A phenotypic approach for targeting pediatric brain tumors

Few novel targeted therapies are available for pediatric brain tumor clinical trials. In ew novel targeted therapies are available for pediatric brain tumor clinical trials. In collaboration with physician scientist Richard Gilbertson, we have used whole-cell phenotypic screening approaches to discover chemical suppressors of oncogenes that induce pediatric brain tumors.

Ependymoma 

In our study of ependymomas, funded by the CERN foundation, Dr. Gilbertson’s laboratory has validated oncogenes using a murine transplantation model of genetically modified radial glial cells1,2. Cells expressing bone fide oncogenes were used to screen for compounds that inhibited growth when cultured in 3D neurosphere cultures, which ensured the cells maintained proper physiology. We have carried out screens with two tumor-derived cell lines, one overexpressing the EphB2 receptor and one overexpressing RTBD.

We tested all FDA-approved active ingredients against EphB2 and RTBDN-driven ependymoma and identified 5-FU and gemcitabine as active. Subsequent PK/PD modeling was used to optimize dosage, schedule and route of administration3 and in vivo efficacy studies confirmed these agents as highly active against ependymoma in both murine allografts and human xenografts. This led to a clinical trial to test 5-FU for pediatricependymoma.4 Gemcitabine is our next candidate under consideration for clinical trials. 

We subsequently used our screening method to test a wide range of kinase inhibitors and determined that PLK1 inhibitors are highly active against ependymoma.3 Due to the poor distribution of PLK1 inhibitors into the brain and because of their systemic toxicity, we are actively working on chemistry to improve blood-brain-barrier penetration. In addition, we are also developing an approach to locally deliver these inhibitors within the brain. 

Our efforts have also focused on identifying novel chemical leads for ependymoma5 from a large collection of natural product extracts.

References

  1. Poppleton, H.; Gilbertson, R. J. Stem cells of ependymoma. Br. J. Cancer 2007, 96, 6-10.
  2. Taylor, M. D.; Poppleton, H.; Fuller, C.; Su, X.; Liu, Y.; Jensen, P.; Magdaleno, S.; Dalton, J.; Calabrese, C.; Board, J.; Macdonald, T.; Rutka, J.; Guha, A.; Gajjar, A.; Curran, T.; Gilbertson, R. J. Radial glia cells are candidate stem cells of ependymoma. Cancer Cell 2005, 8, 323-335.
  3. Atkinson, J. M.; Shelat, A. A.; Carcaboso, A. M.; Kranenburg, T. A.; Arnold, L. A.; Boulos, N.; Wright, K.; Johnson, R. A.; Poppleton, H.; Mohankumar, K. M.; Feau, C.; Phoenix, T.; Gibson, P.; Zhu, L.; Tong, Y.; Eden, C.; Ellison, D. W.; Priebe, W.; Koul, D.; Yung, W. K.; Gajjar, A.; Stewart, C. F.; Guy, R. K.; Gilbertson, R. J. An integrated in vitro and in vivo high-throughput screen identifies treatment leads for ependymoma. Cancer Cell 2011, 20, 384-399.
  4. Wright, K. ClinicalTrials.gov Identifier NCT01498783: Phase I Study of 5-Fluorouracil in Children and Young Adults With Recurrent Ependymoma (SJREFU).
  5. Yang, J.; Liang, Q.; Wang, M.; Jeffries, C.; Smithson, D.; Tu, Y.; Boulos, N.; Jacob, M. R.; Shelat, A. A.; Wu, Y.; Ravu, R. R.; Gilbertson, R.; Avery, M. A.; Khan, I. A.; Walker, L. A.; Guy, R. K.; Li, X. C. UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small-molecule natural product libraries. J. Nat. Prod. 2014, 77, 902-909.

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