Neuroblastoma is the most common extracranial solid tumor in the pediatric population, accounting for greater than 15% of all cancer-related deaths in infants and children. Despite recent advances in combined modality treatment, the overall mortality for all stages of tumors remains significant at 50%. As a neural crest-derived tumor, neuroblastoma can produce various gastrointestinal (GI) hormones which can affect tumor progression. We have determined that expressions of gastrin-releasing peptide (GRP) and its receptor (GRPR) are increased in aggressive, undifferentiated neuroblastomas and that GRP, acting through GRPR, acts as an autocrine/paracrine growth factor. We have also found that GRPR expression regulates anchorage-independence in neuroblastoma cells in vitro and that GRPR stimulation increases the growth and angiogenesis of neuroblastoma xenografts in vivo. Moreover, we have made exciting innovative progress with in vivo silencing techniques, where we found that GRPR knockdown effectively blocked tumor development and metastasis. Additionally, our studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as an emergent signaling mechanism for GRPR-mediated tumor progression. Furthermore, PI3K pathway components are regulated by GRPR overexpression and silencing. Based on our preliminary findings, the central hypothesis of this proposal is that GRP/GRPR expression critically regulates neuroblastoma tumorigenesis through the activation of the crucial PI3K signal transduction pathway. To examine this hypothesis, we have planned experiments with the following Specific Aims: 1) to determine the cellular function of GRP/GRPR mechanisms on essential tumorigenic processes in human neuroblastomas, 2) to discern the exact role of PI3K/Akt pathway during GRP/GRPR-mediated cell signaling in human neuroblastomas, 3) to ascertain the effects of targeting GRP/GRPR expression on in vivo tumor growth and metastatic potential of neuroblastomas. A better understanding of the cellular mechanisms and signaling pathways regulating neuroblastoma tumorigenesis could potentially lead to the development of novel therapeutic agents as adjuvant treatment for this devastating disease. This information is clinically significant because GRPR may be an important novel therapeutic target for high-risk neuroblastomas. Furthermore, these studies will also enhance our knowledge of hormone- regulated cancer pathogenesis by elucidation of the complex signaling pathways involved.

Public Health Relevance

In spite of advances in therapy, patients with neuroblastoma still have a staggering mortality rate of 50%. This highly malignant childhood tumor is derived from cells of neural crest origin and as such, its tumor behavior is significantly affected by neuroendocrine peptides. Our project is clinically significant because it will aid in the understanding of the hormonal regulation of neuroblastoma, which could lead to a breakthrough in the treatment of this devastating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK061470-10
Application #
8288195
Study Section
Special Emphasis Panel (ZRG1-SBIB-E (03))
Program Officer
Serrano, Jose
Project Start
2002-04-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
10
Fiscal Year
2012
Total Cost
$332,550
Indirect Cost
$119,377
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Rellinger, Eric J; Padmanabhan, Chandrasekhar; Qiao, Jingbo et al. (2017) ML327 induces apoptosis and sensitizes Ewing sarcoma cells to TNF-related apoptosis-inducing ligand. Biochem Biophys Res Commun 491:463-468
Paul, Pritha; Rellinger, Eric J; Qiao, Jingbo et al. (2017) Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma. Oncotarget 8:82609-82620
Rellinger, Eric J; Padmanabhan, Chandrasekhar; Qiao, Jingbo et al. (2017) Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma. Oncotarget 8:91040-91051
Qiao, Jingbo; Grabowska, Magdalena M; Forestier-Roman, Ingrid S et al. (2016) Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression. Oncotarget 7:61955-61969
Craig, Brian T; Rellinger, Eric J; Alvarez, Alexandra L et al. (2016) Induced differentiation inhibits sphere formation in neuroblastoma. Biochem Biophys Res Commun 477:255-9
Mobley, Bret C; Kwon, Minjae; Kraemer, Bradley R et al. (2015) Expression of MYCN in Multipotent Sympathoadrenal Progenitors Induces Proliferation and Neural Differentiation, but Is Not Sufficient for Tumorigenesis. PLoS One 10:e0133897
Zhu, Yueming; Paul, Pritha; Lee, Sora et al. (2015) Antioxidant inhibition of steady-state reactive oxygen species and cell growth in neuroblastoma. Surgery 158:827-36
Rellinger, Eric J; Romain, Carmelle; Choi, SunPhil et al. (2015) Silencing gastrin-releasing peptide receptor suppresses key regulators of aerobic glycolysis in neuroblastoma cells. Pediatr Blood Cancer 62:581-6
Lee, Sora; Rellinger, Eric J; Kim, Kwang Woon et al. (2015) Bromodomain and extraterminal inhibition blocks tumor progression and promotes differentiation in neuroblastoma. Surgery 158:819-26
Romain, Carmelle; Paul, Pritha; Kim, Kwang Woon et al. (2014) Targeting Aurora kinase-A downregulates cell proliferation and angiogenesis in neuroblastoma. J Pediatr Surg 49:159-65

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