Authors' Reply to "Translating palbociclib to the clinic for DIPG - What is truly achievable?"

We thank Franshaw et al. for expressing their concern about the palbociclib doses used in our preclinical study for DIPG [1]. We are also pleased to see growing interest in fighting this incurable disease.

Franshaw et al pointed out that the dose of palbociclib we used to treat the DIPG xenograft mouse models was much higher than the equivalent maximum tolerated dose (MTD) for humans established based on a Phase I trial. Our goal of the study was to examine whether CDK4/6 is a worthy target for high grade treatment-naïve H3.3-K27 M mutant DIPG. As the blood brain barrier (BBB) of brainstem is relatively intact [2,3], higher starting dose of the drug would be needed to deliver similar dose to the pons than to other tissues. According to our literature search, the doses of palbociclib used in preclinical cancer studies in xenograft mouse models, ranged from 12.5 to 150 mg/kg (Table 1). Therefore, we chose 150 mg/kg in order to deliver sufficient concentration of drug to the pons.

Table 1

The doses of palbociclib used to treat xenograft mouse model.

Dose	Length	References
150 mg/kg	28 days	Cen L, Carlson BL, Schroeder MA, Ostrem JL, Kitange GJ, Mladek AC, Fink SR, Decker PA, Wu W, Kim JS, Waldman T, Jenkins RB, Sarkaria JN. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro Oncol. 2012;14(7):870–81.
150 mg/kg	2 weeks	Michaud K, Solomon DA, Oermann E, Kim JS, Zhong WZ, Prados MD, Ozawa T, James CD, Waldman T. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 2010;70(8):3228–38.
150 mg/kg	7 days	Zhang J, Zhang M, Acampora D, Voitek M, Yuan D, Simeone A, Chambers I. OTX2 restricts entry to the mouse germline. Nature. 2018;562(7728):595–599.
50 mg/kg	4 days a week for at least 4 weeks	Olmez I, Brenneman B, Xiao A, et al. Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms. Clin Cancer Res. 2017;23(22):6958–6968.
75 mg/kg	14 days	Elmi A, Makvandi M, Weng CC, Hou C, Clark AS, Mach RH, Mankoff DA. Cell-Proliferation Imaging for Monitoring Response to CDK4/6 Inhibition Combined with Endocrine-Therapy in Breast Cancer: Comparison of [18F]FLT and [18F]ISO-1 PET/CT. Clin Cancer Res. 2019;25(10):3063–3073.
100 mg/kg	5 days	Mosteiro L, Pantoja C, Alcazar N, Marión RM, Chondronasiou D, Rovira M, Fernandez-Marcos PJ, Muñoz-Martin M, Blanco-Aparicio C, Pastor J, Gómez-López G, De Martino A, Blasco MA, Abad M, Serrano M. Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science. 2016;354(6315)
12.5 mg/kg–150 mg/kg	13–27 days	Fry DW, Harvey PJ, Keller PR, Elliott WL, Meade M, Trachet E, Albassam M, Zheng X, Leopold WR, Pryer NK, Toogood PL. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther. 2004;3(11):1427–38.
150 mg/kg	12 days	Baughn LB, Di Liberto M, Wu K, Toogood PL, Louie T, Gottschalk R, Niesvizky R, Cho H, Ely S, Moore MA, Chen-Kiang S. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res. 2006;66(15):7661–7

Our study has provided strong evidence that sufficient concentration of palbociclib could be a potential drug for DIPG therapy. To alleviate the toxicity caused by high doses of palbociclib, different drug delivery systems such as Convection Enhanced Delivery (CED) should be tried to lower the drug doses [4]. Furthermore, as we and others pointed out that palbociclib alone is unlikely to have durable effects for a complex disease like DIPG, searching for combination therapy of palbociclib with other drugs should be encouraged [5].

Authors contribution

All authors contribute to the reply.