Regression of meningioma tumor growth by combination therapy Fifteen percent of meningiomas have malignant characteristics and these aggressive invasive tumors are frequently fatal. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign meningiomas. In patients with residual or recurring benign tumors, there is increasing concern about radiation- related side effects that may occur even with highly accurate therapies such as radiosurgery. Besides therapeutic effect, recent evidence has shown that irradiation may promote malignant behaviors of cancer cells both in vitro and in vivo by activating several pathways involved in tumor invasiveness, angiogenesis and metastasis. Several studies, including ours, demonstrated significantly increased levels of uPA, uPAR, MMP- 9, and cathepsin B in malignant meningiomas. To determine the molecular interactions between radiation and uPA, uPAR, MMP-9, and cathepsin B in meningiomas, we propose the following specific aims:
Specific Aim 1 : Determine the effect of various siRNA bicistronic constructs combined with irradiation on meningioma cell growth, attachment, apoptosis, migration, and invasion in vitro.
Aim 1 a: Determine the effect of various siRNA bicistronic constructs combined with irradiation on the levels of uPA, uPAR, MMP-9 and cathepsin B in meningioma cell lines.
Aim 1 b: Evaluate the effect of various siRNA bicistronic constructs combined with irradiation on the molecular mechanisms of proliferation in meningioma cell lines.
Aim 1 c: Investigate the effect of various siRNA bicistronic constructs combined with irradiation on the molecular mechanisms of apoptosis in meningioma cell lines.
Aim 1 d: Determine the effect of various siRNA bicistronic constructs combined with irradiation on adhesion, migration and invasion in meningioma cell lines.
Specific Aim 2 : Evaluate the effect of various bicistronic siRNA constructs combined with irradiation treatment on meningioma tumor growth and angiogenesis in nude mice.
Aim 2 a: Determine the optimal dosage of various bicistronic siRNA constructs in the absence of irradiation for inhibition of pre- established intracranial tumor growth or invasiveness of human meningioma cell lines injected intracerebrally in nude mice.
Aim 2 b: Determine the effect of various bicistronic siRNA constructs combined with irradiation of pre-established intracranial tumor growth in nude mice.
Aim 2 c: Evaluate the effect of various bicistronic siRNA constructs alone or in combination with irradiation on cerebral angiogenesis in both in vitro and in vivo. The proposed studies should generate major insights into the pathogenesis of radiation-induced alterations in tumors and, in turn, should suggest novel targets for therapeutic interventions of meningiomas.

Public Health Relevance

Fifteen percent of meningiomas have malignant characteristics and these aggressive, invasive tumors are frequently fatal. Radiotherapy remains a major component of treatment modalities for controlling both malignant and benign meningiomas. However, an increasing number of long survivors with secondary side effects from this treatment highlighted the need for development of novel therapeutic approaches. This proposal represents a combinational therapeutic approach using bicistronic siRNA. This strategy may improve radiotherapy outcomes for the treatment of meningiomas.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061835-05
Application #
8213742
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Fountain, Jane W
Project Start
2008-02-15
Project End
2013-03-31
Budget Start
2012-02-01
Budget End
2013-03-31
Support Year
5
Fiscal Year
2012
Total Cost
$336,569
Indirect Cost
$122,194
Name
University of Illinois at Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Gogineni, Venkateswara Rao; Nalla, Arun Kumar; Gupta, Reshu et al. (2011) Chk2-mediated G2/M cell cycle arrest maintains radiation resistance in malignant meningioma cells. Cancer Lett 313:64-75
Gupta, Reshu; Rao Gogineni, Venkateswara; Nalla, Arun Kumar et al. (2011) Oncogenic role of p53 is suppressed by si-RNA bicistronic construct of uPA, uPAR and cathepsin-B in meningiomas both in vitro and in vivo. Int J Oncol 38:973-83
Gupta, Reshu; Nalla, Arun Kumar; Gogineni, Venkateswara Rao et al. (2011) uPAR/cathepsin B overexpression reverse angiogenesis by rescuing FAK phosphorylation in uPAR/cathepsin B down regulated meningioma. PLoS One 6:e17123
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Gogineni, Venkateswara Rao; Nalla, Arun Kumar; Gupta, Reshu et al. (2011) ?3?1 integrin promotes radiation-induced migration of meningioma cells. Int J Oncol 38:1615-24
Rao Gogineni, Venkateswara; Kumar Nalla, Arun; Gupta, Reshu et al. (2010) Radiation-inducible silencing of uPA and uPAR in vitro and in vivo in meningioma. Int J Oncol 36:809-16
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Kunigal, Sateesh; Lakka, Sajani S; Sodadasu, Prasanna Kumar et al. (2009) Stat3-siRNA induces Fas-mediated apoptosis in vitro and in vivo in breast cancer. Int J Oncol 34:1209-20
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