Melanoma is the most serious form of skin cancer. It is a cancer “– of melanocytes which are found predominantly in skin but also in the bowel and the eye (see uveal melanoma). — Melanocytes are normally present in skin, being responsible for the production of the dark pigment melanin.[2] Despite many years of intensive laboratory and clinical research, the greatest chance of cure is in the early surgical resection of thin tumors(ref).” In 2009, 68,720 new cases of melanoma were reported in the US and the disease led to 8,650 deaths(ref). “According to a WHO report about 48,000 melanoma related deaths occur worldwide per year(ref).”[6]
Melanoma is also among the most-studied cancers. The US government clinical trials database shows 910 clinical trials for melanoma in various stages. This blog entry reports a selection of recent (2010) published research findings.
An April 2010 e-publication Vaccination with autologous dendritic cells pulsed with multiple tumor antigens for treatment of patients with malignant melanoma: results from a phase I/II trial provides a testimony to the relative inefficacy of a high-technology vaccine in the face of progressive malignant melanoma. See the earlier blog post Dendritic cell cancer immunotherapy. According to the new publication “Dendritic cells are regarded as the most effective antigen presenting cells and coordinators of the immune response and therefore suitable as vaccine basis. Here we present results from a clinical study in which patients with malignant melanoma (MM) with verified progressive disease received vaccination with autologous monocyte-derived mature dendritic cells (DC) pulsed with p53, survivin and telomerase-derived peptides (HLA-A2(+) patients) or with autologous/allogeneic tumor lysate (HLA-A2(-) patients) in combination with low-dose interleukin (IL)-2 and interferon (IFN)-alpha2b. Results: Of 46 patients who initiated treatment, 10 stopped treatment within 1-4 weeks because of rapid disease progression and deterioration. After 8 weeks, 36 patients were evaluable: no patient had an objective response, 11 patients had stable disease (SD); six had continued SD after 4 months, and three patients had prolonged SD for more than 6 months. The mean overall survival time was 9 months, with a significantly longer survival (18.4 months) of patients who attained SD compared with patients with progressive disease (PD) (5 months). Induction of antigen-specific T-cell responses was analyzed by multidimensional encoding of T cells using HLA-A2 major histocompatibility complex (MHC) multimers. Immune responses against five high-affinity vaccine peptides were detectable in the peripheral blood of six out of 10 analyzed HLA-A2(+) patients. There was no observed correlation between the induction of immune responses and disease stabilization. A significant lower blood level of regulatory T cells (CD25(high) CD4 T cells) was demonstrable after six vaccinations in patients with SD compared with PD. Conclusions: Vaccination was feasible and safe. Treatment-associated SD was observed in 24% of the patients. SD correlated with prolonged survival suggesting a clinical benefit. Differences in the level of regulatory T cells among SD and PD patients could indicate a significant role of these immune suppressive cells” I decode this to mean that about a quarter of the treated patients extended their mean survival time from 9 months to 18.4 months. While this is only a Phase I/II study, it casts doubt on whether dendritic cell cancer immunotherapy, a major focus of current cancer research, will provide a magic bullet against aggressive cancers.
A study published this week in the journal Cell A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth may help explain several key aspects of melanoma, such as its aggressiveness. The study suggests that there are two important temporary subpopulations of melanoma cells, both tumorigenic but different in their differentiation and replication potentials. There is at any time a relatively small slowly-dividing population of cells characterized by the JARID1B demethylase biomarker. This population is stem-cell-like and necessary for continuous tumor growth. The JARID1B- cells, on the other hand, divide very rapidly but are insufficient for continuous tumor maintenance. Moreover, JARID1B- cells can transform into being JARID1B+ cells and the other way around. “Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation. º The H3K4 demethylase JARID1B marks a subpopulation of slow-cycling melanoma cells. º The JARID1B+ subpopulation is required for continuous tumor maintenance . º Cells can lose or gain JARID1B expression and do not follow a stem cell hierarchy. º Tumor initiation is not necessarily linked with tumor maintenance.” A possible implication if the study is that an effective therapy regimen for melanoma will have to target both the fast (JARID1B-) and slow-growing (JARID1B+) cell populations if it is to be effective. The study is also important for pointing out how the JARID1B- cells can convert themselves into the stem-cell-like JARID1B+ cells, an effect not observed in other cancers. For background relating to cancer stem cells you can check out the earlier blog entries On cancer stem cells, Big pharma is targeting cancer stem cells, Update on cancer stem cells, and News on disabling cancer stem cells.
The April 2010 publication Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications reports on a review study, the purpose of which was to identify molecular biomarkers for melanoma. A vivid view is provided of how melanoma originates: “RESULTS: Melanocyte precursors undergo several genome changes -UV-induced or not- which could be either mutations or epigenetic. These changes provide stem cells with abilities to self-invoke growth signals, to suppress antigrowth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis. Melanocyte stem cells are able to progressively collect these changes in their genome. These new potential functions, drive melanocyte precursors to the epidermis were they proliferate and might cause benign nevi. In the epidermis, they are still capable of acquiring new traits via changes to their genome. With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell. CONCLUSIONS: Melanoma cannot be considered a “black box” for researchers anymore. Current trends in the diagnosis and prognosis of melanoma are to individualize treatment based on molecular biomarkers. Pharmacogenomics constitute a promising field with regard to melanoma patients’ treatment. Finally, development of novel monoclonal antibodies is expected to complement melanoma patient care while a number of investigational vaccines could find their way into everyday oncology practice.” I find it interesting here that the genome changes leading up to a cancer could be epigenetic as well as mutations in the genome. Until recently the conventional wisdom has been that cancers are caused only by gene mutations.
The January 2010 review publication Molecular cytogenetics of cutaneous melanocytic lesions – diagnostic, prognostic and therapeutic aspects is concerned with cytogenetic alterations in melanocytic tumours. The focus in this paper is on molecular biology and genetic changes rather than on cancer stem cells. “This review demonstrates that at present cytogenetics has mainly increased our understanding of the pathogenesis of melanocytic tumours, with an important role for activation of the mitogen-activated protein kinase (MAPK) signaling pathway in the initiation of melanocytic tumours. Mutations in BRAF (in common naevocellular naevi), NRAS (congenital naevi), HRAS (Spitz naevi) and GNAQ (blue naevi) can all cause MAPK activation. All these mutations seem early events in the development of melanocytic tumours, but by themselves are insufficient to cause progression towards melanoma. Additional molecular alterations are implicated in progression towards melanoma, with different genetic alterations in melanomas at different sites and with varying levels of sun exposure. This genetic heterogeneity in distinct types of naevi and melanomas can be used for the development of molecular tests for diagnostic purposes. However, at the moment only few molecular tests have become of diagnostic value and are performed in daily routine practice. This is caused by lack of large prospective studies on the diagnostic value of molecular tests including follow-up, and by the low prevalence of certain molecular alterations. For the future we foresee an increasing role for cytogenetics in the treatment of melanoma patients with the increasing availability of targeted therapy. Potential targets for metastatic melanoma include genes involved in the MAPK pathway, such as BRAF and RAS. More recently, KIT has emerged as a potential target in melanoma patients. These targeted treatments all need careful evaluation, but might be a promising adjunct for treatment of metastatic melanoma patients, in which other therapies have not brought important survival advantages yet.” As pointed out in the previously-cited paper, there is a need for identifying biomarkers and developing better molecular tests related to them.
One potentially useful biomarker for melanoma is Nestin, as pointed out in the January 2010 publication Stem cell marker nestin expression in peripheral blood of patients with melanoma. “There is continued interest in markers indicative of circulating melanoma cells. Nestin is a neuroepithelial intermediate filament protein that was found to be expressed in melanoma and in various cancer stem cells. Objective: We investigated expression of nestin in peripheral blood of melanoma patients. Patients/Methods: We analyzed nestin expression by flow cytometry and by quantitative reverse transcription polymerase chain reaction (qRT-PCR) both in tissues (n=23) and blood samples (n=102) from patients with AJCC stage III-IV melanoma. Forty-six negative controls were also added. Results: Flow cytometry did not reveal nestin expressing cells in peripheral blood of healthy volunteers. In melanoma patients, however, nestin protein was expressed in a proportion of melanoma cells enriched from peripheral blood by immunomagnetic sorting. In melanoma tissue samples a significant correlation was found between mRNAs encoding for nestin and tyrosinase (p=0.001) and Mart-1 (p=0.002), whereas in blood a significant correlation was only observed for tyrosinase (p=0.015), but not for Mart-1 (p=0.53). Nestin expression was higher in stage IV patients compared to stage III/IV with no evidence of disease (NED), positively correlated to tumour burden, and positively correlated to expression of tyrosinase and Mart-1. Conclusions: Nestin showed to be an additional marker of interest for circulating melanoma cells.”
The February 2010 publication Prognostic significance of the hair follicle stem cell marker nestin in patients with malignant melanoma also looked at the use of Nestin as a predictive biomarker, this time related to prognosis of outcome in melanoma patients. “Nestin is an intermediate filament protein, and serves as a hair follicle stem cell and neural stem cell marker. Recent studies have suggested that nestin expression is also important for tumorigenesis. Previous reports from our laboratory have revealed that nestin is a marker of HMB-45-negative melanoma cells in dermal invasive lesions of nodular malignant melanoma. The present study examines nestin expression in malignant melanoma and investigates the relationship between nestin expression and prognosis in patients. We immunohistochemically stained 78 formalin-fixed and paraffin-embedded malignant melanomas for nestin, HMB-45 and S100 reactivity. We found that nestin, HMB-45 and S100 protein were detected in 56.5%, 88.4% and 100% of malignant melanomas, respectively. The 5-year survival rate of stage I and II nestin-positive cases was significantly decreased compared to the nestin-negative cases (p < 0.05). In addition, the 5-year survival rate exceeded 80% in nestin-negative malignant melanomas at all stages of tumor development. We conclude that nestin expression may be a predictor of poor prognosis in patients with malignant melanoma.”
Similar points are made in the January 2010 paper The stem cell marker nestin predicts poor prognosis in human melanoma. “These results suggest that nestin expression in both tumoral and endothelial cells may be considered an important early prognostic marker in melanoma.”
Collectively, these papers indicate the importance of developing biomarker tests for melanoma, and the emergence of Nestin as such a biomarker. I note that the emphasis on discovering reliable predictive biomarkers applies to diseases across the spectrum. See the recent blog entry Harnessing the engines of finance and commerce for life-extension . The discovery of disease biomarkers is identified there as central to a new paradigm in medicine, Personalized Predictive Preventative Participatory Medicine.
There is much more going on in the world of Melanoma research and I will pick this thread up again in a later blog entry. I will also discuss research relating various supplements to melanomas.
As a final note, by far the most effective protection against melanomas and other skin cancers is UV avoidance. Wear sunhats, clothes, sunglasses and sunscreen protective against both UVa and UVb when outdoors in the summer and at high altitudes, and stay away from tanning beds.
