Synergy of molecular targeted approaches and immunotherapy in melanoma: preclinical basis and clinical perspectives

Introduction: Targeted therapy and immunotherapies are the novel pharmacologic treatment strategies for metastatic melanoma. BRAF and MEK inhibitors effectively block the hyperactivation of the MAPK pathway in BRAF mutant melanomas and also have several other effects on melanoma cells and on the immune response. The aim of this work is to discuss the rationale, evidence and perspectives of approaches combining target and immunotherapy against melanoma.

Areas covered: We first review the effects of BRAF and MEK inhibitors on melanoma cells and on the different components of the immune system. Afterwards, we summarize the results of the preclinical and clinical studies that have combined targeted therapy and immunotherapy for the treatment of melanoma.

Expert opinion: Clinical applications of immunotherapy strategies have recently changed the therapeutic mainstay for metastatic melanoma. Biologic and initial preclinical data support their integration with innovative molecular targeted therapies, opening enormous perspectives for researchers in the effort of finding a definitive cure. Main open challenges are the definition of reliable research models, assessment of effective schedules, safety issues and designing of personalized approaches.     

PLX4032: does it keep its promise for metastatic melanoma treatment?

Importance of the field: Activating mutations in the BRAF kinase gene have been identified in 50% of all melanomas. PLX4032, a selective and potent inhibitor of BRAF V600E mutant tumor cells, has shown inhibition of tumor growth in cell lines harboring BRAF V600E mutations. Data from early clinical trials showed promising results in the treatment of patients with metastatic melanoma.

Areas covered in this review: An extensive literature search was conducted that included published articles and abstracts on PLX4032 to evaluate the existing data in both preclinical and Phase I–II studies.

What the reader will gain: The review comprises the rationale for choosing a selective BRAF inhibitor for certain types of melanoma, its mode of action, associated toxicities and potential pitfalls.

Take home message: Despite the convincing response rates in Phase I trials, duration of tumor response is limited in some patients, and a cure cannot be expected. Intrinsic and acquired PLX4032 resistance still has to be investigated; signaling pathway switching is probably the most important factor for development of resistance. Combination therapy with simultaneous inhibition of different pathways might be more effective and warrants further investigation. The toxicity profile of PLX4032 is considerably low, and special attention is needed to address the development of keratoacanthomas and cutaneous squamous cell carcinomas.     

Serrated polyps of the large intestine: a molecular study comparing sessile serrated adenomas and hyperplastic polyps

Aims:  To compare the molecular profile of a series of sessile serrated adenomas (SSAs) and hyperplastic polyps (HPs), in order to distinguish these lesions, SSAs having a potential role in the genesis of serrated adenocarcinomas through a serrated pathway in which methylation plays a key role.
Methods and results:  Twelve HPs and sixteen SSAs of the right and left colon were investigated for microsatellite instability, DNA mismatch repair genes, p53, p16, and β-catenin expression, MLH1 and p16 ( CDKN2A ) gene methylation, and KRAS and BRAF mutations. Both SSAs and HPs were microsatellite stable. MLH1 and MSH2 protein silencing , aberrant cytoplasmic expression and methylation of p16 were found to be exclusive to right-sided SSAs. The MLH1 promoter gene was frequently methylated in right-sided SSAs in contrast with HPs. Abnormal p53 and β-catenin expression was present in both SSAs and HPs. BRAF and KRAS mutation were mutually exclusive, but KRAS mutation was present only in left-sided SSAs and HPs.
Conclusions:  HPs and SSAs may be related lesions. However, at least right-sided SSAs differ from left-sided SSAs and HPs in the occurrence of MLH1 and p16 methylation, supporting the hypothesis that SSAs could be precursors of serrated adenocarcinomas.     

甲状腺微小乳头状癌中BRAF V600E基因突变的临床意义

目的 探讨甲状腺微小乳头状癌(PTMC)中BRAF V600E基因突变与淋巴结以及其他临床病理学特征的关系.方法 利用荧光PCR法检测经过手术切除及中央区和/或患侧淋巴结清扫的PTMC患者中BRAF V600E基因的突变情况,深入研究BRAF V600E基因和PTMC淋巴结转移两者之间的联系.结果 在患者性别、年龄以及...     

Analysis of KRAS,NRAS, BRAF,PIK3CA and TP53 mutations in a large prospective series of locally advanced rectal cancer patients

Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.     

严重表型心- 面- 皮肤综合征2 例临床特征和基因突变分析

目的探讨心-面-皮肤综合征严重表型患儿的临床特征和基因变异。方法回顾分析2例具有心-面-皮肤综合征严重表型患儿的临床资料,以及高通量测序技术检测的基因分析结果。结果 2例男性患儿,生后即出现喂养困难及精神运动发育迟缓,除有颅面部和心脏畸形外,还伴喉气管畸形,均在6月龄内死亡。基因检测发现2例患儿的BRAF基因存在新生变异c.1783TC(p.F595L)、c.770AG(p.Q257R)。结论发现2例国内未见报道的BRAF基因变异致心-面-皮肤综合征严重表型患儿。