Figure provided by Dr. Cook Sangar.
Medulloblastoma is the most common form of brain cancer affecting children. 70% of patients are cured with treatments such as surgery, multi-agent cytotoxic therapy or radiation. However, associated side effects such as neurocognitive impairments, endocrinopathy or other malignancies remain a concern. For this reason, new treatments lowering toxicities without diminishing efficacy are necessary. More specific targeted treatment with minimal impact on the healthy tissues should address these issues. To this end the molecular biology of different types of medulloblastoma have been investigated and four main groups were characterized based on the molecular pathways involved: WNT, SHH, group 3 and group 4.
In a study recently published in Clinical Cancer Research, Drs. Michelle Cook Sangar and Jim Olson, from the Fred Hutch (Clinical Research Division) along with researchers from the Institute for Molecular Bioscience and the Walter and Eliza Hall Institute of Medical Research Australia and colleagues from the Department of Veterinary Biosciences in Ohio used a bioinformatic approach to determine new target genes. Cyclin Dependent Kinase 6 (CDK6) a protein belonging to the CDK4 / CDK6 / Cyclin D / Rb pathway was identified as a commonly mutated gene for three different subgroups of medulloblastoma: SHH, groups 3 and 4. Mutations in this pathway had previously been associated with poor prognosis.
To investigate the efficacy of CDK4/6 inhibition as a therapeutic strategy for medulloblastoma in vivo, the authors used Palbociclib (IBRANCE, Pfizer, Inc), a specific inhibitor of CDK4 and 6 that arrests cells in G1 phase of the cell cycle. Palbociclib has been FDA approved for the treatment of advanced breast cancer and is effective against several types of brain tumors.
The efficacy of palbociclib was tested in pediatric patient-derived medulloblastomas xenografted into immunodeficient mice within hours following surgical removal of the tumor. Palbociclib treatment was administrated orally daily. Palbociclib modulates the CDK4/CDK6 pathway by inhibiting Rb protein phosphorylation. To determine whether this occurred in the native context in medulloblastoma tumors, the authors xenografted the tumor tissue in the flank of the mice. Upon drug-induced tumor regression, cells were isolated for analysis of Rb protein phosphorylation by immunoblot and immunohistochemistry. Palbociclib efficiently decreased Rb protein phosphorylation and resulted in a significant increase in cancer cells arrested in G1 phase of the cell cycle (97% of the tumor cells relative to 80% of mock treated cells), suggesting that this drug functions against medulloblastoma using similar molecular mechanisms as described previously.
Significant reduction in tumor growth was observed following drug treatment against different types of medulloblastoma with a 63% decrease in tumor size for both group 3 and SHH tumor types along with a decrease of 84% and 32% in Ki67 proliferation marker expression in group 3 and SHH tumors, respectively. The morphological appearance of the tumors was also different between groups suggesting variability in the tumor response to Palbociclib. All treated tumors volumes decreased until no measurement was possible. At day 16 the treatment was withdrawn and 15 out of 20 treated mice recurred within two months.
The authors also evaluated Palbociclib efficiency in the brain microenvironment against orthotopically (tumors implanted into their tissue of origin) xenografted medulloblastoma tumors by MRI (Magnetic Resonance Imaging). A significant reduction of the tumor size was observed between early and late stages of the drug administration relative to the vehicle-treated mice. Drug-treated mice survived for 29 days while the vehicle-treated mice were all euthanized due to brain tumor burden prior to the end of the study. The blood brain barrier (BBB) frequently impairs drug delivery to the central nervous system, therefore the integrity of the BBB was assessed during the MRI study. The imaging showed a disrupted BBB in tumor-bearing mice that could improve drug accessibility to the brain. “Most patients have disrupted BBB. However, some cells are protected by the BBB and these cells could repopulate the tumor. There are drugs from other companies that target CDK4/6 and that are likely to have better BBB penetration. We are studying those now”, explained Dr. Olson.
In a definitive efficacy study in mice bearing Group 3 medulloblastoma brain tumors, all palbiciclib-treated mice survived up to 31 days while twelve out of thirteen vehicle-treated mice were euthanized due to tumor burden. Half of the treated surviving mice were withdrawn from treatment. From these, 1 out of 5 mice in the withdrawn group survived as compared to 4 out of 5 mice in a group that continued drug treatment. These data demonstrate that palbociclib is highly effective in the treatment of Group 3 medulloblastomas but there is likely persistence of tumor cells resistant to the drug treatment leading to tumor recurrence. A combination treatment might be necessary to eliminate all of the tumor cells. However, as explained by Dr. Olson, there is a lack of evidence indicating, “whether Palbociclib will work in patients who were previously irradiated. In cancer research, we do most of our pre-clinical work on models that are chemotherapy and radiotherapy naïve. In human trials, most of the first patients treated are in Phase I or II studies and most of these patients will have seen prior radiation or chemotherapy. We are currently studying the impact of prior radiation on Palbociclib response.”
Financial support for this study was provided by the National Cancer Institute (NIH/NCI), Seattle Children’s Brain Tumor Endowment (JO), the Kids Cancer Project (BW), the Cure Brain Cancer Foundation (BW) and the Brainchild Foundation (BW).
Cook Sangar ML,Genovesi LA,Nakamoto MW,Davis MJ,Knoblaugh SE,Ji P,Millar A,Wainwright B,Olson JM. 2017. Inhibition of CDK4/6 by Palbociclib Significantly Extends Survival in Medulloblastoma Patient-Derived Xenograft Mouse Models. Clinical Cancer Research.