Pediatric Surgery
Tumor Biology
The Pediatric Tumor Biology Laboratory, co-directed by Drs. Darrell Yamashiro and Jessica Kandel, focuses on the role of new blood vessel growth (called angiogenesis) in the growth and metastasis of pediatric solid tumors.
Because pediatric cancers arise from different causes than adult tumors, and have a different set of molecular drivers, we have investigated this process using experimental models that reproduce these childhood diseases as closely as possible. Our goal is to find a way to halt the development and progression of childhood tumors by blocking their blood supply, a strategy called “anti-angiogenesis."
To test this strategy and evaluate its effects, we have developed models of common pediatric solid tumors of the abdomen—including neuroblastoma, Wilms tumor, hepatoblastoma, Ewing sarcoma, and rhabdoid tumor of the kidney. We have found that blocking vascular endothelial growth factor (VEGF), can markedly suppress the growth of microscopic tumors by inhibiting angiogenesis. In addition, we have shown in some models that large, established tumors and metastases can be substantially regressed.
However, we have also found that the response to VEGF blockade is not uniform, with tumors behaving differently depending on their type. For example, neuroblastoma is more resistant to treatment than hepatoblastoma or Wilms tumor. Our current work is determine the factors that contribute to refractory tumors, and to determine the mechanisms of acquired resistance to anti-angiogenic therapy and
tumor recurrence in the different pediatric solid tumors. By targeting these "resistance" pathways we hope to develop new strategies to effectively treat resistant tumors.
Some papers from our group:
Kadenhe-Chiweshe A, Papa J, McCrudden KW, Frischer J, Bae JO, Huang J, Fisher J, Lefkowitch JH, Feirt N, Rudge J, Holash J, Yancopoulos GD, Kandel JJ, Yamashiro DJ. Sustained VEGF blockade results in microenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol Cancer Res. 2008 Jan;6(1):1-9.
Bender JL, Adamson PC, Reid JM, Xu L, Baruchel S, Shaked Y, Kerbel RS, Cooney-Qualter EM, Stempak D, Chen HX, Nelson MD, Krailo MD, Ingle AM, Blaney SM, Kandel JJ, Yamashiro DJ; Children's Oncology Group Study. Phase I trial and pharmacokinetic study of bevacizumab in pediatric patients with refractory solid tumors: a Children's Oncology Group Study. J Clin Oncol. 2008 Jan 20;26(3):399-405.
Masciotti J, Abdoulaev G, Provenzano F, Hur J, Papa J, Bae J, Huang J, Yamashiro D, Kandel J, Hielscher A.
Optical Tomographic and Magnetic Resonance Imaging of Tumor Growth and Regression in Mice treated with VEGF Blockade.
Conf Proc IEEE Eng Med Biol Soc. 2005;1:205-8.
Lee A, Frischer J, Serur A, Huang J, Bae JO, Kornfield ZN, Eljuga L, Shawber CJ, Feirt N, Mansukhani M, Stempak D, Baruchel S, Bender JG, Kandel JJ, Yamashiro DJ. Inhibition of cyclooxygenase-2 disrupts tumor vascular mural cell recruitment and survival signaling. Cancer Res. 2006 Apr 15;66(8):4378-84. PMID: 16618763
Yuan E, Li CM, Yamashiro DJ, Kandel J, Thaker H, Murty VV, Tycko B. Genomic profiling maps loss of heterozygosity and defines the timing and stage dependence of epigenetic and genetic events in Wilms' tumors. Mol Cancer Res. 2005 Sep;3(9):493-502. PMID: 16179496
Glade Bender J, Cooney EM, Kandel JJ, Yamashiro DJ. Vascular remodeling and clinical resistance to antiangiogenic cancer therapy.Drug Resist Updat. 2004 Aug-Oct;7(4-5):289-300. Review. PMID: 15533766
Frischer JS, Huang J, Serur A, Kadenhe-Chiweshe A, McCrudden KW, O'Toole K, Holash J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. Effects of potent VEGF blockade on experimental Wilms tumor and its persisting vasculature. Int J Oncol. 2004 Sep;25(3):549-53.
PMID: 15289855
Huang J, Frischer JS, New T, Kim ES, Serur A, Lee A, Kadenhe-Chiwishe A, Pollyea DA, Yokoi A, Holash J, Yancopoulos GD, Kandel JJ, Yamashiro DJ. TNP-470 promotes initial vascular sprouting in xenograft tumors. Mol Cancer Ther. 2004 Mar;3(3):335-43.
PMID: 15026554
Frischer JS, Huang J, Serur A, Kadenhe A, Yamashiro DJ, Kandel JJ. Biomolecular markers and involution of hemangiomas.J Pediatr Surg. 2004 Mar;39(3):400-4. PMID: 15017560
Davidoff AM, Kandel JJ. Antiangiogenic therapy for the treatment of pediatric solid malignancies. Semin Pediatr Surg. 2004 Feb;13(1):53-60. Review. PMID: 14765371
Huang J, Soffer SZ, Kim ES, McCrudden KW, Huang J, New T, Manley CA, Middlesworth W, O'Toole K, Yamashiro DJ, Kandel JJ.ascular remodeling marks tumors that recur during chronic suppression of angiogenesis. Mol Cancer Res. 2004 Jan;2(1):36-42. PMID: 14757844
Yokoi A, McCrudden KW, Huang J, Kim ES, Soffer SZ, Frischer JS, Serur A, New T, Yuan J, Mansukhani M, O'toole K, Yamashiro DJ, Kandel JJ. Human epidermal growth factor receptor signaling contributes to tumor growth via angiogenesis in her2/neu-expressing experimental Wilms' tumor. J Pediatr Surg. 2003 Nov;38(11):1569-73. PMID: 14614702
Kaicker S, McCrudden KW, Beck L, New T, Huang J, Frischer JS, Serur A, Kadenhe-Chiweshe A, Yokoi A, Kandel JJ, Yamashiro DJ.Thalidomide is anti-angiogenic in a xenograft model of neuroblastoma. Int J Oncol. 2003 Dec;23(6):1651-5. PMID: 14612937
Yokoi A, McCrudden KW, Huang J, Kim ES, Soffer SZ, Frischer JS, Serur A, New T, Yuan J, Mansukhani M, O'Toole K, Yamashiro DJ, Kandel JJ. Blockade of her2/neu decreases VEGF expression but does not alter HIF-1 distribution in experimental Wilms tumor.
Oncol Rep. 2003 Sep-Oct;10(5):1271-4. PMID: 12883692
Huang J, Frischer JS, Serur A, Kadenhe A, Yokoi A, McCrudden KW, New T, O'Toole K, Zabski S, Rudge JS, Holash J, Yancopoulos GD, Yamashiro DJ, Kandel JJ. Regression of established tumors and metastases by potent vascular endothelial growth factor blockade.
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7785-90. Epub 2003 Jun 12. PMID: 12805568
Contact
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