Inhibition of the BRAF(V600E) oncoprotein by the small-molecule drug PLX4032 (vemurafenib) is highly effective in the treatment of melanoma. However, colon cancer patients harbouring the same BRAF(V600E) oncogenic lesion have poor prognosis and show only a very limited response to this drug. To investigate the cause of the limited therapeutic effect of PLX4032 in BRAF(V600E) mutant colon tumours, here we performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition. We find in multiple BRAF(V600E) mutant colon cancers that inhibition of EGFR by the antibody drug cetuximab or the small-molecule drugs gefitinib or erlotinib is strongly synergistic with BRAF(V600E) inhibition, both in vitro and in vivo. Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition. Melanoma cells express low levels of EGFR and are therefore not subject to this feedback activation. Consistent with this, we find that ectopic expression of EGFR in melanoma cells is sufficient to cause resistance to PLX4032. Our data suggest that BRAF(V600E) mutant colon cancers (approximately 8-10% of all colon cancers), for which there are currently no targeted treatment options available, might benefit from combination therapy consisting of BRAF and EGFR inhibitors.

/pdf/unresponsiveness-of-colon-cancer-to-braf-v600e-inhibition-15uajlun39.pdf

Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR

Ductal carcinoma in situ (DCIS) of the breast represents a heterogeneous group of neoplastic lesions in the breast ducts. The goal for management of DCIS is to prevent the development of invasive breast cancer. This manuscript focuses on the NCCN Guidelines Panel recommendations for the workup, primary treatment, risk reduction strategies, and surveillance specific to DCIS.

https://www.unitypoint.org/desmoines/filesimages/Cancer%20Education/Oncology%20Nursing%20Conference/2015/2014%20NCCN%20Clin%20Pract%20Guidelines%20Male%20Sex%20Dysf.pdf

Clinical practice guidelines in oncology

Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast-moving field.

EMT in cancer

UV radiation (UV) is classified as a "complete carcinogen" because it is both a mutagen and a non-specific damaging agent and has properties of both a tumor initiator and a tumor promoter. In environmental abundance, UV is the most important modifiable risk factor for skin cancer and many other environmentally-influenced skin disorders. However, UV also benefits human health by mediating natural synthesis of vitamin D and endorphins in the skin, therefore UV has complex and mixed effects on human health. Nonetheless, excessive exposure to UV carries profound health risks, including atrophy, pigmentary changes, wrinkling and malignancy. UV is epidemiologically and molecularly linked to the three most common types of skin cancer, basal cell carcinoma, squamous cell carcinoma and malignant melanoma, which together affect more than a million Americans annually. Genetic factors also influence risk of UV-mediated skin disease. Polymorphisms of the melanocortin 1 receptor (MC1R) gene, in particular, correlate with fairness of skin, UV sensitivity, and enhanced cancer risk. We are interested in developing UV-protective approaches based on a detailed understanding of molecular events that occur after UV exposure, focusing particularly on epidermal melanization and the role of the MC1R in genome maintenance.

/pdf/uv-radiation-and-the-skin-2ub2qrbyk1.pdf

UV Radiation and the Skin

From bench to bedside

The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy.

Deregulation of signaling pathways that control differentiation, expansion and migration of neural crest-derived melanoblasts during normal development contributes also to melanoma progression and metastasis. Although several epithelial-to-mesenchymal (EMT) transcription factors, such as zinc finger E-box binding protein 1 (ZEB1) and ZEB2, have been implicated in neural crest cell biology, little is known about their role in melanocyte homeostasis and melanoma. Here we show that mice lacking Zeb2 in the melanocyte lineage exhibit a melanoblast migration defect and, unexpectedly, a severe melanocyte differentiation defect. Loss of Zeb2 in the melanocyte lineage results in a downregulation of the Microphthalmia-associated transcription factor (Mitf) and melanocyte differentiation markers concomitant with an upregulation of Zeb1. We identify a transcriptional signaling network in which the EMT transcription factor ZEB2 regulates MITF levels to control melanocyte differentiation. Moreover, our data are also relevant for human melanomagenesis as loss of ZEB2 expression is associated with reduced patient survival.

/pdf/identification-of-a-zeb2-mitf-zeb1-transcriptional-network-4j68jqziko.pdf

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.

Background: Few studies have paid attention to the effects of treatment interventions on the psychosocial consequences of vitiligo. Objectives: To quantify and an

Quality of life and stigmatization profile in a cohort of vitiligo patients and effect of the use of camouflage.

9. Tezcan I et al: Successful bone marrow transplantation in a case of Griscelli disease which presented in accelerated phase with neurological involvement. Bone Marrow Transplant 24:931-933, 1999 10. Schuster F et al: Griscelli syndrome: Report of the first peripheral blood stem cell transplant and the role of mutations in the RAB27A gene as an indication for BMT. Bone Marrow Transplant 28:409-412, 2001

http://www.fitzpatricksdermatology.com/references/Fitzpatricks_Derm8e_Ref_Ch075.pdf

Hypomelanoses and hypermelanoses

We present a review of current literature concerning the significance of serological markers in melanoma patients. Results for cytokines, cytokine receptors, cell adhesion molecules, S100 protein, melanoma inhibitory activity, tissue-specific reverse transcription-polymerase chain reaction, neurone-specific enolase, lipid-bound sialic acid and melanin metabolites such as 5-S-cysteinyldopa and 6-hydroxy-5-methoxyindole-2-carboxylic acid are discussed. For most of these substances, serum levels are more pronounced in the more advanced stages of disease. Therefore, these markers seem to have no place in the early detection of melanoma. On the other hand, sensitivity in the advanced stages of disease seems to be < 100%, compromising their use as a new staging procedure. Some markers show promising results as a possible prognostic factor in the early detection of disease progression or in the prediction of therapy outcome. If confirmed by further studies, this could direct future therapeutic strategies and could help to select patients who would benefit most from more aggressive (adjuvant) therapies. In addition, the study of some of these substances could add to the knowledge of tumour biology and immunology.

Lieve Brochez

Papers

The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy.

Identification of a ZEB2-MITF-ZEB1 transcriptional network that controls melanogenesis and melanoma progression.

Quality of life and stigmatization profile in a cohort of vitiligo patients and effect of the use of camouflage.

Hypomelanoses and hypermelanoses

Serological markers for melanoma.