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NCI Pediatric Preclinical Testing Program (PPTP) Laboratories

In the Best Pharmaceuticals for Children Act (BPCA), Congress directed the National Cancer Institute (NCI) to amply and expand preclinical drug testing for childhood cancer. In response to this directive, the NCI established a consortium of institutions to carry out preclinical testing of anti-cancer drugs in both cell culture and mouse xenograft models known as the Pediatric Preclinical Testing Program (PPTP).

The overall PI for the PPTP is Peter Houghton, PhD, of St Jude's Childrens Research Hospital. The NCI project officer is Malcolm Smith, MD PhD.

The PPTP focuses on testing the most common pediatric cancers for which patients are eligible for phase I and phase II clinical trials: brain tumors, acute lyphoblastic leukemia, acute myelogenous leukemia, lymphomas, Ewing's sarcoma family tumors (ESFT), osteogenic sarcoma, brain tumors, and neuroblastoma.

The goal for the PPTP is to complete testing of one drug per month in all the xenograft panels. Drugs are batched in groups of 4 drugs tested over 4 months in the in vitro panel. Drugs are obtained under MTA from various sources by the NCI and provided to investigators in a blinded fashion for testing. The NCI determines an appropriate drug dosing for xenograft experiments and an appropriate range of concentrations for in vitro testing. In addition to new drugs, older drugs for which activity of the drug is known in patients have also been tested by the PPTP labs in a blinded fashion.

Cryopreserved banks of xenografts and cell lines are maintained by program investigators and replicates are stored at St Jude's. Molecular characterization of the panel of xenografts and cell lines is being carried out by microarrays for gene expression as well as single nucleotide polymorphisms.

PPTP Laboratories

Cell Culture Testing (all diseases) Texas Tech University Health Sciences Center

Disease-Focused Xenograft Testing Laboratories

ESFT, Brain tumors, rhabdomyosarcoma St Jude's Children's Research Hospital
Glioblastoma Duke University
Osteogenic Sarcoma Childrens Hosp at Montefiore, Bronx,NY
Neuroblastoma Children's Hospital of Philadelphia
Acute Lymphoblastic Leukemia Children's Cancer Institute of Australia B

PPTP In vitro Laboratory

Lab Layout Dr. Kang's laboratory conducts the in vitro preclinical testing for the PPTP. The assay employed is DIMSCAN, a fluorescence-based multi-well assay with a dynamic range of 4 logs of cell kill. The in vitro testing lab is equipped with 3 biological safety cabinets, a robot pipettor, 4 incubators (O2 control capable), a DIMSCAN, centrifuges,-80° and 4° GLP storage, and accesses to the COG Cell Culture Repository.


Program Funding

NCI PPTP Grant

Laboratory Publications

  1. Whiteford CC, Bilke S, Greer BT, Braunschweig TA, Cenacchi N, Wei JS, Smith M, Houghton P, Reynolds CP, Lock R, Gorlick R, Khanna C, Thiele CJ, COG Phase 1 Consortium, Hewitt SM, Khan J: Credentialing preclinical pediatric xenograft models using gene expression and tissue microarray analysis. Cancer Research 67:32-40, 2007.
  2. Houghton PJ, Morton CL, Tucker C, Payne D, Favours E, Cole C, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Tajbakhsh M, Reynolds CP, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Zeidner J, Wu J, Liu T, Billups CA, Khan J, Ansher S, Zhang J, Smith MA: The Pediatric Preclinical Testing Program: Description of models and early testing results. Pediatric Blood & Cancer 49:928-940, 2007.
  3. Maris JM, Courtright J, Houghton PJ, Morton CL, Gorlick R, Kolb EA, Lock R, Tajbakhsh M, Reynolds CP, Keir ST, Wu J, Smith MA: Initial testing (Stage 1) of the VEGFR inhibitor AZD2171 by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:581-587, 2008.
  4. Houghton PJ, Morton CL, Tucker C, Gorlick R, Kolb EA, Zhang W, Lock R, Carol H, Reynolds CP, Keshelava N, Maris JM, Courtright J, Keir ST, Friedman HS, Stopford C, Wu J, Smith MA: Stage 1 testing of the proteasome inhibitor bortezomib by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:37-45, 2008.
  5. Kolb EA, Gorlick R, Houghton PJ, Morton CL, Lock R, Tajbakhsh M, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA: Initial testing of dasatinib by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:1198-1206, 2008.
  6. Tajbakhsh M, Houghton PJ, Morton CL, Kolb EA, Maris JM, Keir ST, Wu J, Reynolds CP, Smith MA, Lock RB: Initial testing (Stage 1) of cisplatin by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:992-1000, 2008.
  7. Houghton PJ, Morton CL, Kolb EA, Lock R, Reynolds CP, Maris JM, Keir ST, Billups CA, Tucker C, Smith MA: Initial testing (Stage 1) of the mTOR inhibitor rapamycin by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:709-805, 2008.
  8. Lock R, Carol H, Houghton PJ, Morton CL, Kolb EA, Reynolds CP, Maris JM, Keir ST, Wu J, Smith MA: Initial testing (Stage 1) of the BH3 Mimetic ABT-263 by the Pediatric Preclinical Testing Program. Pediatric Blood & Cancer 50:1181-1189, 2008.
  9. Kolb EA, Gorlick R, Houghton PJ, Morton CL, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA: Initial testing (stage 1) of a monoclonal antibody (SCH 717454) against the IGF-1 receptor by the pediatric preclinical testing program. Pediatr Blood & Cancer 50:1190-1197, 2008.
  10. Smith MA, Morton CL, Phelps DA, Kolb EA, Lock R, Carol H, Reynolds CP, Maris JM, Keir ST, Wu J, Houghton PJ. Stage 1 testing and pharmacodynamic evaluation of the HSP90 inhibitor alvespimycin (17-DMAG, KOS-1022) by the pediatric preclinical testing program. Pediatric Blood & Cancer 51(1):34-41, 2008.
  11. Maris JM, Courtright J, Houghton PJ, Morton CL, Kolb EA, Lock R, Tajbakhsh M, Reynolds CP, Keir ST, Wu J, Smith MA. Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program. Pediatric Blood & Cancer 51:42-8, 2008.
  12. Neal G, Su X, Morton CL, Phelps D, Gorlick R, Lock RB, Reynolds CP, Maris JM, Friedman HS, Dome J, Khoury J, Triche TJ, Seeger RC, Gilbertson R, Khan J, Smith MA, Houghton PJ: Molecular characterization of the Pediatric Preclinical Testing panel. Clinical Cancer Research 14:4572-83, 2008.
  13. Morton C, Houghton PJ, Gorlick R, Kolb EA, Lock RB, Carol H, Keir ST, Reynolds CP, Kang MH, Maris JM, Billups C, Smith MA: Initial testing of aplidin by the pediatric preclinical testing program. Pediatr Blood & Cancer 53:509-12, 2009
  14. \Keshelava N, Houghton PJ, Morton CL, Lock RB, Keir ST, Maris JM, Reynolds CP, Gorlick R, Wu J, Smith MA: Initial testing (stage 1) of vorinostat (SAHA) by the Pediatric Preclinical Testing Program. Pediatr Blood & Cancer 53:505-8, 2009.
  15. Gorlick R, Kolb EA, Houghton PJ, Morton CL, Phelps D, Schaiquevich P, Stewart C, Keir ST, Lock R, Carol H, Reynolds CP, Maris JM, Wu J, Smith MA: Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program. Pediatr Blood & Cancer 53:594-8, 2009
  16. Carol H, Lock R, Houghton PJ, Morton CL, Kolb EA, Gorlick R, Reynolds CP, Maris JM, Keir ST, Billups CA, Smith MA: Initial testing (stage 1) of the kinesin spindle protein inhibitor ispinesib by the pediatric preclinical testing program. Pediatr Blood & Cancer 24;53(7):1255-1263, 2009.
  17. Houghton PJ, Morton CL, Kang MH, Reynolds CP; Billups CA, Favours E, Payne-Turner D, Tucker C, Smith MA: Evaluation of cytarabine against Ewing sarcoma xenografts by the Pediatric Preclinical Testing Program. Pediatr Blood & Cancer (in press, 2009).
  18. Carol H, Houghton PJ, Morton CL, Kolb A, Gorlick R, Reynolds CP, Kang MH, Maris JM, Keir ST, Watkins A Smith MA, Lock RB: Initial testing of topotecan by the Pediatric Preclinical Testing Program. Pediatr Blood & Cancer 54(5):707-715, 2009.
  19. Smith MA, Morton CL,: Kolb, EA, Gorlick, R, Keir ST, Carol H, Lock RB, Kang MH, Reynolds CP, MD, Maris JM, Watkins AE, Houghton PJ: Initial testing (Stage 1) of mapatumumab (HGS-ETR1) by the Pediatric Preclinical Testing Program. Pediatr Blood & Cancer 54:307-10, 2010.
  20. Houghton PJ, Morton CL, Gorlick R, Lock RB, Carol H, Reynolds CP, Kang MH, Maris JM, Keir ST, Kolb EA, Wu J, Wozniak AW, Billups CA, Rubinstein L, Smith MA: Stage 2 combination testing of rapamycin with cytotoxic agents by the Pediatric Preclinical Testing Program. Mol Cancer Therapeutics 9:101-12, 2010.
  21. Maris JM, Morton CL, Gorlick R, Kolb EA, Lock R, Carol H, Keir ST, Reynolds CP, Kang MH, Wu J, Smith MA, Houghton PJ: Initial testing of the aurora kinase a inhibitor MLN8237 by the Pediatric Preclinical Testing Program (PPTP). Pediatr Blood & Cancer. 2010 Jan 27. [Epub ahead of print]
  22. Houghton PJ, Morton CL, Gorlick R, Kolb EA, Keir ST, Reynolds CP, Kang MH, Maris JM, Wu J, Smith MA: Initial testing of a monoclonal antibody (IMC-A12) against IGF-1R by the pediatric preclinical testing program. Pediatr Blood & Cancer. 2010 Feb 17. [Epub ahead of print].
  23. Kang MH, Smith MA, Morton CL, Nino Keshelava N, Houghton PJ, Reynolds CP: National Cancer Institute Pediatric Preclinical Testing Program: Model description for in vitro cytotoxicity testing. Pediatr Blood & Cancer (In Press, 2010).

Bibliography

  1. Proffitt RT, Tran JV, Reynolds CP: A fluorescence digital image microscopy system for quantitating relative cell numbers in tissue culture plates. Cytometry 24:204-213,1996.
  2. Keshelava N, Frgala T, .Krejsa J, Kalous O, Reynolds, CP: DIMSCAN: a microcomputer fluorescence-based cytotoxicity assay suitable for pre-clinical testing of combination chemotherapy. Methods in Molecular Medicine Chemosensitivity Vol 1 ed. Blumenthal RD, Totowa: Humana Press pp 139-154, 2005.
  3. Keshelava N, Seeger RC, Groshen S, Reynolds CP: Drug resistance patterns of human neuroblastoma cell lines derived from patients at different phases of therapy. Cancer Research 58:5396-5405, 1998.
  4. Maurer BJ, Cabot MC, Reynolds CP: Syngergism of N-(4-hydroxypheynl)retinamide cytotoxcity by modulators of ceramide metabolism in solid tumor cell lines. J Natl Cancer Inst 92:1897-1908, 2000.
  5. O'Donnell PH, Guo WX, Reynolds CP, Maurer BJ: N-(4-hydroxyphenyl)retinamide increases ceramide and Is cytotoxic to acute lymphoblastic leukemia cell lines, but not to non-malignant lymphocytes. Leukemia 16:902-910, 2002.
  6. Grigoryan R, Keshelava N, Anderson C, Reynolds, CP: In vitro testing of chemosensitivity in physiological hypoxia. Methods in Molecular Medicine Chemosensitivity Vol 1 ed. Blumenthal RD, Totowa: Humana Press pp 87-100, 2005.
  7. Reynolds, CP, Maurer BJ: Assessing response to anti-neoplastic drug combinations in tissue culture models. Methods in Molecular Medicine Chemosensitivity Vol 1 ed. Blumenthal RD, Totowa: Humana Press pp 173-184, 2005.
  8. Frgala T, Kalous O, Proffitt RT, Reynolds CP: A novel cytotoxicity assay with a 4 log dynamic range that identifies synergistic drug combinations. Molecular Cancer Therapeutics 6:886-89, 2007.

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