2001 — 2005 |
Yamashiro, Darrell J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Neurotrophin Receptors in Neuroblastoma @ Columbia University Health Sciences
DESCRIPTION: (Adapted from the investigator's abstract) Neuroblastoma has a wide spectrum of clinical behavior, with tumors regressing spontaneously in infants, to widely metastatic disease and poor outcome despite intensive chemotherapy and bone marrow transplantation. The biological mechanism for these disparate clinical behaviors is likely to involve the neurotrophin receptors TrkA, TrkB, and TrkC, and their respective ligands, NGF, BDNF, and NT3. Favorable neuroblastomas express TrkA and TrkC, but not NGF or NT3. In contrast, unfavorable, metastatic neuroblastomas express TrkB and BDNF. Based on these observations we have proposed a model in which TrkA and TrkC promote favorable neuroblastoma by inducing neuronal d~(ferentiation, while an autocrine loop of TrkB and BDNF promotes unfavorable neuroblastoma by enhancing tumor growth, cell survival, and metastasis. In support of this model, studies have shown that TrkA and TrkC can induce neuronal differentiation, that TrkB can increase cell survival, stimulate cell invasiveness, and is chemoprotective. TrkB can also increase the expression of vascular endothelial growth factor (VEGF), suggesting that TrkB can induce angiogenesis, a critical step in tumor proliferation and metastases. The overall goal of this grant to obtain in vivo evidence for the Trk-NBL model. Our experiments will focus on TrkB and the autocrine/paracrine loop formed with BDNF, with the results compared with TrkC and NT3. For the in vivo studies we will use a xenograft model in the nude mouse that we have developed in our laboratory that produces large primary tumors and metastases to lung, liver, or bone marrow. Aim 1. We hypothesize that in vivo, TrkB promotes cell survival, proliferation, and metastases, while TrkC promotes differentiation. We will compare the ability of TrkB and TrkC to promote cell survival, tumor growth, metastases, differentiation, and protect against chemotherapy in vivo. Aim 2. We hypothesize that an autocrine or paracrine loop of BDNF/TrkB or NT3/TrkC promotes cell survival and differentiation. We will determine if autocrine expression of BDNF or NT3 in neuroblastoma cell lines or fibroblasts promotes differentiation or survival. Aim 3. We hypothesize that Trk receptors regulate angiogenesis in neuroblastoma. We will determine if TrkB and TrkC regulate the expression of VEGF and determine the signal pathways involved. We will determine if TrkB and TrkC protect neuroblastoma against hypoxia induced by anti-VEGF agents. By systematically comparing TrkB with TrkC in vivo, these studies will allow us to determine the validity of the Trk-NBL model.
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2008 — 2012 |
Yamashiro, Darrell J |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Vegf Blockade and Alternative Angiogenic Pathways in Neuroblastoma @ Columbia University Health Sciences
[unreadable] DESCRIPTION (provided by applicant): Most children diagnosed with neuroblastoma after infancy have a poor prognosis, and few will survive despite intensive therapy. New treatments are urgently needed. Recently, drugs which block blood vessel growth (angiogenesis) into tumors have been clinically validated in adults, and may offer promise for these patients. One validated anti-angiogenic target is vascular endothelial growth factor (VEGF), which is expressed in essentially all human cancers, including neuroblastoma. VEGF can bind to both VEGF-receptor-1 (VEGFR1) and VEGFR2, but much prior work indicates that VEGF stimulates angiogenesis primarily via VEGFR2. Therefore, antagonism of VEGF/VEGFR2 signaling has been the principal approach tested against experimental and human cancers. We have previously demonstrated that drugs which block VEGF and VEGFR2 lessen angiogenesis and growth of experimental early-stage neuroblastoma tumors, suggesting that this therapy may be therapeutically useful in children with this cancer. However, our experiments also demonstrate that these tumors ultimately become resistant to VEGF/VEGFR2 blockade. These results suggest that an alternative mechanism may support angiogenesis in neuroblastoma when VEGF/ VEGFR2 signaling is blocked. In these studies, we will determine if activation of VEGFR1 and Notch pathways in neuroblastoma tumor vessels constitutes one such alternative. Both VEGFR1 and Notch proteins are known to contribute to angiogenesis in disease states. In addition, activation of each of these two pathways may stimulate the other. Our initial experiments support this concept, and demonstrate VEGFR1 and Notch activation in the vessels of neuroblastoma tumors that are resistant to anti-VEGF treatment. These observations lead us to propose that one mechanism by which neuroblastomas compensate for anti-VEGF treatment is to preserve tumor blood supply by activating these alternative pathways in vasculature. Utilizing our well-characterized xenograft model, in which NB cell lines are implanted in the kidney of athymic mice, and the TH-MYCN genetic model of NB, we will, in Aim 1, determine whether VEGFR1 signaling can rescue tumor vasculature from VEGFR2 blockade; and in Aim 2, we will determine whether Notch activation in vessels promotes tumor resistance to VEGFR2 blockade. Our overall goal in these studies is to develop effective new treatments children with neuroblastoma by identifying and then overcoming the mechanisms by which these tumors evade inhibition of VEGF. PUBLIC HEALTH RELEVANCE: Children with metastatic neuroblastoma have a poor prognosis with only 30-35% surviving despite intensive therapy. Drugs which block blood vessel growth (angiogenesis) into tumors have been clinically validated in adults, and may offer promise for these patients. Our overall goal in these studies is to develop an effective anti-angiogenic therapy for children with neuroblastoma by identifying and then overcoming the mechanisms by which these tumors evade VEGF-blocking therapies. [unreadable] [unreadable] [unreadable] [unreadable]
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