Targeted agents in GI radiotherapy: Clinical efficacy and side effects

Approximately 50% of all patients with cancer receive radiotherapy (RT) at some point during their treatment. Despite the advent of modern imaging and advances in planning and delivering highly-conformal and precise RT, further dose escalation to improve clinical outcome is often limited by the potential side-effects to adjacent tissues. Addition of chemotherapy to radiotherapy (CRT) has led to significant clinical improvements in many gastrointestinal malignancies but at the expense of increased toxicity as most chemotherapy drugs lack specificity. Targeted agents modulate specific biological pathways and can potentially enhance RT efficacy. However, so far, the majority of clinical studies incorporating targeted agents into RT and CRT have produced disappointing results in gastrointestinal malignancies. Also, we lack validated biomarkers and methods for monitoring and predicting the efficacy of these agents when combined with RT/CRT. In the present article, we will review the most important targeted therapies, and examine the efficacy and toxicity of these agents when combined with RT/CRT in gastrointestinal malignancies. The shortcomings as well as future challenges and perspectives for the successful use of these compounds with RT/CRT in future trials will also be outlined.     

Development of molecularly targeted agents and immunotherapies in small cell lung cancer

Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC.     

培美曲塞对化疗及靶向治疗失败的晚期肺腺癌的疗效观察

目的 探讨培美曲塞对化疗及靶向治疗失败的晚期肺腺癌的治疗价值.方法 随机抽取2012年8月至2014年8月54例晚期肺腺癌患者的临床资料.按照临床治疗方法将患者分为实验组(28例)和对照组(26例).实验组采用培美曲塞单药化疗,对照组患者经常规治疗无效后采取其他化疗方案、支持治疗等措施.观察患者临床疗效、不良反应发生情况、生活质量变化情况.结果 实验组近期疗效优于对照组,差异有统计学意义(P<0.05).实验组不良反应发生率低于对照组,差异有统计学意义(P<0.05).实验组患者QOL总评分高于对照组,差异具有统计学意义(P<0.05).结论 培美曲塞治疗化疗及靶向治疗失败的晚期肺腺癌,可有效提高临床疗效,降低不良反应发生情况,改善患者生活质量.     

Personalized therapy for hepatocellular carcinoma: Where are we now?

Following the approval of sorafenib, a large number of molecular targeted agents have been tested clinically for advanced hepatocellular carcinoma (HCC), but all have failed to demonstrate significant efficacy in clinical trials. Multiple reasons for this phenomenon have been discussed in the literature, with one reason being the lack of patient selection on the basis of molecular profile in clinical trials. The concept of drug testing in selected populations has been recently suggested by retrospective analyses of HCC clinical trials in which a particular subgroup of patients, either enriched by clinical factors or by tissue biomarkers, derived more benefits from the novel drug. In addition, recent advances in genomic medicine have enhanced the understanding of genetic and epigenetic events occurring in HCC, raising the possibility of personalizing targeted agents in accordance with the genetic make-up of the tumors. The development of ‘personalized’ treatment for HCC is, however, hindered by the lack of fresh biopsy of advanced HCC, the low incidence of genetic driver mutations in HCC and the tumor heterogeneity. These limitations may be overcome by sequencing cell-free DNA in plasma, frequently known as liquid biopsy, and revolution in the concept of the design of clinical trials. In this review article, we aim to: (1) give a summary of the recent sequencing results of HCC and the related implications for drug development; (2) highlight potential individual targeted agents and existing research on biomarker selection in clinical trials; and (3) discuss future directions, including the potential of liquid biopsy and umbrella clinical trials, to enhance personalized drug testing for HCC.     

Emerging strategies of blood group genotyping for patients with hemoglobinopathies

Red cell alloimmunization is a serious problem in chronically transfused patients. A number of high-throughput DNA assays have been developed to extend or replace traditional serologic antigen typing. DNA-based typing methods may be easily automated and multiplexed, and provide reliable information on a patient. Molecular genotyping promises to become cheaper, being not dependent on serologic immunoglobulin reagents. Patients with hemoglobinopathies could benefit from receiving extended genomic typing. This could limit post transfusional complications depending on subtle antigenic differences between donors and patients. Patient/donor compatibility extended beyond the phenotype Rh/Kell may allows improved survival of transfused units of red blood cells (RBC) and lead to reduced need for blood transfusion and leading to less iron overload and reduced risk of alloimmunization. Here we discuss the advantages and limitations of current techniques, that detect only predefined genetic variants. In contrast, target enrichment next-generation sequencing (NGS) has been used to detect both known and de novo genetic polymorphisms, including single-nucleotide polymorphisms, indels (insertions/deletions), and structural variations. NGS approaches can be used to develop an extended blood group genotyping assay system.     

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact

BackgroundPre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT).Patients and methodsPatients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).ResultsThirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6–32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31–69%); DCR was 76% (95% CI: 59–88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients.All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%).ConclusionsSorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.     

Dual-Targeted Microbubbles Specific to Integrin αVβ3 and Vascular Endothelial Growth Factor Receptor 2 for Ultrasonography Evaluation of Tumor Angiogenesis

Aggressive tumors are characterized by angiogenesis that promotes the migration and dissemination of tumor cells. Our aim was to develop a dual-targeted microbubble system for non-invasive evaluation of tumor angiogenesis in ultrasound. Avidinylated microbubbles were conjugated with biotinylated arginylglycylaspartic acid and vascular endothelial growth factor receptor 2 (VEGFR2) antibodies. Subcutaneous MHCC-97H liver carcinoma models were established. Non-targeted, αvβ3-targeted, VEGFR2-targeted and dual-targeted microbubbles was intravenously injected in series while acquiring ultrasound images of the tumor. The microbubbles were destroyed by a high-mechanical-index pulse 4?min after the injection. Peak intensity (PI) before and after the destructive pulse was recorded to compare contrast enhancement by different microbubbles. The targeting rates of the integrin-targeted, VEGFR2-targeted and dual-targeted groups were 95.02%, 96.04% and 94.23%, respectively, with no significant differences. Tumors in all groups were significantly enhanced. The time–intensity curve indicated no significant differences in arrival time, PI, area under the curve, amplitude and mean transit time. The difference in ultrasound signal intensity before and after the destructive pulse (⊿PI) for all targeted microbubble groups was significantly greater than that for the non-targeted microbubble group (all p values?<?0.05), and the difference for the dual-targeted microbubble group was significantly greater than those of both mono-targeted groups (p?<0.05).     

Improvement in survival end points of patients with metastatic renal cell carcinoma through sequential targeted therapy

Survival of patients with metastatic renal cell carcinoma (mRCC) has improved since the advent of targeted therapy. Approved agents include the multi-targeted tyrosine kinase inhibitors (TKIs) sunitinib, sorafenib, axitinib, pazopanib, cabozantinib, and lenvatinib (approved in combination with everolimus), the anti-VEGF monoclonal antibody bevacizumab, the mammalian target of rapamycin (mTOR) inhibitors everolimus and temsirolimus, and the programmed death-1 (PD-1) targeted immune checkpoint inhibitor nivolumab. The identification of predictive and prognostic factors of survival is increasing, and both clinical predictive factors and pathology-related prognostic factors are being evaluated. Serum-based biomarkers and certain histologic subtypes of RCC, as well as clinical factors such as dose intensity and the development of some class effect adverse events, have been identified as predictors of survival. Expression levels of microRNAs, expression of chemokine receptor 4, hypermethylation of certain genes, VEGF polymorphisms, and elevation of plasma fibrinogen or d-dimer have been shown to be prognostic indicators of survival. In the future, prognosis and treatment of patients with mRCC might be based on genomic classification, especially of the 4 most commonly mutated genes in RCC (VHL, PBRM1, BAP1, and SETD2). Median overall survival has improved for patients treated with a first-line targeted agent compared with survival of patients treated with first-line interferon-α, and results of clinical trials have shown a survival benefit of sequential treatment with targeted agents. Prognosis of patients with mRCC will likely improve with optimization and individualization of current sequential treatment with targeted agents.