We currently have several active protocols approved by the Animal Care and Use Committee for preclinical pharmacokinetic analysis of new agents,a continued collaborative relationship with the Pharmacology and Experimental Therapeutics Section of the POB, and a new collaborative relationship with the Molecular Pharmacology Section (Doug Figg) of NCI to partner in pharmacologic investigations of new agents. We have successfully obtained new agents from intramural and extramural sources to evaluate, and are developing biomarkers in the preclinical setting. In general, for an antitumor agent to have an effect, you need: a) an active agent,b) Delivery to tumor c) it must be present at tumor site in its active form, d)Effective concentrations f) Long enough period of time (i.e.e effective exposure) and g) Tolerability at doses necessary to achieve above. For targeted therapy, we need to know if the target is present. We are developing methods to further investigate the mechanisms of action of agents currently in clinical trials, and investigate biomarkers or surrogate markers of drug activity and tumor response. We have developed a new animal model for brain microdialysis in an effort to determine if Cerebrospinal fluid penetration is an appropriate surrogate for CNS tissue penetration. We are also evaluating effects of common concurrent medications such as steroids on the pharmacokinetics of chemotherapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011340-07
Application #
9343885
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Nellan, Anandani; McCully, Cynthia M Lester; Cruz Garcia, Rafael et al. (2018) Improved CNS exposure to tocilizumab after cerebrospinal fluid compared to intravenous administration in rhesus macaques. Blood 132:662-666
Nellan, Anandani; Rota, Christopher; Majzner, Robbie et al. (2018) Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. J Immunother Cancer 6:30
Miyahara, Hiroaki; Yadavilli, Sridevi; Natsumeda, Manabu et al. (2017) The dual mTOR kinase inhibitor TAK228 inhibits tumorigenicity and enhances radiosensitization in diffuse intrinsic pontine glioma. Cancer Lett 400:110-116
League-Pascual, James C; Lester-McCully, Cynthia M; Shandilya, Shaefali et al. (2017) Plasma and cerebrospinal fluid pharmacokinetics of select chemotherapeutic agents following intranasal delivery in a non-human primate model. J Neurooncol 132:401-407
Shah, Nirali N; Cole, Diane E; Lester-McCully, Cynthia M et al. (2016) Plasma and cerebrospinal fluid pharmacokinetics of vincristine and vincristine sulfate liposomes injection (VSLI, marqibo®) after intravenous administration in Non-human primates. Invest New Drugs 34:61-5
Cole, Diane E; Lester-McCully, Cynthia M; Widemann, Brigitte C et al. (2015) Plasma and cerebrospinal fluid pharmacokinetics of the Akt inhibitor, perifosine, in a non-human primate model. Cancer Chemother Pharmacol 75:923-8
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McCully, Cynthia M; Pastakia, Devang; Bacher, John et al. (2013) Model for concomitant microdialysis sampling of the pons and cerebral cortex in rhesus macaques (Macaca mulatta). Comp Med 63:355-60
Marcus, Leigh; Murphy, Robert; Fox, Elizabeth et al. (2012) The plasma and cerebrospinal fluid pharmacokinetics of the platinum analog satraplatin after intravenous administration in non-human primates. Cancer Chemother Pharmacol 69:247-52