Inhibiting microcephaly genes as alternative to microtubule targeting agents to treat brain tumors

Abstract

Medulloblastoma (MB) and gliomas are the most frequent high-grade brain tumors (HGBT) in children and adulthood, respectively. The general treatment for these tumors consists in surgery, followed by radiotherapy and chemotherapy. Despite the improvement in patient survival, these therapies are only partially effective, and many patients still die. In the last decades, microtubules have emerged as interesting molecular targets for HGBT, as various microtubule targeting agents (MTAs) have been developed and tested pre-clinically and clinically with encouraging results. Nevertheless, these treatments produce relevant side effects since they target microtubules in normal as well as in cancerous cells. A possible strategy to overcome this toxicity could be to target proteins that control microtubule dynamics but are required by HGBT cells much more than in normal cell types. The genes mutated in primary hereditary microcephaly (MCPH) are ubiquitously expressed in proliferating cells, but under normal conditions are selectively required during brain development, in neural progenitors. There is evidence that MB and glioma cells share molecular profiles with progenitors of cerebellar granules and of cortical radial glia cells, in which MCPH gene functions are fundamental. Moreover, several studies indicate that MCPH genes are required for HGBT expansion. Among the 25 known MCPH genes, we focus this review on KNL1, ASPM, CENPE, CITK and KIF14, which have been found to control microtubule stability during cell division. We summarize the current knowledge about the molecular basis of their interaction with microtubules. Moreover, we will discuss data that suggest these genes are promising candidates as HGBT-specific targets.

The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes

“…Targeting of microcephaly-associated genes has been proposed as an alternative to microtubule-targeting agents to treat brain tumors (Iegiani et al, 2021). In line with this idea, our results…”

“…Targeting of microcephaly-associated genes has been proposed as an alternative to microtubule-targeting agents to treat brain tumors (Iegiani et al, 2021). In line with this idea, our results showed that MAGOH and MAGOHB knockdown is well-tolerated in astrocytes but not in GBM cells.…”

ASPM induces radiotherapy resistance by disrupting microtubule stability leading to chromosome malsegregation in non-small cell lung cancer

“…Indeed, high expression of ASPM correlated directly with chromosome missegregation and increased numbers of micronuclei, suggesting that high expression of ASPM in NSCLC is more likely to be intrinsic and integral to RT resistance rather than incidental. This notion is also supported by recent comprehensive functional analyses of ASPM in different types of tumors in patients [39][40][41]. We propose that mis-segregation of chromosomes could have much broader effects extending beyond radiation resistance in cancer, which underscores the broad clinical value of understanding the exact role of the genomic instability in cancer progression and therapy.…”

Nonviral nanoparticle gene delivery into the CNS for neurological disorders and brain cancer applications

“…Consequently, nonviral gene therapy presents an attractive, low‐cost alternative to current standards of care, especially as new biological mechanisms can be targeted. Beyond delivery of cytotoxic genes, some examples of additional nonviral gene therapy approaches with mechanisms that can suppress brain tumors include nanoparticles delivering miR‐486‐5p antagomirs or cancer inhibiting miRNAs (Lopez‐Bertoni et al, 2018, 2020), delivering factors such as bone morphogenetic proteins to inhibit cancer cell stem cells (Piccirillo et al, 2006), or targeting microcephaly genes (Iegiani et al, 2021).…”