Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment

Augustine, Christina K.; Yoshimoto, Yasunori; Gupta, Mukur; Zipfel, Patricia A.; Selim, M. Angélica; Febbo, Phillip G.; Pendergast, Ann Marie; Peters, William P.; Tyler, Douglas S.

doi:10.1158/0008-5472.can-07-5949

Cited by 88 publications

(94 citation statements)

References 44 publications

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“…However, more recent data suggest that downregulation of Mcl-1 alone is not sufficient to induce cell death or enhance the sensitivity of cells to chemotherapy or radiation (19,42), consistent with our observations. Systemic treatment of rats with a small peptide inhibitor of N-cadherin has recently been shown to increase the levels of melphalan adducts in tumor cells in our xenograft melphalan ILI animal model (43). Likewise, alterations in drug delivery have been reported for other vascular targeting agents, including Gleevec (imatinib) and Avastin (bevacizumab; refs.…”

Section: Discussionmentioning

confidence: 67%

“…Our results show that this approach may be effective not only with regionally administered chemotherapeutic agents like temozolomide (currently being evaluated in a phase I dose escalation ILI trial) but also with other systemically administered targeted agents or modulators. In addition to sorafenib, as described here, preclinical studies using systemically administered agents that target the glutathione detoxification system, such as the reduced glutathione-depleting agent buthionine sulfoximine, and cell adhesion, such as the small peptide inhibitor of N-cadherin ADH-1 (43,49), have proved very effective in improving tumor responses. Phase I/II clinical trials examining the efficacy of these agents, including sorafenib, to enhance the response of melanoma to ILI with melphalan are currently in progress or under development.…”

Section: Discussionmentioning

confidence: 99%

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Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Augustine

Toshimitsu

Jung

et al. 2010

Molecular Cancer Therapeutics

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Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 μmol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Augustine

Toshimitsu

Jung

et al. 2010

Molecular Cancer Therapeutics

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“…Many novel drugs are being developed that target specific molecular or genetic lesions, and although targeted therapies alone often show only modest antitumor activity (48), it is likely that when combined with standard chemotherapies, the responses will be higher and more durable (28). Our laboratory has recently shown that targeted disruption of N-cadherin signaling with the small molecule ADH-1 can significantly improve the antimelanoma activity of temozolomide in a murine xenograft model (49). Fig.…”

Section: Discussionmentioning

confidence: 99%

Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma

Augustine

Yoo²,

Potti

et al. 2009

Clinical Cancer Research

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Purpose: Despite objective response rates of only f13%, temozolomide remains one of the most effective single chemotherapy agents against metastatic melanoma, second only to dacarbazine, the current standard of care for systemic treatment of melanoma. The goal of this study was to identify molecular and/or genetic markers that correlate with, and could be used to predict, response to temozolomide-based treatment regimens and that reflect the intrinsic properties of a patient's tumor. Experimental Design: Using a panel of 26 human melanoma-derived cell lines, we determined in vitro temozolomide sensitivity, O 6 -methylguanine-DNA methyltransferase (MGMT) activity, MGMT expression and promoter methylation status, and mismatch repair proficiency, as well as the expression profile of 38,000 genes using an oligonucleotide-based microarray platform. Results: The results showed a broad spectrum of temozolomide sensitivity across the panel of cell lines, with IC 50 values ranging from 100 Amol/L to 1mmol/L. There was a significant correlation between measured temozolomide sensitivity and a gene expression signature^derived prediction of temozolomide sensitivity (P < 0.005). Notably, MGMT alone showed a significant correlation with temozolomide sensitivity (MGMT activity, P < 0.0001; MGMT expression, P V 0.0001). The promoter methylation status of the MGMT gene, however, was not consistent with MGMT gene expression or temozolomide sensitivity. Conclusions: These results show that melanoma resistance to temozolomide is conferred predominantly by MGMTactivity and suggest that MGMTexpression could potentially be a useful tool for predicting the response of melanoma patients to temozolomide therapy.Malignant melanoma is increasing at a rate faster than any other cancer, with an expected 62,000 new cases this year (1). Despite advances in our understanding of melanoma biology and the development of several targeted therapeutics, the overall response rates of malignant melanomas to therapy continue to be low.Currently, the drug of choice for the treatment of systemic melanoma is dacarbazine (DTIC). Although DTIC as a single agent has yielded response rates of f15% against melanoma, most of these are incomplete and last only a few months. Temozolomide is a second-generation alkylating agent with a mechanism of action similar to DTIC through the active metabolite 5-(3-methyltriazen-1-yl)imidazole-4-carboximide (MTIC; ref. 2). A randomized phase III trial comparing temozolomide with DTIC showed that temozolomide improved health-related quality of life, had greater systemic exposure to both the parent drug and active metabolite, and was associated with longer progression-free survival (3).

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“…N-cadherin overexpression via cadherin switching was observed in various invasive cancer cell lines and tumors and, therefore, is emerging as a potential therapeutic target. ADH-1, a peptide antagonist that disrupts N-cadherin-mediated adhesion, has been shown to inhibit cell growth and motility in vitro, as well as tumor growth and invasion in vivo (11,12); ADH1 is currently undergoing phase 1 clinical trials.…”

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confidence: 99%

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

Zhang

Yan²,

Zhang³

et al. 2010

Clinical Cancer Research

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Purpose: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models.Experimental Design: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated.Results: PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3′-[18 F]fluoro-3′-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane β-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3′-[ 18 F]fluoro-3′-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts. Conclusions: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials. Clin Cancer Res; 16(21); 5177-88. ©2010 AACR.

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Targeting N-Cadherin Enhances Antitumor Activity of Cytotoxic Therapies in Melanoma Treatment

Cited by 88 publications

References 44 publications

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Sorafenib, a Multikinase Inhibitor, Enhances the Response of Melanoma to Regional Chemotherapy

Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma

PF-03732010: A Fully Human Monoclonal Antibody against P-Cadherin with Antitumor and Antimetastatic Activity

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