Molecular therapeutics: promise and challenges

Kohn, Elise C.; Lu, Yiling; Wang, Hongwei; Yu, Qinghua; Yu, Shuangxing; Hall, Hassan; Smith, Debra L.; Meric‐Bernstam, Funda; Hortobágyi, Gabriel N.; Mills, Gordon B.

doi:10.1053/j.seminoncol.2004.01.009

Cited by 23 publications

(8 citation statements)

References 57 publications

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“…The concept of molecular therapeutics aims at developing treatments that modulate a specific factor or cellular pathway thought to play a critical role in the survival, proliferation, or invasion of a tumorous cell (573). Although there are many genetic aberrations that can be identified in pituitary adenomas, only a subset of these are critically involved in cell proliferation, cell survival, and tumor progression.…”

Section: F Molecular Therapeuticsmentioning

confidence: 99%

“…Thus, validation that a proposed genetic aberration has tumorigenic causality using stringent criteria with multiple lines of scientific evidence is essential for the selection of "critical targets" (575). Although it remains to be proven as a general principle, most authorities believe that interference with tumor-initiating events will ultimately be necessary for effective targeted therapy (573,576). The optimal implementation of this type of approach will require the development of molecular diagnostic markers able to identify patients with tumors whose growth is governed by the chosen therapy.…”

Section: F Molecular Therapeuticsmentioning

confidence: 99%

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Advances in the Treatment of Prolactinomas

et al. 2006

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Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future.

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Section: F Molecular Therapeuticsmentioning

confidence: 99%

Section: F Molecular Therapeuticsmentioning

confidence: 99%

Advances in the Treatment of Prolactinomas

et al. 2006

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“…ALK meets most criteria to be classed as a valid molecular target (82). Targeting mutated ALK in neuroblastoma is likely to produce clinical benefit, for the following reasons: (i) point mutations and amplifications, which occur in approximately 8–10% and 2% of primary neuroblastoma tumors respectively, are oncogenic both in vitro and in vivo , leading to constitutive phosphorylation of ALK and of downstream signaling molecules critical for cell proliferation and survival.…”

Section: Alk As a Therapeutic Target In Neuroblastomamentioning

confidence: 99%

Promising Therapeutic Targets in Neuroblastoma

Matthay

George²,

Yu³

2012

Clinical Cancer Research

171

143

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Neuroblastoma, the most common extra- cranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease, and have 5-year EFS of less than 50%. New approaches with targeted therapy may improve efficacy without increased toxicity. The current review will evaluate three promising targeted therapies, including 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical taken up by the human norepinephrine transporter expressed in 90% of neuroblastomas, immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, expressed on 98% of neuroblastoma cells, and inhibitors of ALK, a tyrosine kinase which is mutated or amplified in approximately 10% of neuroblastoma and expressed on the surface of most neuroblastoma cells. Early phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of about 30%, but the technical aspects of administration of large amounts of radioactivity in young children and the limited access have hindered incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also demonstrated activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small molecule inhibitor of ALK has promising pre-clinical activity for neuroblastoma, and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma.

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“…Thus, to establish reliable therapeutic strategies for human cancer, it is important to seek the genetic and epigenetic targets present only in cancer cells. The emerging fields of functional genomics and functional proteomics provide an expanding repertoire of clinically applicable targeted therapeutics (Kohn et al, 2004). Telomerase is a ribonucleoprotein complex responsible for the addition of TTAGGG repeats to the telomeric ends of chromosomes (Greider and Blackburn, 1985;Collins and Mitchell, 2002), and contains the enzymatic subunit human telomerase reverse transcriptase (hTERT) (Nakamura et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’)

et al. 2005

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Replication-competent oncolytic viruses are being developed for human cancer therapy. We previously reported that an attenuated adenovirus (OBP-301, 'Telomelysin'), in which the hTERT promoter element drives expression of E1A and E1B genes linked with an IRES, could replicate in cancer cells, and causes selective lysis of cancer cells. We further constructed OBP-405 ('Telomelysin-RGD') that contains an RGD motif in the HI loop of the fiber knob. We examined whether OBP-405 could be effective in overcoming the limitations of OBP-301, specifically their inefficient infection into cells lacking the primary receptor, the coxsackievirus and adenovirus receptor (CAR). By flow cytometric analysis, H1299 (lung) and SW620 (colorectal) tumor cells showed high levels of CAR expression, whereas LN444 (glioblastoma), LNZ308 (glioblastoma), and H1299-R5 (lung) tumor cells were negative for CAR expression. A quantitative realtime PCR analysis demonstrated that fiber-modified OBP-405 infected more efficiently than OBP-301, although the intracellular replication rate of both viruses was consistent. The comparative antitumor effect of fibermodified OBP-405 and unmodified OBP-301 for human cancer cells was evaluated in vitro by XTT assay as well as in vivo by using athymic mice carrying xenografts. OBP-405 had a profound oncolytic effect on human cancer cell lines compared to OBP-301, in particular on cells with low CAR expression. Intratumoral injection of 10 7 plaque-forming units of OBP-405 into CAR-negative H1299-R5 lung tumor xenografts in nu/nu mice resulted in a significant inhibition of tumor growth and long-term survival in all treated mice. Moreover, selective replication of OBP-405 in the distant, uninjected H1299-R5 tumors was demonstrated. Our results suggest that fiber-modified replication-competent adenovirus OBP-405 exhibits a broad target range by increasing infection efficiency, an outcome that has important implications for the treatment of human cancers.

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Molecular therapeutics: promise and challenges

Cited by 23 publications

References 57 publications

Advances in the Treatment of Prolactinomas

Advances in the Treatment of Prolactinomas

Promising Therapeutic Targets in Neuroblastoma

Enhanced oncolysis by a tropism-modified telomerase-specific replication-selective adenoviral agent OBP-405 (‘Telomelysin-RGD’)

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