Veliparib Is an Effective Radiosensitizing Agent in a Preclinical Model of Medulloblastoma

Abstract

Medulloblastoma is the most common malignant childhood brain tumor, and 5-year overall survival rates are as low as 40% depending on molecular subtype, with new therapies critically important. As radiotherapy and chemotherapy act through the induction of DNA damage, the sensitization of cancer cells through the inhibition of DNA damage repair pathways is a potential therapeutic strategy. The poly-(ADP-ribose) polymerase (PARP) inhibitor veliparib was assessed for its ability to augment the cellular response to radiation-induced DNA damage in human medulloblastoma cells. DNA repair following irradiation was assessed using the alkaline comet assay, with veliparib inhibiting the rate of DNA repair. Veliparib treatment also increased the number of γH2AX foci in cells treated with radiation, and analysis of downstream pathways indicated persistent activation of the DNA damage response pathway. Clonogenicity assays demonstrated that veliparib effectively inhibited the colony-forming capacity of medulloblastoma cells, both as a single agent and in combination with irradiation. These data were then validated in vivo using an orthotopic implant model of medulloblastoma. Mice harboring intracranial D425 medulloblastoma xenografts were treated with vehicle, veliparib, 18 Gy multifractionated craniospinal irradiation (CSI), or veliparib combined with 18 Gy CSI. Animals treated with combination therapy exhibited reduced tumor growth rates concomitant with increased intra-tumoral apoptosis observed by immunohistochemistry. Kaplan–Meier analyses revealed a statistically significant increase in survival with combination therapy compared to CSI alone. In summary, PARP inhibition enhanced radiation-induced cytotoxicity of medulloblastoma cells; thus, veliparib or other brain-penetrant PARP inhibitors are potential radiosensitizing agents for the treatment of medulloblastoma.

The pivotal role of irradiation‐induced apoptosis in the pathogenesis and therapy of medulloblastoma

“…130 It was observed a single dose of veliparib in combination with IR significantly augmented intratumoral apoptosis on immunohistochemistry staining, signifying that veliparib augmented IR induced MB cell death in vivo. 130 Notably, knockout of RBM5-AS1 triggered sensitization of DAOY xenograft tumors to IR, which was associated with augmented apoptosis. 51 Thus, RBM5-AS1 is a promising target to mitigate radioresistance in MB via apoptosis.…”

“…Interestingly, interfering with the Ptch1/SMO/SUFU/GLI axis in the hedgehog pathway with small molecules has been implicated as a promising therapy for SHH MBs via apoptosis 27 . Remarkably, veliparib was tested as a radiosensitizing agent in both in vitro and a mouse model of MB 130 . It was observed a single dose of veliparib in combination with IR significantly augmented intratumoral apoptosis on immunohistochemistry staining, signifying that veliparib augmented IR induced MB cell death in vivo 130 …”

The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma

“…Thus, it will be interesting to see whether non-WNT/non-SHH patients will be included in currently running trials using PARP inhibitors (NCT03233204 and NCT04236414). Lastly, several preclinical studies with different compounds indicate that the concept of sensitizing cancer cells to radiotherapy using small molecules could be potentially interesting for non-WNT/non-SHH MB [165][166][167]…”

Current Treatments and New Possible Complementary Therapies for Epithelial Ovarian Cancer

“…Similarly, the U.S. FDA approved rucaparib as a single agent for treating relapsed ovarian cancer with mutations in BRCA genes in patients who had received two or more lines of chemotherapy [ 74 ]. Unlike the other PARP inhibitors, veliparib has not shown anti-proliferative activity, but radio and chemo-sensitizing effects were reported in cancer cells [ 75 ].…”