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Open Full Page Published OnlineFirst December 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1421 Cancer Therapy: Preclinical Clinical Cancer Research Mechanistic Investigation of Bone Marrow Suppression Associated with Palbociclib and its Differentiation from Cytotoxic Chemotherapies Wenyue Hu1, Tae Sung1, Bart A. Jessen1, Stephane Thibault1, Martin B. Finkelstein2, Nasir K. Khan3, and Aida I. Sacaan1 Abstract Purpose: Palbociclib (PD-0332991) is the first selective cyclin- doxorubicin) resulted in DNA damage and apoptotic cell death in dependent kinase (CDK) 4/6 inhibitor approved for metastatic hBMNCs. In the presence or absence of the antiestrogen, palbo- breast cancer. Hematologic effects, especially neutropenia, are ciclib-treated hBMNCs did not become senescent and resumed dose-limiting adverse events for palbociclib in humans. proliferation following palbociclib withdrawal, consistent with Experimental Design: Reversible hematologic effects and bone pharmacologic quiescence. The breast cancer cells, MCF-7, con- marrow hypocellularity have been identified in toxicology studies versely, became senescent following palbociclib or antiestrogen in rats and dogs after palbociclib treatment. To understand the treatment with additive effects in combination and remained mechanism by which the hematologic toxicity occurs, and to arrested in the presence of antiestrogen. further differentiate it from the myelotoxicity caused by cytotoxic Conclusions: Palbociclib causes reversible bone marrow sup- chemotherapeutic agents, an in vitro assay using human bone pression, clearly differentiating it from apoptotic cell death caused marrow mononuclear cells (hBMNC) was utilized. by cytotoxic chemotherapeutic agents. This study also distin- Results: This work demonstrated that palbociclib-induced guished the cell-cycle arresting action of palbociclib on normal bone marrow suppression occurred through cell-cycle arrest, with bone marrow cells from the senescent effects observed in breast no apoptosis at clinically relevant concentrations, was not lineage- cancer cells. These results shed light on the mechanism and specific, and was reversible upon palbociclib withdrawal. In support risk management of palbociclib-induced bone marrow contrast, treatment with chemotherapeutic agents (paclitaxel and toxicity in the clinic. Clin Cancer Res; 22(8); 2000–8. Ó2015 AACR. Introduction eral CDKs, was described over 20 years ago. Flavopiridol has been tested in clinical trials for over a decade (3), and has demonstrated Cyclin-dependent kinases (CDK) are a family of serine/threo- limited efficacy with a toxicity profile consisting of diarrhea, nine protein kinases with more than 20 members that are transient transaminitis, cytokine release syndrome, and tumor characterized by the requirement of most CDKs for binding to lysis syndrome (4). The nonclinical toxicity of another broad- cyclins or other protein partners to induce kinase activity. CDKs spectrum CDK inhibitor, AG-012986, has been extensively 1–4 and 6 regulate transition through specific checkpoints in the profiled and demonstrated toxicities in multiple organs, includ- cell cycle, whereas CDKs 7–9 are involved in regulation of the ing hematopoietic system (5), retina, peripheral nerves (6), transcriptional machinery. CDK5 is involved in neuron-specific gastrointestinal tract, and pancreas (7). functions while other family members have not been extensively In contrast to the first-generation broad-spectrum CDK inhi- studied (1, 2). bitors, palbociclib is an oral small-molecule selective inhibitor of Given the pivotal role of CDKs in cellular proliferation, they CDK 4 and 6 that specifically blocks the G –S cell-cycle transition have been among the first targeted therapy approaches pursued 1 and avoids other CDK targets that may induce apoptosis in for the treatment of cancer (2, 3). One of the first CDK inhibitors, quiescent cells (8). Palbociclib was recently approved by the FDA flavopiridol, a broad-spectrum ATP-competitive inhibitor of sev- in combination with letrozole for the treatment of first-line advanced breast cancer. The safety profile and oral dosing route 1Drug Safety Research and Development, Pfizer Inc. San Diego, Cali- enables a more convenient dosing regimen (3 weeks on, 1 week fornia. 2Drug Safety Research and Development, Pfizer Inc. Pearl River, off per cycle) than chemotherapeutic agents that are intravenously New York. 3Drug Safety Research and Development, Pfizer Inc. Gro- administered that has facilitated the demonstration of efficacy in ton, Connecticut. the treatment of breast cancer when given in combination with Note: Supplementary data for this article are available at Clinical Cancer antiestrogens (8, 9). In the PALOMA-1/TRIO-18 randomized Research Online (http://clincancerres.aacrjournals.org/). phase II study, which evaluated the efficacy and safety of palbo- þ À Corresponding Author: Wenyue Hu, Drug Safety Research and Development, ciclib in combination with letrozole in ER /Her2 breast cancer, La Jolla Laboratories, Pfizer Inc., 10646 Science Center Drive, San Diego, CA hematologic toxicities, especially neutropenia, were identified as 92121. Phone: 858-622-7530; Fax: 858-678-8290; E-mail: dose-limiting toxicities and were the most frequently reported wenyue.hu@pfizer.com adverse events for palbociclib (10). Findings from this study doi: 10.1158/1078-0432.CCR-15-1421 suggest the neutropenia associated with palbociclib differs from Ó2015 American Association for Cancer Research. that seen with cytotoxic chemotherapeutics in that it is transient, 2000 Clin Cancer Res; 22(8) April 15, 2016 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst December 2, 2015; DOI: 10.1158/1078-0432.CCR-15-1421 Mechanism of Palbociclib-Induced Bone Marrow Suppression preserved in 10% neutral-buffered formalin, embedded in par- Translational Relevance affin, sectioned to slides, stained with hematoxylin and eosin and Palbociclib is a highly effective cyclin-dependent kinase 4/6 examined by a board-certified veterinary pathologist. inhibitor approved for metastatic breast cancer. Although manageable, neutropenia is one of the most frequent adverse In vitro cell culture events associated with palbociclib in the clinic. The current Human bone marrow mononuclear cells (hBMNC: a hetero- investigative work sheds light on the mechanism of palboci- geneous population that includes hematopoietic lineage cells clib-induced bone marrow suppression and differentiates the such as lymphocytes, monocytes, stem cells, and progenitor cells) þ mechanism of bone marrow suppression from that induced by and CD34 human bone marrow hematopoietic stem cells were cytotoxic chemotherapeutic agents. These results potentially primary cells purchased from Lonza. The cells were cultured in explain the rapid reversibility of palbociclib-induced neutro- the hematopoietic progenitor growth (HPGM) medium (Lonza) penia and its uncomplicated nature when compared with supplemented with 10% FBS and in the presence of the following traditional cytotoxic agents. Moreover, these data support the cytokines (R&D Systems): 25 ng/mL stem cell factor (SCF), current dosing regimen in the clinic, which provides time for 3 U/mL erythropoietin (EPO), 10 ng/mL G-CSF, 10 ng/mL bone marrow cells to resume proliferation during the one- granulocyte-macrophage colony-stimulating factor (GM-CSF), fi week treatment-free period without impacting tumor ef cacy. 15 ng/mL thrombopoietin (TPO), 10 ng/mL IL3, 10 ng/mL IL6, This investigative work provides information to the clinicians and 25 ng/mL Flt3 ligand, in a 37 C5%CO2 and 98% humidity treating breast cancer patients in managing palbociclib- incubator. Human peripheral blood mononuclear cells (hPBMC) induced neutropenia and could have broader implications to were primary cells purchased from Lonza, and cultured in the future indications and combinations with palbociclib. Roswell Park Memorial Institute media (RPMI). MCF-7 breast cancer cells were purchased from the ATCC and cultured in RPMI media supplemented with 10% FBS, in a 37C 5% CO2 and 98% humidity incubator. reversible, and does not commonly lead to febrile neutropenia (10). To aid in understanding the mechanism by which neutro- In vitro testing of lineage-specific effects þ penia occurs and why it differs from the myelotoxicity seen with The CD34 hematopoietic stem cells were stimulated with the cytotoxic chemotherapeutic agents, an in vitro bone marrow following cytokines for 4 days to induce lineage-specific differ- toxicity assay was utilized to evaluate the cellular mechanism entiation: SCF, EPO, and IL3 for erythroid lineage; SCF, G-CSF, and the reversibility of bone marrow suppression induced by GM-CSF, IL3, and Flt3 ligand for myeloid lineage; SCF, TPO, and palbociclib as a single agent or in combination with antiestrogens IL3 for megakaryocyte lineage. Cells were subjected to palbociclib (the currently approved indication). In addition, the differential treatment for 5 days and cell viability measurement was effects of palbociclib and antiestrogens toward bone marrow cells conducted. and breast cancer cells, as well as their effects relative to cytotoxic chemotherapy agents in bone marrow cells, were investigated. In vitro cell viability and apoptosis assay The hPBMCs or hBMNCs cultured in RPMI or conditioned Materials and Methods HPGM media were treated with test compounds at specified Test article concentrations in a 3-fold serial dilution in triplicate. After 24 Palbociclib
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