Powered By Bing

Stewart Lab: Research

For over 25 years, research from the Stewart laboratory has changed the way clinicians at St. Jude Children’s Research hospital treat children with brain and solid tumor malignancies. We focus on:

  • Analyzing high-quality pharmacokinetic data from preclinical studies to translate into frontline chemotherapy regimens for children with cancer

  • Assisting in the development of new anticancer drugs for use in the clinic at St. Jude and worldwide

Pediatric Brain Tumors

Tumors of the central nervous system (CNS) are the most common cause of cancer-related deaths in children, and developing new and effective anticancer drugs will require innovative approaches. Tumors are often heterogeneous, and many biological barriers can prevent drugs from reaching therapeutic exposures at target sites within the CNS. As a result, many CNS drug candidates fail in the clinic. But more extensive, rational preclinical pharmacology studies could optimize the transition to the clinic and increase success rates.

Our primary role in this drug development process is the application of rational pharmacological principles in the design of effective chemotherapy dosing regimens for children with brain tumors.

Recently, the Stewart lab has collaborated with scientists in the St. Jude Neurobiology and Brain Tumor Program to develop a sophisticated, integrated in vitro and in vivo high-throughput screen to identify treatment leads for pediatric brain cancers. Tumors investigated so far include ependymoma, Group 3 medulloblastoma, choroid plexus carcinoma, and high-grade glioma17,18.

Read about our recent work on medulloblastoma.

In these efforts, we contribute pharmacokinetic modeling and simulations to optimize drug dosing and scheduling in preclinical efficacy studies (Figure 1)19. When possible we use this modeling to translate the preclinical laboratory findings to clinical drug dosing guidelines for children with brain tumors. Finding the correct chemotherapy dose for these cancers is particularly challenging because these drugs do not always penetrate through the blood-brain barrier.

Figure 1: Schematic overview of our approach to identifying new anticancer drugs for treatment of pediatric CNS tumors. Tumor specific genomic data informs the generation of mouse models of pediatric CNS tumors. In vitro screening of drug and/or chemical libraries against mouse model-derived or patient tumors prioritizes which anticancer agents will move forward in the process for each tumor type (left panel). Once high priority leads have been identified, we perform in vivo pharmacokinetic studies in mouse models of CNS tumors and perform modeling and simulation of the data generated (upper, center panel). The results of the pharmacokinetic and pharmacodynamics modeling and simulations are then used to help design clinical trials and inform dosing decisions for the treatment pediatric CNS tumors (right panel; Jacus et al., Eur J Pharm Sci. 2014).

Figure 1: Schematic overview of our approach to identifying new anticancer drugs for treatment of pediatric CNS tumors. Tumor-specific genomic data informs the generation of mouse models of pediatric CNS tumors. In vitro screening of drug and/or chemical libraries against mouse model-derived or patient tumors prioritizes which anticancer agents will move forward in the process for each tumor type (left panel). Once high priority leads have been identified, we perform in vivo pharmacokinetic studies in mouse models of CNS tumors and perform modeling and simulation of the data generated (upper, center panel). The results of the pharmacokinetic and pharmacodynamics modeling and simulations are then used to help design clinical trials and inform dosing decisions for the treatment pediatric CNS tumors (right panel; Jacus et al., Eur J Pharm Sci. 2014).

Using our collaborators’ in vitro findings about the relationship between drug sensitivity and time (e.g., in vitro drug exposure), we perform cerebral microdialysis studies in mice with implanted pediatric brain tumors which allow us to measure the in vivo drug exposure needed to shrink tumors. These data guide our choices about whether preclinical efficacy studies should be performed, and, if so, the optimal dosing for those studies. The results of these studies provide valuable information about the blood-brain and blood-tumor barriers of each of the brain tumor models, which help us prioritize drug development.

Clinical Pharmacology Research

Over the past 25 years, the Stewart laboratory has investigated the clinical pharmacology of anticancer drugs in children with cancer. More recently we have focused our efforts on determining rational dosing regimens for infants and young children by better understanding how development changes the movement and fate of chemotherapies, and applying this knowledge to treat other childhood malignancies and chronic medical conditions.

A current project focuses on developmental pharmacology in very young children receiving chemotherapy (CA154619). Since little is known about the disposition of anticancer agents in infants and young children less than 3 years of age, they often have increased risk of morbidity, poor tumor control, and increased incidence of late effects. This paucity of data is particularly relevant in children with malignant brain tumors where intensive chemotherapy has been used to replace or delay craniospinal irradiation.

Our work is part of an ongoing St. Jude clinical trial of infants and children who are younger than 3 years of age whose brain tumors were treated with multi-agent chemotherapy. We will use modeling to characterize the disposition of methotrexate (MTX), cyclophosphamide (CTX), and topotecan (TPT) in infants and young children with malignant brain tumors. We will also use statistical and mechanistic models to identify pharmacodynamic (PD) and PKPD response relationships for these drugs in infants and young children.

As well as our clinical pharmacokinetic, pharmacogenetic, and pharmacodynamic studies in children enrolled on clinical trials at St. Jude, we also collaborate on studies initiated by the Pediatric Brain Tumor Consortium (PBTC), Children's Oncology Group (COG), and Collaborative Ependymoma Research Network (CERN).

References

  1. Pawlik CA, Houghton PJ, Stewart CF, Cheshire PJ, Richmond LB, Danks MK. Effective schedules of exposure of medulloblastoma and rhabdomyosarcoma xenografts to topotecan correlate with in vitro assays. Clinical Cancer Research 1998;4:1995-2002.
  2. Zamboni WC, Stewart CF, Thompson J, Santana VM, Cheshire PJ, Richmond LB, Luo X, Poquette C, Houghton JA, Houghton PJ. Relationship between topotecan systemic exposure and tumor response in human neuroblastoma xenografts. J Natl Cancer Inst 1998;90:505-511.
  3. Thompson J, George EO, Poquette CA, Cheshire PJ, Richmond LB, de Graaf SS, Ma M, Stewart CF, Houghton PJ. Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts. Clinical Cancer Research 1999;5:3617-3631.
  4. Zamboni WC, Houghton PJ, Hulstein JL, Kirstein M, Walsh J, Cheshire PJ, Hanna SK, Danks MK, Stewart CF. Relationship between tumor extracellular fluid exposure to topotecan and tumor response in human neuroblastoma xenograft and cell lines. Cancer Chemother Pharmacol 1999;43:269-276.
  5. Turner PK, Johnston B, Wingo S, Schuetz JD, Stewart CF. MRP4 and P-glycoprotein (PgP) expression associated with topotecan (TPT) sensitivity in neuroblastoma (NB) cell lines. Proc Am Assoc Cancer Res 2003;44:705.
  6. Leggas M, Adachi M, Scheffer GL, Sun D, Wielinga P, Du G, Mercer KE, Zhuang Y, Panetta JC, Johnston B, Scheper RJ, Stewart CF, Schuetz JD. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol 2004;24:7612-7621.
  7. Dickson PV, Hagedorn NL, Hamner JB, Fraga CH, Ng CY, Stewart CF, Davidoff AM. Interferon beta-mediated vessel stabilization improves delivery and efficacy of systemically administered topotecan in a murine neuroblastoma model. J Pediatr Surg 2007;42:160-165; discussion 165.
  8. Stewart CF, Zamboni WC, Crom WR, Houghton PJ. Disposition of irinotecan and SN-38 following oral and intravenous dosing in mice. Cancer Chemother Pharmacol 1997;40:259-265.
  9. Thompson J, Zamboni WC, Cheshire PJ, Richmond LB, Luo X, Houghton JA, Stewart CF, Houghton PJ. Efficacy of oral administration of irinotecan against neuroblastoma xenografts. Anti-Cancer Drugs 1997;8:313-322.
  10. Stewart CF, Leggas M, Schuetz JD, Panetta JC, Cheshire PJ, Peterson J, Daw N, Jenkins JJ, III, Gilbertson R, Germain GS, Harwood FC, Houghton PJ. Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice. Cancer Res 2004;64:7491-7499.
  11. Stewart CF, Baker SD, Heideman RL, Jones D, Crom WR, Pratt CB. Clinical pharmacodynamics of continuous infusion topotecan in children: systemic exposure predicts hematologic toxicity. Journal of Clinical Oncology 1994;12:1946-1954.
  12. Tubergen DG, Stewart CF, Pratt CB, Zamboni WC, Winick N, Santana VM, Dryer ZA, Kurtzberg J, Bell B, Grier H, Vietti TJ. Phase I trial and pharmacokinetic (PK) and pharmacodynamics (PD) study of topotecan using a five-day course in children with refractory solid tumors: A Pediatric Oncology Group Study. J Ped Hem/Onc 1996;18:352-361.
  13. Santana VM, Zamboni WC, Kirstein MN, Tan M, Liu T, Gajjar A, Houghton PJ, Stewart CF. A pilot study of protracted topotecan dosing using a pharmacokinetically guided dosing approach in children with solid tumors. Clinical Cancer Research 2003;9:633-640.
  14. Santana VM, Furman WL, Billups CA, Hoffer FA, Davidoff AM, Houghton PJ, Stewart CF. Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach. J Clin Oncol 2005;23:4039-4047.
  15. Stewart CF, Iacono LC, Chintagumpala M, Kellie SJ, Ashley D, Zamboni WC, Kirstein MN, Fouladi M, Seele LG, Wallace D, Houghton PJ, Gajjar A. Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor. Journal of Clinical Oncology 2004;22:3357-3365.
  16. Metzger ML, Stewart CF, Freeman BB, III, Billups CA, Hoffer FA, Wu J, Coppes MJ, Grant R, Chintagumpala M, Mullen EA, Alvarado C, Daw NC, Dome JS. Topotecan is active against Wilms' tumor: results of a multi-institutional phase II study. J Clin Oncol 2007;25:3130-3136.
  17. Atkinson JM, Shelat AA, Carcaboso AM, Kranenburg TA, Arnold LA, Boulos N, Wright K, Johnson RA, Poppleton H, Mohankumar KM, Feau C, Phoenix T, Gibson P, Zhu L, Tong Y, Eden C, Ellison DW, Priebe W, Koul D, Yung WK, Gajjar A, Stewart CF, Guy RK, Gilbertson RJ. An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell 2011;20:384-399.
  18. Morfouace M, Shelat A, Jacus M, Freeman BB, 3rd, Turner D, Robinson S, Zindy F, Wang YD, Finkelstein D, Ayrault O, Bihannic L, Puget S, Li XN, Olson JM, Robinson GW, Guy RK, Stewart CF, Gajjar A, Roussel MF. Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 2014;25:516-529.
  19. Jacus MO, Throm SL, Turner DC, Patel YT, Freeman Iii BB, Morfouace M, Boulos N, Stewart CF. Deriving therapies for children with primary CNS tumors using pharmacokinetic modeling and simulation of cerebral microdialysis data. European Journal of Pharmaceutical Sciences 2014;57:41-47.