Strategies to overcome resistance to targeted protein kinase inhibitors

Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR-ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr-Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.     

Strategies to overcome drug resistance using SHP2 inhibitors

Encoded by PTPN11, the SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2) is widely recognized as a carcinogenic phosphatase. As a promising anti-cancer drug target, SHP2 regulates many signaling pathways such as RAS-RAF-ERK, PI3K-AKT and JAK-STAT. Meanwhile, SHP2 plays a significant role in regulating immune cell function in the tumor microenvironment. Heretofore, five SHP2 allosteric inhibitors have been recruited in clinical studies for the treatment of cancer. Most recently, studies have proved the therapeutic potential of SHP2 inhibitor in overcoming drug resistance of kinase inhibitors and programmed cell death-1 (PD-1) blockade. Herein, we review the structure, function and small molecular inhibitors of SHP2, and highlight recent progress in overcoming drug resistance using SHP2 inhibitor. We hope this review would facilitate the future clinical development of SHP2 inhibitors.     

Modulation of gut microbiota to overcome resistance to immune checkpoint blockade in cancer immunotherapy

1. Download : Download high-res image (142KB)
2. Download : Download full-size image

     

Strategies to overcome or circumvent P-glycoprotein mediated multidrug resistance

Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.     

Strategies to overcome resistance to tyrosine kinase inhibitors in non-small-cell lung cancer

The use of molecularly targeted agents has dramatically improved the prognosis of defined subsets of patients with non-small-cell lung cancer harboring somatically activated oncogenes, such as mutant EGFR or rearranged ALK. However, after initial marked responses to EGFR or ALK tyrosine kinase inhibitors (TKIs), almost all patients inevitably progress due to development of acquired resistance. Multiple molecular mechanisms of resistance have been identified; the best characterized are secondary mutations in the tyrosine kinase domain of the oncogene, such as T790M in EGFR and L1196M in ALK, which prevent target inhibition by the corresponding TKI. Other mechanisms include copy number gain of the ALK fusion gene and the activation of bypass signaling pathways that can maintain downstream proliferation and survival signals despite inhibition of the original drug target. Here, the authors provide an overview of the known mechanisms of resistance to TKIs and outline the therapeutic strategies, including new investigational agents and targeted therapies combinations, that have been developed to overcome resistance.     

Strategies to overcome resistance to targeted protein kinase inhibitors in the treatment of cancer

Inhibition of oncogenic protein kinases by small compound inhibitors has proven to be a valuable strategy for the directed and target-specific treatment of an ever-increasing number of cancer types. These include the treatment of chronic myeloid leukemia with the Bcr-Abl inhibitor imatinib and non-small-cell lung cancer with the epidermal growth factor inhibitors erlotinib and gefitinib. Unfortunately, initially successful therapy is often hampered by relatively rapid onset of resistance to the drug and subsequent relapse, particularly in patients with advanced disease. In the majority of cases this is caused by expansion of clones containing mutated forms of the targeted kinases, which confer insensitivity to the drug of the cancer cell. In addition, multiple factors including pharmacokinetic issues such as suboptimal drug delivery further contribute to resistance formation. Loss of target dependence due to the activation of parallel signaling pathways has also been reported as cause for acquired drug insensitivity. Here, we discuss currently applied as well as potential future strategies that can be applied to overcome and avoid resistance to drug therapy.     

A role of immunotherapy in metastatic malignant melanoma

Malignant melanoma is a tumor of the melanocytes of the skin with different types, that can metastasize to many organs including the brain at the advanced stages. Metastasis to brain is most dreadful complication, and at times untreatable as it's noted in the late stages. Therefore, tremendous effort has been made in the past decades to treat metastatic melanoma patients more efficiently. Although chemotherapy is one of the treatment options, it also interferes with all rapidly dividing cells including the non-cancerous cells; therefore one should consider the side effects. As there is lot of evidence that melanoma is immunogenic, a concept of immunotherapy has risen. Immunotherapy uses molecules of the body's own immune system and disrupts the growth of cancer cells has gained a lot of attention in the past two decades. Adoptive cell therapies (ACT), vaccines, viruses, and cytokine administration in immunotherapy stimulate T cells to recognize and destroy the cancer cells. This article is a brief review of various molecules and strategies that are currently used in immunotherapy against malignant melanoma. These include the anti-Cytotoxic T-lymphocyte antigen-4 (CTLA4) antibody, cytokine administration, vaccine therapy, oncolytic viruses, adoptive cell therapy, and inhibitor of STAT3 activation.     

恶性黑色素瘤的细胞免疫治疗研究进展

恶性黑色素瘤是一种恶性程度极高且发病率持续增长的肿瘤,对术后辅助放、化疗不敏感,预后较差。研究发现,恶性黑色素瘤为免疫原性较高的肿瘤,因此,肿瘤生物治疗得到广泛应用,细胞免疫治疗已成为恶性黑色素瘤个体化综合治疗的重要组成部分及研究热点。本文就恶性黑色素瘤的细胞免疫治疗研究进展作一综述。     

Glycan targeting nanoparticle for photodynamic immunotherapy of melanoma

Interaction between tumour cells and macrophages enables cancer cells to evade immune detection and clearance by interfering with macrophage phagocytosis. The anti-phagocytic signals regulated by anti-phagocytic proteins are termed "don’t eat me" signals; these signals include sialic acidbinding immunoglobulin-type lectin-10(Siglec-10) and the recently revealed CD24 immune checkpoint(ICP). In this study, we demonstrate that targeting a specific glycan on CD24 exhibits the potential to inhibit IC...     

Opportunities and obstacles of targeted therapy and immunotherapy in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive malignant tumour which accounts for approximately 13–15% of all newly diagnosed lung cancer cases. To date, platinum-based chemotherapy are still the first-line treatments for SCLC. However, chemotherapy resistance and systemic toxicity limit the long-term clinical outcome of first-line treatment in SCLC. Recent years, targeted therapy and immunotherapy have made great breakthrough in cancer therapy, and researchers aim to exploit both as a single agent or in combination with chemotherapy to improve the survival of SCLC patients, but limited effectiveness and the adverse events remain the major obstacles in the treatment of SCLC. To overcome these challenges for SCLC therapies, prevention and early diagnosis for this refractory disease is very important. At the same time, we should reveal more information about the pathogenesis of SCLC and the mechanism of drug resistance. Finally, new treatment strategies should also be taken into considerations, such as repurposing drug, optimising of targets, combination therapy strategies or prognostic biomarkers to enhance therapeutic effects and decrease the adverse events rates in SCLC patients. This article will review the molecular biology characteristics of SCLC and discuss the opportunities and obstacles of the current therapy for SCLC patients.     

Strategies for successful clinical management of schizophrenia with ziprasidone

Importance of the field: This review addresses practical clinical issues related to the use of ziprasidone in the treatment of schizophrenia using information from clinical trials, unpublished data, manufacturer's information, and input from an expert faculty of European psychiatrists with extensive experience of the use of ziprasidone, both in clinical trials and in everyday clinical practice.

Areas covered in this review: A Medline search of published data (1998 – 2010) was carried out, together with a review of unpublished data and manufacturer's information. In addition, expert opinion was sought from psychiatrists with extensive experience of ziprasidone in the treatment of schizophrenia in clinical settings across Europe.

What the reader will gain: This review has been undertaken to determine how the information from clinical trials can be optimally translated into ‘real-life’ practice and to establish how a decade of experience with ziprasidone in clinical practice can inform its optimal use to maximize effectiveness and minimize side effects.

Take home message: Effective use of ziprasidone in everyday clinical practice usually requires rapid titration to doses in the range of 120 – 160 mg/day and administration with proper meals, thereby achieving the high levels of schizophrenia symptom control reported in clinical trials. Additional guidance is provided about effective management of side effects, and appropriate coadministration of benzodiazepines and other agents, to achieve desired outcomes.     

恶性黑色素瘤的基因靶向治疗及生物免疫治疗的研究现状

恶性黑色素瘤是一种很难有效治疗的侵袭性恶性肿瘤,其对放化疗的敏感性很低。对于手术后或者已经失去手术时机的患者,基因靶向治疗及生物免疫治疗可以巩固治疗,延长患者生存期或者改善患者生存质量。基因靶向治疗具有一定特异性与靶向性,能切断突变基因诱导的信号传导,抑制肿瘤细胞的增殖。生物免疫治疗通过增强或者诱导患者自身的免疫应答来对抗、抑制和杀灭肿瘤细胞。本文就目前基因靶向治疗及生物免疫治疗的研究现状进行综述。     

基于纳米递送系统的黑色素瘤免疫治疗的研究进展

目的了解基于纳米递送系统的黑色素瘤免疫治疗的进展。方法通过文献阅读和归纳总结,对近年采用纳米递送系统进行黑色素瘤免疫治疗的文献进行综述。结果应用于黑色素瘤免疫治疗的纳米载体主要是无机材料、有机材料和细胞仿生型纳米载体。结论基于纳米递送系统的黑色素瘤免疫治疗取得了一定进展,有望改善黑色素瘤免疫治疗效果。     

Drug repurposing to overcome microbial resistance

Infections are a growing global threat, and the number of resistant species of microbial pathogens is alarming. However, the rapid development of cross-resistant or multidrug-resistant strains and the development of so-called ‘superbugs’ are in stark contrast to the number of newly launched anti-infectives on the market. In this review, I summarize the causes of antimicrobial resistance, briefly discuss different approaches to the discovery and development of new anti-infective drugs, and focus on drug repurposing strategy, which is discussed from all possible perspectives. A comprehensive overview of drugs of other indications tested for their in vitro antimicrobial activity to support existing anti-infective therapeutics is provided, including several critical remarks on this strategy of repurposing non-antibiotics to antibacterial drugs.     

Controlled trial of active immunotherapy in management of stage IIB malignant melanoma.

The prognosis for patients who undergo surgery for stage IIB malignant melanoma is poor. Animal studies have suggested that BCG and tumour cell vaccines given together may provide effective immunotherapy. To assess the effectiveness of this treatment 15 patients with stage IIB malignant melanoma who had their tumour excised were studied. Seven were treated conservatively, and eight were vaccinated with BCG and autologous irradiated cells. Three vaccinated patients suffered widespread recurrence within three months. All four vaccinated patients who suffered a recurrence within the first year died, while none of the three controls with recurrent disease died. In view of this alarming trend the trial was stopped after a year. BCG and the tumour cells may have enhanced the tumour growth, although there was no apparent reason for this. The results of uncontrolled or unrandomised trials that have suggested that this treatment is beneficial should be treated with scepticism.