The Use of a Tropism-Modified Measles Virus in Folate Receptor–Targeted Virotherapy of Ovarian Cancer

Hasegawa, Kosei; Nakamura, Takafumi; Harvey, Mary; Ikeda, Yasuhiro; Oberg, Ann L.; Figini, Mariangela; Canevari, Silvana; Hartmann, Lynn C.; Peng, Kah Whye

doi:10.1158/1078-0432.ccr-06-0992

Cited by 83 publications

(66 citation statements)

References 48 publications

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“…These strategies include use of anti-FRα antibodies [10] or folic acid-conjugates to localize drugs [28][29][30], imaging compounds [31][32][33], T cells [34,35], nanoparticles [36], or oncolytic viruses [37] to FRα-expressing tumors. Besides these efforts, we have recently shown that FRα may have potential as a target for immunotherapeutic approaches in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

Folate receptor alpha as a tumor target in epithelial ovarian cancer

Kalli¹,

Oberg²,

Keeney³

et al. 2008

Gynecologic Oncology

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Objectives-Folate receptor α (FRα) is a folate-binding protein overexpressed on ovarian and several other epithelial malignancies that can be used as a target for imaging and therapeutic strategies. The goal of this study is to improve historical data that lack specific information about FRα expression in rare histological subtypes, primary disease versus metastatic foci, and recurrent disease.Methods-FRα expression was analyzed by immunohistochemistry on 186 primary and 27 recurrent ovarian tumors, including 24 pairs of samples obtained from the same individuals at diagnosis and at secondary debulking surgery. For 20 of the 186 primaries, simultaneous metastatic foci were also analyzed. FRα staining was analyzed in light of disease morphology, stage, grade, debulking status, and time from diagnosis to recurrence and death.Results-FRα expression was apparent in 134 of 186 (72%) primary and 22 of 27 (81.5%) recurrent ovarian tumors. In 21 of 24 (87.5%) matched specimens, recurrent tumors reflected the FRα status detected at diagnosis. Metastatic foci were similar to primary tumors in FRα staining. FRα status was not associated with time to recurrence or overall survival in either univariate or multivariable analyses.Conclusion-FRα expression occurs frequently, especially in the common high-grade, high-stage serous tumors that are most likely to recur. New findings from this study show that FRα expression is maintained on metastatic foci and recurrent tumors, suggesting that novel folate-targeted therapies may hold promise for the majority of women with either newly diagnosed or recurrent ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Folate receptor alpha as a tumor target in epithelial ovarian cancer

Kalli¹,

Oberg²,

Keeney³

et al. 2008

Gynecologic Oncology

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383

271

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“…CD133 cDNA fragment was sub-cloned into a lentiviral-based vector (pHR-SIN-CSGW) (Hasegawa et al, 2006).…”

Section: Cloning Of Human Cd133 Cdnamentioning

confidence: 99%

CD133 suppresses neuroblastoma cell differentiation via signal pathway modification

et al. 2010

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CD133 (prominin-1) is a transmembrane glycoprotein expressed on the surface of normal and cancer stem cells (tumor-initiating cells), progenitor cells, rod photoreceptor cells and a variety of epithelial cells. Although CD133 is widely used as a marker of various somatic and putative cancer stem cells, its contribution to the fundamental properties of cancer cells, such as tumorigenesis and differentiation, remains to be elucidated. In the present report, we found that CD133 was expressed in several neuroblastoma (NB) cell lines/tumor samples. Intriguingly, CD133 repressed NB cell differentiation, for example neurite extension and the expression of differentiation marker proteins, and was decreased by several differentiation stimuli, but accelerated cell proliferation, anchorage-independent colony formation and in vivo tumor formation of NB cells. NB cell line and primary tumor-sphere experiments indicated that the molecular mechanism of CD133-related differentiation suppression in NB was in part dependent on neurotrophic receptor RET tyrosine kinase regulation. RET transcription was suppressed by CD133 in NB cells and glial cell linederived neurotrophic factor treatment failed to induce RET in CD133-expressing cells; RET overexpression rescued CD133-related inhibition of neurite elongation. Of note, CD133-related NB cell differentiation and RET repression were mainly dependent on p38MAPK and PI3K/Akt pathways. Furthermore, CD133 has a function in growth and RET expression in NB cell line-and primary tumor cell-derived tumor spheres. To the best of our knowledge, this is the first report of the function of CD133 in cancer cells and our findings may be applied to improve differentiation induction therapy for NB patients.

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“…[8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue.…”

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confidence: 99%

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

et al. 2007

Clin Pharmacol Ther

112

125

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MV-NIS is an oncolytic measles virus encoding the human thyroidal sodium iodide symporter (NIS).Here, we report the results of preclinical pharmacology and toxicology studies conducted in support of our clinical protocol "Phase I Trial of Systemic Administration of Edmonston Strain of Measles Virus, Genetically Engineered to Express NIS, with or without Cyclophosphamide, in Patients with Recurrent or Refractory Multiple Myeloma." Dose-response studies in the KAS-6/1 myeloma xenograft model demonstrated a minimum effective dose of 4 × 10 6 TCID 50 (tissue culture infectious dose 50)/kg. Toxicity studies in measles-naive squirrel monkeys and measles-susceptible transgenic mice were negative at intravenous doses up to 10 8 and 4 × 10 8 TCID 50 /kg, respectively. Abundant viral mRNA, maximal on day 8, was detected in cheek swabs of squirrel monkeys, more so after pretreatment with cyclophosphamide. On the basis of these data, the safe starting dose of MV-NIS for our clinical protocol was set at 1 -2 × 10 4 TCID 50 /kg (10 6 TCID 50 per patient).Measles virus (MV, family Paramyxoviridae) was isolated in 1954 from the throat washings of a measles patient, David Edmonston. 1 Tissue culture passage resulted in loss of pathogenicity and attenuation of wild-type MV (Figure 1), giving rise to the Edmonston measles vaccines used worldwide today. 2 We recently discovered that attenuated Edmonston strain MV has potent antitumor activity in vitro and in vivo. 3 Intravenous, intratumoral, or intraperitoneal administration of the virus inhibited tumor growth or induced tumor regression in a variety of human tumor xenograft models. [4][5][6][7] To tailor the virus for cancer therapy, we Correspondence: SJ Russell (sjr@mayo.edu). CONFLICT OF INTERESTThe authors declared no conflict of interest. NIH Public Access Author ManuscriptClin Pharmacol Ther. Author manuscript; available in PMC 2009 October 28. Published in final edited form as:Clin Pharmacol Ther. 2007 December ; 82(6): 700-710. doi:10.1038/sj.clpt.6100409. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscripthave genetically engineered the viral coat protein to display tumor-targeting ligands to enable tumor-specific killing or inserted trackable transgenes into the viral genome to enable noninvasive monitoring of viral gene expression. [8][9][10][11][12] MV-NIS is an Edmonston-lineage MV that expresses the human sodium iodide symporter (hNIS) (Figure 2). 12 The NIS protein is normally expressed in the thyroid, mammary glands, stomach, and salivary tissue. Expression of NIS allows cells to actively transport iodide ions into the cell. Thus, patients with thyroid cancer are typically treated with 131 I to destroy the NIS-expressing thyroid cancer while leaving most normal tissues undamaged. 13 Loss of thyroid function due to the radiotherapy can be treated by replacement therapy with synthetic thyroid hormones. Insertion of NIS into MV facilitates pharmacokinetic evaluation and enhancement of MV oncolytic activity. MV-NIS-infected cells express...

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The Use of a Tropism-Modified Measles Virus in Folate Receptor–Targeted Virotherapy of Ovarian Cancer

Cited by 83 publications

References 48 publications

Folate receptor alpha as a tumor target in epithelial ovarian cancer

Folate receptor alpha as a tumor target in epithelial ovarian cancer

CD133 suppresses neuroblastoma cell differentiation via signal pathway modification

Preclinical Pharmacology and Toxicology of Intravenous MV-NIS, an Oncolytic Measles Virus Administered With or Without Cyclophosphamide

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