Improved Gene Transfer to Neuroblastoma Cells by a Monoclonal Antibody Targeting RET, a Receptor Tyrosine Kinase

Yano, Lisa; Mari, Shimura; Taniguchi, Mika; Hayashi, Yasuhide; Suzuki, Toshimitsu; Hatake, Kiyohiko; Takaku, Fumimaro; Yukihito, Ishizaka

doi:10.1089/10430340050015301

Cited by 21 publications

(10 citation statements)

References 28 publications

(29 reference statements)

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“…Targeting RET with a monoclonal antibody might also be therapeutically useful [135,136,137]. In a study by Stein et al [137], the effect of labetuzumab, a humanized anti-CEA monoclonal antibody, on the growth of MTC, alone and in combination with chemotherapy, was investigated.…”

Section: Novel Treatment Modalities: Preclinical Studiesmentioning

confidence: 99%

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Çakır¹,

Grossman²

2009

Neuroendocrinology

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Medullary thyroid cancer (MTC) arises from neural-crest-derived parafollicular C cells of the thyroid gland and accounts for approximately 4% of all thyroid cancers. Up to 25–30% of MTC cases occur as inherited disorders while the remaining cases represent the sporadic form of the disease. In this review, the structure and signalling properties of the RET proto-oncogene in its wild-type and mutant forms, and its role in hereditary and sporadic MTC, are discussed. A full data search was performed through PubMed over the years 2000–2008 with the key words ‘medullary thyroid cancer, treatment, molecular biology, RET, molecular mechanism’, and all relevant publications have been included, together with selected publications prior to that date. We also review novel therapies for metastatic MTC, especially the tyrosine kinase inhibitors which have activity at multiple receptor subtypes, and summarize the current ongoing trials in this area. While such tyrosine kinase inhibitors, particularly those affecting RET activity such as vandetanib, sorafenib and sunitinib, are promising, the low rate of partial responses and absence of complete responses in all of the various trials of monotherapy emphasize the need for new and more effective single agents or combinations of therapeutic agents with acceptable toxicity.

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Section: Novel Treatment Modalities: Preclinical Studiesmentioning

confidence: 99%

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Çakır¹,

Grossman²

2009

Neuroendocrinology

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“…In breast cancer, the monoclonal antibody trastuzumab, that targets the HER2/neu protein, has had remarkable success [52]. While several anti-ret antibodies have been reported, none have been used clinically to date [53,54].…”

Section: Ongoing Challenges and Unmet Needsmentioning

confidence: 99%

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Lodish¹,

Stratakis²

2008

Expert Review of Anticancer Therapy

102

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SummaryHereditary medullary thyroid carcinoma (MTC) is caused by specific autosomal dominant gain-of function mutations in the RET proto-oncogene. Genotype-phenotype correlations exist that help predict the presence of other associated endocrine neoplasms as well as the timing of thyroid cancer development. MTC represents a promising model for targeted cancer therapy, as the oncogenic event responsible for initiating malignancy has been well characterized. The RET proto-oncogene has become the rational target for molecularly designed drug therapy. Tyrosine kinase inhibitors targeting activated RET are currently in clinical trials for the treatment of patients with MTC. This review will provide a brief overview of MTC and the associated RET oncogenic mutations, as well as a summary of the therapies designed to strategically interfere with pathologic activation of the RET oncogene. KeywordsMultiple endocrine neoplasia; tyrosine kinase inhibitors; thyroid cancer; oncogenes; clinical trial Introductory overview of the disease: epidemiology and pathophysiologyThyroid cancer represents approximately 1% of malignancies occurring in the United States, accounting for an estimated 33,550 cancer diagnoses and 1,530 cancer deaths per year. Of these cancers, 2% to 3% are due to medullary thyroid cancer (MTC) [1]. MTC is a rare calcitoninproducing tumor that arises from the thyroid gland parafollicular C cells, which are derived from the embryonic neural crest. While the majority of patients with MTC have sporadic disease, 25% to 30% of cases are due to hereditary forms of MTC [2]. The presentation of disease in hereditary MTC is usually bilateral and multicentric, compared with a single, unilateral thyroid tumor found in sporadic cases [3].Hereditary MTC is classified according to three distinct clinical subtypes (Table 1 Summary of current optimal therapeutic practicesMTC is relatively unresponsive to radiation therapy and to standard chemotherapeutic regimens [8,9]. Various chemotherapeutic regimens, including alkylating agents, antimetabolites, and anthracyclines have shown no proven benefit in patients with metastatic MTC [10][11][12]. Radiation therapy has only a palliative role in the treatment of MTC [13]. Surgery remains the only standard treatment for patients with MTC: total thyroidectomy that is performed before MTC grows or spreads beyond the gland is currently the only curative therapy.Once MTC metastasizes, it has a tendency to spread to local and regional lymph nodes, and more distantly to lung, liver, and bone [8]. Although MTC is often widely metastatic, it tends to be a slow growing tumor. Patients with metastatic disease continue to have 5 and 10 year survival rates of 80% and 70%, respectively [14]. However, and despite its slow growth, the average survival for MTC is lower than that for other more common types of thyroid cancer, such as papillary and follicular carcinoma which have a 90% to 94% 5-year survival rate, respectively [15]. Decreased survival in MTC can be correlated with the stage of diagnos...

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“…Yano et al [76] have generated an antibody that can induce internalization of RET, but its efficacy has not been demonstrated. Alternatively, gene therapy might become available.…”

Section: Hirschsprung Combined With Men2mentioning

confidence: 99%

Current concepts in RET-related genetics, signaling and therapeutics

et al. 2006

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The receptor tyrosine kinase RET is expressed in cell lineages derived from the neural crest and has a key role in regulating cell proliferation, migration, differentiation and survival during embryogenesis. Germline and somatic mutations in RET that produce constitutively activated receptors cause the cancer syndrome multiple endocrine neoplasia type 2 and several endocrine and neural-crest-derived tumors, whereas mutations resulting in nonfunctional RET or lower expression of RET are found in individuals affected with Hirschsprung disease. This review focuses on the genetics and molecular mechanisms underlying the different inherited human neural-crest-related disorders in which RET dysfunction has a crucial role and discusses RET as a potential therapeutic target. IntroductionThe human gene RET is localized on chromosome 10 (10q11.2) and contains 21 exons [1]; alternative splicing generates three isoforms, which contain 51 (RET51), 43 (RET43) and 9 (RET9) amino acids in the carboxyl (C)-terminal tail [2]. RET51 and RET9 are the most prevalent and best-characterized isoforms in vivo; RET43 has not yet been characterized. The RET51 isoform shows the highest transforming and kinase activity in vitro [3], and several observations suggest that these isoforms have different tissue-specific effects during embryogenesis [4]. Monoisoformic RET9 mice are viable and normal, whereas the monoisoformic RET51 mice (which lack RET9) have kidney hypoplasia and lack enteric ganglia from the colon [4].RET (Figure 1) is the receptor for members of the glial cell-derived neurotrophic factor (GDNF) family of ligands (GFLs): namely GDNF, Neurturin, Persephin and Artemin [5]. To stimulate RET, these GFLs first need to form a complex with their glycosylphosphatidylinositol (GPI)-anchored co-receptor, a member of the GDNF receptor-a family (GFRa1-GFRa4), after which the GFL-GFRa complex activates RET [6,7]. The GFRs differ in their specificity for GFLs (Figure 1).

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Improved Gene Transfer to Neuroblastoma Cells by a Monoclonal Antibody Targeting RET, a Receptor Tyrosine Kinase

Cited by 21 publications

References 28 publications

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

Medullary Thyroid Cancer: Molecular Biology and Novel Molecular Therapies

RET oncogene in MEN2, MEN2B, MTC and other forms of thyroid cancer

Current concepts in RET-related genetics, signaling and therapeutics

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