Systemic therapy for metastatic malignant melanoma – from deeply disappointing to bright future?

Lorigan, Paul; Eisen, Tim; Hauschild, Axel

doi:10.1111/j.1600-0625.2007.00673.x

Cited by 48 publications

(37 citation statements)

References 122 publications

(120 reference statements)

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“…Chemoresistance in melanoma may be mediated by one of many intrinsic anti-apoptotic mechanisms as well, which in turn affects the relative contribution of proliferation and apoptosis to melanoma progression. NF-ĸB inhibits both the intrinsic and the extrinsic apoptotic pathways [40], and it is a downstream effector of the RAS/RAF/MAPK cascade, which is constitutively activated in the majority of melanomas [42,43]. Constitutive signaling through this pathway results from activating mutations of the oncogene NRAS or BRAF, both of which are common in melanoma [42,43].…”

Section: Discussionmentioning

confidence: 99%

A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

Michelle²,

Monni³

et al. 2011

Oncology

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Objective: Previous melanoma studies evaluating prognostic factors of survival at recurrence have focused on primary tumor characteristics and clinical variables at first recurrence. We examined the prognostic relevance of recurrent tumor proliferation. Methods: 114 melanoma patients with available recurrent tissues who were prospectively enrolled at New York University Medical Center were studied. Standard of care prognostic variables (e.g. stage at initial diagnosis and lactate dehydrogenase level) and recurrent tissue expression of proliferative marker Ki-67 were evaluated for their association with overall survival. Results: High Ki-67 expression was observed in 57 (50%) of the 114 recurrent melanomas. On univariate analysis, the median overall survival of patients whose recurrent tumors overexpressed Ki-67 was significantly shorter than that of patients whose recurrent tumors had low Ki-67 expression (3.6 vs. 9.5 years, p = 0.03). On multivariate analysis, a high proliferative index of the recurrent melanoma remained an independent predictor of worse overall survival, controlling for stage at initial diagnosis, disease-free survival, and stage at first recurrence [HR = 2.09 (95% CI 1.24–3.54), p = 0.006]. Conclusions: Our results demonstrate the prognostic relevance of tumor proliferation in recurrent melanoma patients. Data also support restratification of risk assessment upon recurrence that considers tumor biology in addition to clinical variables evaluated as part of the standard of care.

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Section: Discussionmentioning

confidence: 99%

A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

Michelle²,

Monni³

et al. 2011

Oncology

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“…Single agent dacarbazine (DTIC) has been standard treatment for many years with response rates of 7% to 13%; however, long-lasting responses are few (3). Importantly, several novel treatment approaches, systemic and targeted, are emerging (4). The concept and arguments for immunotherapy in melanoma include reports on spontaneous remissions and lymphocytic infiltration in tumors (5).…”

confidence: 99%

Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome

Jönsson

Busch

Knappskog

et al. 2010

Clinical Cancer Research

241

305

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Purpose: The incidence of malignant melanoma is increasing worldwide in fair-skinned populations. Melanomas respond poorly to systemic therapy, and metastatic melanomas inevitably become fatal. Although spontaneous regression, likely due to immune defense activation, rarely occurs, we lack a biological rationale and predictive markers in selecting patients for immune therapy.Experimental Design: We performed unsupervised hierarchical clustering of global gene expression data from stage IV melanomas in 57 patients. For further characterization, we used immunohistochemistry of selected markers, genome-wide DNA copy number analysis, genetic and epigenetic analysis of the CDKN2A locus, and NRAS/BRAF mutation screening.Results: The analysis revealed four distinct subtypes with gene signatures characterized by expression of immune response, pigmentation differentiation, proliferation, or stromal composition genes. Although all subtypes harbored NRAS and BRAF mutations, there was a significant difference between subtypes (P < 0.01), with no BRAF/NRAS wild-type samples in the proliferative subtype. Additionally, the proliferative subtype was characterized by a high frequency of CDKN2A homozygous deletions (P < 0.01). We observed a different prognosis between the subtypes (P = 0.01), with a particularly poor survival for patients harboring tumors of the proliferative subtype compared with the others (P = 0.003). Importantly, the clinical relevance of the subtypes was validated in an independent cohort of 44 stage III and IV melanomas. Moreover, low expression of an a priori defined gene set associated with immune response signaling was significantly associated with poor outcome (P = 0.001).Conclusions: Our data reveal a biologically based taxonomy of malignant melanomas with prognostic effect and support an influence of the antitumoral immune response on outcome. Clin Cancer Res; 16(13); 3356-67. ©2010 AACR.Malignant melanoma is an aggressive form of skin cancer with a rapidly increasing incidence in the western world (1). Approximately 15% of patients diagnosed with primary melanoma develop distant metastases (2), and current treatment regimens for metastatic melanoma have little effect on long-term survival. Single agent dacarbazine (DTIC) has been standard treatment for many years with response rates of 7% to 13%; however, long-lasting responses are few (3). Importantly, several novel treatment approaches, systemic and targeted, are emerging (4). The concept and arguments for immunotherapy in melanoma include reports on spontaneous remissions and lymphocytic infiltration in tumors (5). However, a rationale for selecting patients eligible for immunotherapy is still lacking.Although there have been several reports on gene expression signatures in malignant melanomas (6-8), only few studies have indicated molecular subtypes of clinical relevance in metastatic melanoma (7, 9). In primary melanoma, genetic profiles are correlated to anatomic site

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“…Combined therapies to treat serious diseases have become a standard method to improve efficiency and to decrease side effects [1][2][3][4], or to prevent resistance mechanisms commonly found in classic chemotherapeutic protocols [5]. Thus, in cancer treatment, a combination of different classes of chemotherapeutic agents or a combination of chemotherapeutics with radiation is now a common form of treatment.…”

Section: Introductionmentioning

confidence: 99%

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

et al. 2008

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Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C 6 H 5 Me or p-Pr i C 6 H 4 Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC 50 B 20 lM), while the mononuclear derivatives were not (IC 50 C 100 lM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 lM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium-DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 lM), LD 50 of the mononuclear derivatives was between 5 and 10 J/cm 2 , while for the tetranuclear derivatives LD 50 was approximately 2.5 J/cm 2 for the [Ru 4 (g 6 -arene) 4 (tetra-4-pp)Cl 8 ] complexes and less than 0.5 J/cm 2 for the [Ru 4 (g 6 -arene) 4 (tetra-3-pp)Cl 8 ] complexes. Examination of cells under a fluorescence microscope revealed the [Ru 4 (g 6 -arene) 4 (tetra-4-pp)Cl 8 ] complexes as cytoplasmic aggregates, whereas the [Ru 4 (g 6 -arene) 4 (tetra-3-pp)Cl 8 ] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.

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Systemic therapy for metastatic malignant melanoma – from deeply disappointing to bright future?

Cited by 48 publications

References 122 publications

A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

A High Proliferative Index of Recurrent Melanoma Is Associated with Worse Survival

Gene Expression Profiling–Based Identification of Molecular Subtypes in Stage IV Melanomas with Different Clinical Outcome

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

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