Medulloblastoma (MB) is the most common malignant brain tumour in children, with 12 molecularly distinct MB subtypes identified to date. Although current standard-of-care results in ~70% cure rate, surviving patients endure a host of long-term side-effects. Moreover, few effective therapies are available for a subset of poor prognosis MB subgroups and tumours that recur following therapy. These findings indicate an urgent need to identify new biologically targeted therapies that can be implemented rapidly into the clinic. CDK4/6–specific inhibitors are a clinically advanced CDK inhibitors, with Palbociclib being the first drug to receive FDA approval for the treatment of metastatic breast cancers. We have previously shown that Palbociclib is capable of extending survival of multiple MB subgroup patient derived xenograft (PDX) mouse models. However, we acknowledge that monotherapy is rarely curative and therefore set out to evaluate the most beneficial approach to combine Palbociclib treatment with chemotherapy treatment regimes.
We first analysed the in vivo cell cycle kinetics of tumour cells in response to Palbociclib treatment of PDX mouse models. Consistent with its role as a cell cycle inhibitor, we observed Palbociclib-induced G1/G0 and G2/M cell cycle arrest. Although target engagement studies revealed a relatively short pharmacological window, Palbociclib induced a state of prolonged cell cycle arrest, with evidence of cell cycle re-entry observed 48hrs post-treatment and average tumour proliferation rates returning 72hr post-treatment. Interestingly, we observed that Palbociclib caused an increased number of tumour cells to be recruited into cycle, which we confirmed using 24hr and 144hr BrdU label retaining analyses. In addition, our preliminary studies reveal that concurrent chemotherapy and CDK4/6 inhibition has no advantage. Consistent with the mechanism of CDK4/6 inhibition and data from other cancers, our data confirm that concurrent dosing has no therapeutic benefit. However, our data clearly reveal the potential for introducing Palbociclib treatment prior to chemotherapy, acting not only to debulk the tumour but also as a Chemosensitizer, optimising the efficacy of multi-agent chemotherapy.