Melanoma genetics and the development of rational therapeutics

Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 05/2005; 115(4):813-24. DOI: 10.1172/JCI24808
Source: PubMed


Melanoma is a cancer of the neural crest-derived cells that provide pigmentation to skin and other tissues. Over the past 4 decades, the incidence of melanoma has increased more rapidly than that of any other malignancy in the United States. No current treatments substantially enhance patient survival once metastasis has occurred. This review focuses on recent insights into melanoma genetics and new therapeutic approaches being developed based on these advances.

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    • "Melanoma is a fatal skin cancer, with increased incidence in recent years [1], [2]. Despite improvements in awareness and early detection, the mortality in patients with melanoma is still quite high [3]. "
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    ABSTRACT: The increased incidence, high rates of mortality and few effective means of treatment of malignant melanoma, stimulate the search for new anti-tumor agents and therapeutic targets to control this deadly metastatic disease. In the present work the antitumor effect of arazyme, a natural bacterial-derived metalloprotease secreted by Serratia proteomaculans, was investigated. Arazyme significantly reduced the number of pulmonary metastatic nodules after intravenous inoculation of B16F10 melanoma cells in syngeneic mice. In vitro, the enzyme showed a dose-dependent cytostatic effect in human and murine tumor cells, and this effect was associated to the proteolytic activity of arazyme, reducing the CD44 expression at the cell surface, and also reducing in vitro adhesion and in vitro/in vivo invasion of these cells. Arazyme treatment or immunization induced the production of protease-specific IgG that cross-reacted with melanoma MMP-8. In vitro, this antibody was cytotoxic to tumor cells, an effect increased by complement. In vivo, arazyme-specific IgG inhibited melanoma lung metastasis. We suggest that the antitumor activity of arazyme in a preclinical model may be due to a direct cytostatic activity of the protease in combination with the elicited anti-protease antibody, which cross-reacts with MMP-8 produced by tumor cells. Our results show that the bacterial metalloprotease arazyme is a promising novel antitumor chemotherapeutic agent.
    PLoS ONE 04/2014; 9(4):e96141. DOI:10.1371/journal.pone.0096141 · 3.23 Impact Factor
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    • "A lower prevalence (22%) of mutations was detected in cutaneous melanoma. Melanoma and BCC share a common carcinogenic factor: solar exposure (Chudnovsky et al., 2005). Ionizing radiation exposure is carcinogenic in BCC but not in melanoma (Dessinioti et al., 2011; Populo et al., 2012). "
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    ABSTRACT: The reactivation or re-expression of telomerase is a widespread feature of neoplasms. TERT promoter mutations were recently reported that werehypothesized to result from UV-radiation. In this retrospective study, we assessedTERT promoter mutations in 196 cutaneous basal cell carcinomas, including 102 tumors from X-irradiated patients, 94 tumors from patients never exposed to ionizing radiation treatment, and 116 melanomas.We sought to evaluate the effects of UV and X-ray irradiation onTERTmutation frequency. TERT mutations were detected in 27% of BCCs fromX-irradiated patients, 51% of BCCs from non-irradiatedpatients and 22% of melanoma patients. TERT mutations were significantly increased in non-X-irradiatedBCC patients compared withX-irradiatedBCC patients; the mutations also presented a different mutation signature. Innon-irradiated patients, TERT mutations were more frequent in BCCsof sun-exposed skin, supporting a possible causative role of UV-radiation. In melanoma, TERT promoter mutations were generally restricted to intermittent sun-exposed areas and associated with nodular and superficial spreading subtypes, increased thickness, ulceration, increased mitotic rate andBRAFV600E mutations. Our results suggest that various carcinogenic factors may cause distinct TERT promoter mutations in BCC and that TERT promoter mutations mightbe associated with a poorer prognosis in melanoma.Journal of Investigative Dermatology accepted article preview online, 01 April 2014; doi:10.1038/jid.2014.163.
    Journal of Investigative Dermatology 04/2014; 134(8). DOI:10.1038/jid.2014.163 · 7.22 Impact Factor
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    • "The high frequency of activating mutations in NRAS and BRAF in melanoma samples, and the clinical effectiveness of BRAF inhibition, suggests that the Ras/Braf/MEK/ERK signaling pathway plays important roles in melanoma tumorigenesis, progression, and development (Chudnovsky et al., 2005; Miller and Mihm, 2006; Gray-Schopfer et al., 2007). We and others have shown that NRAS Q61K and BRAF V600E mutations contribute to melanoma's resistance to apoptosis in part by down-regulating BH3 (Bcl-2 homolog domain 3)-only pro-apoptotic Bcl-2 family members such as Bim and Bad (Wang et al., 2007; Boisvert-Adamo and Aplin, 2008; Cartlidge et al., 2008; Goldstein et al., 2008; Hendrickson et al., 2008). "
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    ABSTRACT: The BH3 mimetic ABT-737 is a potent inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L), and Bcl-w. The Bcl-2 family modulates sensitivity to anticancer drugs in many cancers, including melanomas. In this study, we examined whether ABT-737 is effective in killing melanoma cells either alone or in combination with a proteasome inhibitor already in clinical use (Bortezomib) in vitro and in vivo, and further evaluated the mechanisms of action. Results showed that ABT-737 alone induced modest cytotoxicity in melanoma cells, but only at higher doses. Knock-down of the anti-apoptotic proteins Bcl-2, Bcl-X(L), or Mcl-1 with siRNAs demonstrated that Mcl-1 is the critical mediator of melanoma's resistance to ABT-737 treatment. However, ABT-737 displayed strong synergistic lethality when combined with Bortezomib. Immunoblot analyses demonstrated that Bortezomib increased expression of Noxa, a pro-apoptotic Bcl-2 member that antagonizes Mcl-1. Additionally, siRNA-mediated inhibition of Noxa expression protected melanoma cells from cytotoxicity induced by the combination treatment. These results demonstrate that Bortezomib synergizes with ABT-737 by neutralizing Mcl-1's function via increased levels of Noxa. In a xenograft mouse model, although drug doses were limited due to toxicity, ABT-737 or Bortezomib slowed melanoma tumor growth compared to the control, and the drug combination significantly decreased growth compared to either drug alone. These data imply that less toxic drugs fulfilling a function similar to Bortezomib to neutralize Mcl-1 are promising candidates for combination with ABT-737 for treating melanomas.
    Biology Open 02/2012; 1(2):92-100. DOI:10.1242/bio.2011035 · 2.42 Impact Factor
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