Chemotherapy and Targeted Therapy Combinations in Advanced Melanoma

Flaherty, Keith T.

doi:10.1158/1078-0432.ccr-05-2505

Cited by 142 publications

(99 citation statements)

References 33 publications

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“…For example, in the transition from radial to vertical growth phase, melanoma as well as angiogenesis is heralded by both the expression and release of vascular endothelial growth factor (VEGF), which facilitates both growth of new blood and the tumor [29,81,82]; inhibition of VEGF receptor (VEGFR) by sorafenib (formally known as BAY 43-9006 [83,84] in combination with antibodies that block VEGF such as bevacizumab might represent important combination therapy in metastatic melanoma patients. Early clinical development of sorafenib given with carboplatin and paclitaxel to patients with relapsed, refractory metastatic melanoma shows striking activity with prolonged progression-free survival (PFS; median PFS, 10 months) [85,86]. Randomized phase III clinical trials are underway in North America, Europe, and Australia evaluating this combination in metastatic melanoma.…”

Section: C-kit (Cd117)mentioning

confidence: 99%

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Carlson

Linette

Aplin

et al. 2007

Dermatologic Clinics

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Melanocytes are an intraepidermal population of dendritic cells responsible for the production of melanin, a pigment that varies from yellow to brown to black pigment that after transfer to neighboring keratinocytes acts both as an endogenous screen and a buffering system against harmful ultraviolet (UV) wavelengths in sunlight [1]. Skin pigmentation has both individual and societal implications. The cosmetic desire for increased pigmentation (tanning) has resulted in many deleterious alterations including hastened skin ageing with wrinkles and poikiloderma and an increase in lentigines, melanocytic nevi, and melanoma. Focal or widespread loss of normal pigmentation not only renders individuals extraordinarily vulnerable to the harmful effects of sunlight (eg, increased risk of skin cancer in albinism), but it can also result in severe emotional stress and, in some societies, ostracism and discrimination (eg, vitiligo).Melanocytes are derived from the neural crest and are located along the basal layer of the epidermis and within the hair follicle, predominately the basal layer of the hair bulb matrix [1,2]. By the 50th day of intrauterine life, melanocytes can be detected in the epidermis; their migration to the epidermis and survival is dependent on receptor tyrosine kinase (RTK) c-Kit and its ligand stem cell factor (SCF) within the epidermis [3,4]. Mutations of the c-Kit gene lead to patches of hypopigmentation caused by lack of melanocyte migration, termed piebaldism [5]. Another important signaling molecule in melanocyte migration and development is Wnt5a, which signals via the Frizzled-5 receptor [6]. Overexpression of Wnt5a/ Frizzled is found in melanomas and associated with increased cell motility and invasiveness [7,8].Skin keratinocytes obtain melanin pigment from melanocytes, and keratinocytes provide the necessary microenvironment for melanocyte survival, proliferation, differentiation, and migration via production of ligands that interact with melanocyte receptors [1,[9][10][11] NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript epidermal melanin unit denotes the symbiotic relationship between one melanocyte transporting melanin via its dendritic processes to approximately 36 keratinocytes [10]. Melanocytes are located on the basement membrane among basal keratinocytes at ratio of 1 melanocyte per 5 basal keratinocytes in hematoxylin and eosin-stained histologic sections. This balance is maintained through regulated induction of melanocyte division. During childhood as the skin surface expands, throughout adulthood to maintain melanocyte numbers, and in response to exposure to sunlight or skin wounding, melanocytes are stimulated to proliferate at a low rate. Melanocyte proliferation entails uncoupling from keratinocytes, loss of their dendrites, cell division, migration along the basement membrane, then recoupling with keratinocytes to form the epidermal melanin unit. Keratinocytes regulate melanocyte growth and expression of melanocyte cell surface receptors via cell adhes...

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Section: C-kit (Cd117)mentioning

confidence: 99%

Melanocyte Receptors: Clinical Implications and Therapeutic Relevance

Carlson

Linette

Aplin

et al. 2007

Dermatologic Clinics

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“…Malignant melanoma represents one of the most aggressive malignancies with a highly chemoresistant and radioresistant metastatic stage (Flaherty, 2006), offering a poor prognosis for affected patients (Lasithiotakis et al, 2006). Therefore, therapeutic strategies combining chemotherapeutic drugs and tumor selective death ligands are under investigation to improve cancer treatment (Ganten et al, 2006;Zhang et al, 2006;Koschny et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Caspase-3 cleaves XIAP in a positive feedback loop to sensitize melanoma cells to TRAIL-induced apoptosis

et al. 2010

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Successful treatment of melanoma is still challenging, because metastasis remain chemoresistant and radioresistant. Accordingly, combinational treatments involving death ligands are mandatory. In a recent study from our lab, the majority out of 18 melanoma cell lines remained resistant against treatment with the death ligand TRAIL (tumor necrosis factor related apoptosis inducing ligand). Resistance was shown to be mainly due to incomplete processing of caspase-3 into catalytically inactive p21 by binding of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP). Coirradiation with sub-lethal ultraviolet (UV) B caused depletion of XIAP resulting in synergistic sensitization of all but two melanoma cell lines to TRAIL. We show here the XIAP depletion to essentially require initial caspasemediated cleavage, which promotes proteasomal degradation of XIAP. Utilizing specific caspase inhibitors and small interfering RNA-mediated knockdown, we further identified caspase-3 to be responsible for performing the initial cleavage of XIAP after UVB treatment. Additional evidence suggests an accelerated mitochondrial outer membrane permeabilization in response to co-treatment with TRAIL and UVB, which directs the release of XIAP antagonizing factors including Smac. Distraction of XIAP consequently liberates caspase-3 to autocatalytically process into active p17. Activated caspase-3 cleaves XIAP and further enhances its activation in a positive regulatory feedback loop. The molecular mechanism discovered here appears to have broader implications, because cleavage of XIAP was also shown to accompany cisplatin-induced sensitization of melanoma cells to TRAIL.

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“…The primary melanoma is characterized by an early and invasive radial growth phase (RGP), which advances through the vertical growth phase (VGP) with competence for metastasis into metastatic melanoma (MM) and highly aggressive melanoma (HM) (Clark, 1991;Elder et al, 1993). The metastatic stage represents a therapeutic challenge, because it remains largely chemo-and radio-resistant (Flaherty, 2006), making alternative therapeutic strategies mandatory to achieve successful cancer treatment.…”

Section: Introductionmentioning

confidence: 99%