Sidharth Mahapatra Lab

Haploinsufficiency of 17p13.3 has been reported in up to 50% of MB cases and correlated with poor prognosis. Chromosomal mapping and microdeletion studies of 17p13.3 have revealed many putative tumor suppressor genes on this locus, including several microRNAs. MicroRNAs (miRs) regulate gene expression by binding to the 3’- untranslated region (3’-UTR) of target mRNAs and inhibiting their expression. MiRs can serve as ideal tumor suppressor genes, given their capacity to serve a regulatory role for hundreds of target proteins.

MiR-1253, found on the terminal end of 17p13.3, is a brain enriched miR that plays a critical role in cerebellar development. We showed that miR-1253 possesses strong tumor-suppressive properties in medulloblastoma and is silenced in MB tumors by hypermethylation. MiR-1253 suppresses the expression of several key oncoproteins, including cell cycle checkpoint proteins ( CDK4, CDK6, cyclin D1), mitochondrial iron transporters (ABCB6, ABCB7, ABCB8), and the immune checkpoint regulator CD276/B7-H3.

Rapidly dividing cancer cells require iron as a critical substrate. Mitochondrial ABC transporters are intimately involved in supplying iron-sulfur and heme proteins to buttress the elevated need for proteins essential to cancer cell growth and proliferation. ABCB7 is expressed in the inner mitochondrial membrane and involved in iron-sulfur cluster export from the mitochondria after synthesis. It is also enriched in group 3 MB and inhibited by miR-1253. Repression of ABCB7 triggers iron overload, ROS generation, and lipid peroxidation, culminating in cell death by ferroptosis. Moreover, the cytotoxic actions of cisplatin, partially mediated by ferroptosis, are potentiated by ABCB7 repression in group 3 tumors. These novel findings unlock the potential to exploit the high iron needs of medulloblastomas as a targetable vulnerability to enhance the effect of chemotherapy in aggressive MB tumors.

B7-H3 is an immunomodulatory protein whose deregulation in many malignancies is linked to more aggressive, metastatic tumors, higher relapse rates, and drug resistance. B7-H3 can serve as an ideal targetable oncoprotein in MB for several reasons. First, similar to various other cancers, its expression is enriched in MB. Second, deregulated B7-H3 expression is strongly associated with poorer outcomes, especially in group 3 tumors. Third, B7-H3 inhibition attenuates tumor growth and mortality. We further showed that targeting B7-H3 in vitro resulted in appreciable inhibition of cancer cell migration, invasion, and the metastasis-associated protein, SLUG. These observations suggest that targeting the tumor-promoting properties of B7-H3 is an efficacious way to curb the aggressiveness of group 3 MB tumors. We are now exploring small-molecule inhibitors of B7-H3, generated through a structure-based drug discovery pipeline.

Medulloblastomas affect children with a 10-fold higher incidence than adults. MB therapy has largely depended on chemo-radiation regimens that result in appreciable toxicities, sometimes precluding effective dosing. Studying the tumor transcriptome may hold the key to designing better treatment option for children with MB.

In this study, we approached novel drug discovery for MB by comparing the tumor transcriptomes of 2 cohorts of pediatric MB patients against a library of integrated network-based cellular signatures (LINCS), which houses omics signatures for cellular perturbations to known drugs. Our intent is to isolate those drugs capable of reverting the tumor transcriptome to a more normal cerebellar phenotype. We applied 2 additional filters, including FDA approval in pediatric patients and blood-brain barrier permeability, and have isolated several promising compounds with strong anti-neoplastic properties in group 3 MB. Amongst the most promising drug classes are statins, selective serotonin-reuptake inhibitors (SSRIs), and tricyclic antidepressants (TCAs).