led to the molecular classification of these tumors into wingless (WNT), sonic hedgehog (SHH), group 3, and group 4 tumors.³ Further, a combinatorial genomic approach expanded the number of subtypes to 12, encompassing two WNT, four SHH, three group 3, and three group 4 subtypes.² These remarkable efforts have provided insights into the considerable biological and clinical heterogeneity noted and highlighted the need for a recalibration of treatment approaches, where medulloblastoma is not viewed as a single disease entity.² Current treatments include tumor resection, craniospinal radiation for those >3 years, and combination chemotherapy, and these have not changed for several years. Treatment intensification has improved overall survival to over 70%, albeit with neurological sequelae and other quality of life issues.² Thus, the urgency for targeted, less toxic therapies that can help minimize radiation exposure and chemotherapy or perhaps even reduce the risk of relapse, is clear. The need is greatest for patients with SHHα, group 3γ, and group 4α medulloblastoma, who are at high risk for metastasis and relapse and have an overall poor prognosis.² Perturbation in MYC (either c-MYC or N-MYC) oncogenic program is a unifying theme amongst these tumors. In the study by Wang et al, the authors have addressed the clinical need for therapeutics for group 3 medulloblastomas by performing a genetic screen to identify therapeutic vulnerabilities in this group of tumors with MYC-amplification.⁴

The CRISPR-Cas9 screen targeting 1140 druggable genes identified the Polo-like kinase 1 (PLK1) as a key mediator of tumor growth in MYC-driven medulloblastomas. This first in brain cancers study by Wang et al, found PLK1 expression to be upregulated in over 55 central nervous system cancer cell lines including medulloblastomas.⁴ This is consistent with observations from a number of groups that have ascribed a poor prognostic outlook to PLK1 overexpression in other solid tumors and hematologic malignancies.⁵ The finding was confirmed in comparison between normal cerebella and group 3 medulloblastomas and a larger publicly available microarray dataset of all medulloblastoma subgroups. Critically, lower PLK1 expression correlated with better survival in group 3γ patients with an especially low overall survival of 30%, suggesting that targeting PLK1 in patients whose tumors express higher levels of the gene/protein may result in a significant improvement in survival.⁴

PLK1 is the most extensively studied molecule among a family of five highly conserved serine-threonine Polo-like kinases (PLKs). Its targets include the tumor suppressor—PTEN, the anti-apoptosis BCL2 family member—MCL1, and the E3 ligase SCFFBXW7, to name a few.⁵ SCFFBXW7 loss under conditions of PLK1 elevation results in increased stability of MYC, NOTCH1, and JUN oncogenes, which in MYC-amplified medulloblastomas, sustains PLK1 expression through a feed-forward loop.⁶ MYC is notoriously difficult to target, and therefore Wang et al argue that PLK1 inhibition and impairment of MYC-PLK1 interaction is a translatable approach to treating MYC-driven medulloblastomas.⁴ PLK1 also plays key roles in controlling entry into mitosis, spindle formation, chromosome segregation, and cytokinesis, and targeting PLK1 induces G2/M-phase arrest and apoptosis.⁵ Surprisingly, despite their pre-clinical promise, PLK1 inhibitors have shown limited success as single agents in clinic studies. However, PLK1 inhibition has found better traction as a modality to overcome resistance to monotherapy. Elevated PLK1 expression confers insensitivity to therapeutic agents, including gemcitabine, doxorubicin, metformin, paclitaxel through mechanisms, including induction of stress-mediated DNA replication, enhanced p53 ubiquitination and degradation, upregulation of multidrug resistance mutation 1 (MDR1) gene, changes in cancer metabolism, and preventing androgen signaling blockade.⁵ PLK1’s role in the DNA damage checkpoint response is of particular relevance to radiosensitization of medulloblastoma by PLK1 inhibition as reported in this issue by Wang et al.⁴ Although data to this effect were not explicitly shown, it would be reasonable to assume that PLK1 inhibition and the failure to trigger the DNA damage checkpoint and promote DNA repair consequent to radiation-induced DNA damage will have lethal consequences for cancer cells. Needless to say, these findings are timely for pediatric brain tumors such as medulloblastoma, where radiation continues to be a mainstay of the therapeutic regimen.

Work by Wang et al., and Schmidt et al., using mouse intracranial models of MYC-driven medulloblastomas⁴ and embryonal tumor with multilayered rosettes ETMR)⁷, respectively, also indicate that the PLK1 inhibitors onvasertib and volasertib can cross the blood brain barrier (BBB). Thus, these studies lend support for the exploration of these agents against other brain tumors. Diffuse intrinsic pontine glioma (DIPG) may be an example of a treatment-refractory, MYC/RAS-driven oncogenic program-driven pediatric brain tumor where PLK1 inhibitors may find application, especially given the importance of radiation as a component of the standard of care.⁸

In clinical studies, the PLK1 inhibitor volasertib appears to have a manageable safety profile and has advanced to phase III trials.⁹ However, it will likely be used only against some solid tumors because of a lack of efficacy against all cancers and development of resistance due to upregulated expression of the ATP-binding cassette (ABC) drug transporter ABCB1.⁵ GSK461364, an ATP-competitive PLK1 inhibitor, has been studied in phase II trials but also seems to be confounded by upregulation of ABCB1 expression.⁵ Onvansertib (PCM-075/NMS-1286937) is an ATP-competitive highly selective PLK1 inhibitor.¹⁰ In pre-clinical studies, it could block the growth of solid and hematological malignancies at nanomolar concentrations, which was recapitulated in the group 3 medulloblastoma study by Wang et al.⁴ A dose-escalation study of onvansertib in patients with advanced/metastatic solid tumors revealed neutropenia and thrombocytopenia as dose-limiting toxicities.¹⁰ The oral bioavailability of the drug and its short half-life (20-30 hours) make these dose limiting toxicities (DLTs) clinically manageable through a better-designed dosing schedule.¹⁰ These data should encourage the initiation of clinical studies in pediatric brain tumor patients, where there is a desperate need for new therapeutic approaches.

Acknowledgments

The text is the sole product of the authors and that no third party had input or gave support to its writing.

Funding

The work in V.G.’s laboratory is supported by funds from the Addi’s Faith Foundation.

References