肾癌靶向治疗药物的研究进展

肾细胞癌的发病率占恶性肿瘤的2%,传统的治疗方法是使用细胞因子(干扰素或者白介素-2),但这些免疫治疗生存优势小,疗效有限,需要开发更有效的药物。肾癌分子生物学的研究,揭示血管内皮生长因子和相关受体以及RAS/RAF/MEK/ERK和PI3K/Akt/mTOR信号传导通路与肾癌的发病密切相关,这些受体和通路促进了肿瘤细胞的生长和增殖。最近开发的药物,包括酪氨酸激酶抑制剂、单克隆抗体和mTOR抑制剂,能靶向作用于肾癌的酪氨酸激酶和细胞内通路,产生抗肿瘤作用。文中总结了肾癌发病的分子生物学机制,靶向治疗药物的作用机制以及临床评价的研究进展。     

Adding to the mix: fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer

The treatment of advanced non ? small cell lung cancer (NSCLC) increasingly involves the use of molecularly targeted therapy with activity against either the tumor directly, or indirectly, through activity against host-derived mechanisms of tumor support such as angiogenesis. The most well studied signaling pathway associated with angiogenesis is the vascular endothelial growth factor (VEGF) pathway, and the only antiangiogenic agent currently approved for the treatment of NSCLC is bevacizumab, an antibody targeted against VEGF. More recently, preclinical data supporting the role of fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR) signaling in angiogenesis have been reported. The platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) pathways may also stimulate tumor growth directly through activation of downstream mitogenic signaling cascades. In addition, 1 or both of these pathways have been associated with resistance to agents targeting the epidermal growth factor receptor (EGFR) and VEGF. A number of agents that target FGF and/or PDGF signaling are now in development for the treatment of NSCLC. This review will summarize the potential molecular roles of PDGFR and FGFR in tumor growth and angiogenesis, as well as discuss the current clinical status of PDGFR and FGFR inhibitors in clinical development.     

Antiangiogenic therapy in malignant glioma: promise and challenge

Malignant glioma represents one of the most lethal and angiogenic cancers. Angiogenesis is a fundamental process of blood vessel growth that is a hallmark of cancer. Although several molecular mechanisms contribute to tumor angiogenesis in gliomas, the vascular endothelial growth factor (VEGF) pathway appears particularly important and has been a prominent therapeutic target in cancer treatment. Several preclinical studies have demonstrated efficacy of antiangiogenic agents in both subcutaneous and orthotopic malignant glioma xenograft models. Recently, a phase II clinical trial of bevacizumab, a neutralizing monoclonal antibody to VEGF, in combination with irinotecan has demonstrated promising radiographic response and survival benefit in patients with recurrent malignant glioma. Several other antiangiogenic agents such as inhibitors to platelet derived growth factors (PDGFs), fibroblast growth factors (FGFs), angiopoietins/Tie-2 system, protein kinase C and integrins are currently in preclinical and clinical development. Despite the encouraging results of antiangiogenic therapies in malignant glioma, there are several challenges to be overcome to achieve optimal clinical benefit. Identification of biomarkers to predict response or resistance and to monitor antiangiogenic effects is important to enrich for patients who are likely to respond to therapy and to define the optimal biological dose. At present, antiangiogenic therapies remain palliative suggesting that overcoming antiangiogenic resistance may require multi-targeted agents, combination of agents targeting different angiogenic pathways or multi-modality combination with radiation, chemotherapy, other targeted therapeutics or immunotherapy. In this review, we will discuss the current development, promise and challenge of antiangiogenic therapy in malignant glioma.     

Adjuvant and neoadjuvant therapy in renal cell carcinoma

Nephrectomy continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). Despite undergoing nephrectomy, recurrence of disease remains a concern in many patients, and different medical therapies are being investigated as means to decrease this risk. The use of the traditional immunotherapy options has not provided benefit as adjuvant treatment in this disease state. Recently, the treatment of metastatic RCC has experienced key advances with the introduction of targeted agents against the vascular endothelial growth factor (VEGF) molecule and related pathways as well as inhibitors of the mammalian target of rapamycin (mTOR), in addition to improvements in surgical technique. Additionally, there are questions about the optimal timing of systemic therapy in the context of high risk non-metastatic disease. There is optimism that locally advanced RCC might benefit from adjuvant or neoadjuvant treatment with these therapies. Ongoing clinical trials are addressing the role of targeted agents in this disease state.     

Downstream intracellular effectors of epidermal growth factor receptor as targets for anticancer therapy

In recent years, the knowledge about mutations in components of the intracellular signal transduction pathway has greatly improved. Pivotal target molecules, such as Ras, PI3K, mammalian target of rapamycin (mTOR) and PKC, form an important biochemical network, which, when mutated, drives cell growth in an unlimited manner. Cancer cells have been shown to be able to harness different growth factor signalling pathways. Protein kinase inhibitors, targeted to the above pathways, have demonstrated activity against several solid tumours and are generally better tolerated than standard cytotoxic agents. The future challenge will be to find the most clever way to use combinations of these novel compounds.     

Downstream intracellular effectors of epidermal growth factor receptor as targets for anticancer therapy

In recent years, the knowledge about mutations in components of the intracellular signal transduction pathway has greatly improved. Pivotal target molecules, such as Ras, PI3K, mammalian target of rapamycin (mTOR) and PKC, form an important biochemical network, which, when mutated, drives cell growth in an unlimited manner. Cancer cells have been shown to be able to harness different growth factor signalling pathways. Protein kinase inhibitors, targeted to the above pathways, have demonstrated activity against several solid tumours and are generally better tolerated than standard cytotoxic agents. The future challenge will be to find the most clever way to use combinations of these novel compounds.     

Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Antiangiogenic agents and targets: A perspective

The first generation of clinically useful antiangiogenic agents focused on VEGF and targets in the VEGF pathway. The strengths and limitations of these therapeutics are now clear. Some tumors do not respond to VEGF-directed therapies de novo and others become non-responsive or resistant over time by switching to other angiogenic pathways. The next generation of angiogenesis-directed therapeutics will expand the field beyond the VEGF pathway and become more disease selective. Placental growth factor, a protein closely related to VEGF, is induced as tumors lose responsiveness to VEGF-directed therapies. Angiopoietins 1 and 2 are being targeted with a unique peptibody, a human recombinant Fc constant region fused to peptides, in clinical trials. The HGF/c-Met pathway is upregulated in some tumors as an alternate angiogenic pathway. The CXCL12 (SDF-1)/CXCR4 pathway represents a stromal chemokine axis involved in tumor angiogenesis. CXCR2 is a G-protein coupled receptor with several ligands including interleukin-8 and other angiogenic cytokines and may represent a useful target for antiangiogenic agents. The notch pathway is being investigated as a target in the setting of tumor angiogenesis. Sphingosine-1-phosphate is a bioactive lipid that can be neutralized with a monoclonal antibody. The anti-S-1-P antibody is under investigation as an antiangiogenic agent. Finally, several multi-targeted kinase inhibitors each with a unique pattern of inhibitory potency are in clinical trial with a focus on antiangiogenic activity. The expansion of the scope of potential antiangiogenic agents in or entering clinical trial should allow the development of antiangiogenic combination regimens and single agents that address diseases refractory to VEGF-directed therapeutics.     

New advances in targeted therapies for squamous cell carcinoma of the head and neck

Several molecular pathways are deregulated and activated in squamous cell carcinoma of the head and neck making this disease attractive for targeted molecular therapies. Cetuximab, a monoclonal antibody that binds to the epidermal growth factor receptor, improves the overall survival when combined with radiation therapy or chemotherapy. Novels agents targeting different molecular pathways in squamous cell carcinoma of the head and neck are currently under development. Among them, dual (epidermal growth factor receptor/human epidermal growth factor receptor-2) or pan-human epidermal growth factor receptor inhibitors and drugs that target the insulin growth factor-1 receptor, the MET receptor, or the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway have shown either interesting preclinical activity or promising preliminary clinical efficacy. Angiogenesis inhibitors should be used with caution in squamous cell carcinoma of the head and neck due to the risk of tumor bleeding. However, only a minority of patients seems to benefit from these new approaches. Understanding the primary and acquired resistance mechanisms to predict the treatment efficacy is of crucial importance to allow a better patient selection.     

Antiangiogenic therapy for advanced renal cell carcinoma: Management of treatment-related toxicities

Treatment of metastatic renal cell carcinoma (mRCC) has evolved rapidly over the last two decades as major pathways involved in pathogenesis have been elucidated. These include the vascular endothelial growth factor (VEGF) axis and mammalian target of rapamycin (mTOR). Therapies targeting the VEGF pathway include bevacizumab, sorafenib, sunitinib, pazopanib, and axitinib, whereas temsirolimus and everolimus inhibit the mTOR pathway. All of these novel therapies-VEGF and mTOR inhibitors-are associated with a variety of unique toxicities, some of which may necessitate expert medical management, treatment interruption, or dose reduction. Common adverse events with newer drugs include hypertension, skin reactions, gastrointestinal disturbances, thyroid dysfunction, and fatigue. Skilled management of these toxicities is vital to ensure optimal therapeutic dosing and maximize patient outcomes, including improved survival and quality of life. This review describes and compares the toxicity profiles of novel molecularly targeted agents used in the treatment of mRCC and presents guidance on how best to prevent and manage treatment-related toxicities. Particular attention is given to axitinib, the newest agent to enter the armamentarium. Axitinib is a second-generation receptor tyrosine kinase inhibitor with potent VEGF receptor inhibition that provides durable responses and superior progression-free survival in advanced RCC compared with sorafenib.     

Safety and tolerability of pazopanib in the treatment of renal cell carcinoma

Introduction: Renal cell carcinoma (RCC) is still a challenging disease. Over the last 6 years, the use of novel targeted therapies interfering with vascularization and inhibition of other downstream pathways has revolutionized the therapy of this disease, leading to an improvement of patient outcomes. In particular, dysregulation of the vascular endothelial growth factor (VEGF) pathway and VEGF protein overexpression have proved important, as they result in increased tumor angiogenesis and RCC growth and development. Areas covered: This review briefly discusses the mechanisms of action and clinical applications of pazopanib . It mainly outlines the safety and tolerability of pazopanib for locally advanced/metastatic RCC. Phase III pazopanib safety data are also indirectly compared with other standard, antiangiogenic receptor tyrosine kinase inhibitors currently used in the management of RCC. Expert opinion: Pazopanib is a new drug available in the oncology portfolio to treat patients with predominantly clear-cell RCC. The toxicity profile of pazopanib is comparable, but in some ways distinct, from other antiangiogenic drugs used in the treatment of RCC. Long-term data about late side effects of this treatment are awaited.     

Targeted therapy in renal cell carcinoma

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1α, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.     

Targeted therapy in renal cell carcinoma

Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are both important for tumour progression in renal cell carcinoma (RCC). Drugs that block these and other pathways have been examined in Phase I and II clinical trials in patients with advanced or metastatic RCC. Results from a randomised study of an anti-VEGF antibody demonstrate a delay in the time to disease progression, suggesting a biological effect and change in the natural history of the disease. Results using small-molecule inhibitors of VEGF, FLT3, KIT and platelet-derived growth factor receptor tyrosine kinases, such as sunitinib, show a 40% objective response rate. Results from a Phase III clinical trial with sorafenib, an inhibitor of multiple tyrosine kinases, show only a 2% response rate; however, a statistically significant improvement in progression-free survival was observed. Objective responses have also been noted using an inhibitor of the mammalian target of rapamycin. Conversely, EGF receptor inhibitors, proteosome inhibitors, microtubule stabilising agents, cell-cycle inhibitors and imatinib were also examined with few objective responses. Ultimately, identifying the predictive factors for responsiveness to these targeted therapies may improve the clinical benefit; for example, RCC with biallelic mutations in the von Hippel-Lindau gene would have higher levels of hypoxia-inducible factor-1alpha, and may be more responsive to inhibitors of angiogenesis. Phase III studies comparing the combinations of targeted therapy could lead to a new standard of care for RCC.     

Has bevacizumab (Avastin) given extra therapeutic gain in metastatic colorectal cancer and malignant brain gliomas? Systematic review answering this question

During the last decade, the development of new drugs known as targeted therapies was the result of a better understanding of the processes involved in the transformation of normal cells into cancer. The term targeted therapy refers to drugs that selectively target specific molecular pathways involved in tumourigenesis or tumour progression. Angiogenesis is important for tumour growth and metastasis and is an important target for new biological agents. Bevacizumab is a humanised recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumour growth. On February 26, 2004, the FDA (Food and Drug Administration) approved Bevacizumab as first-line treatment for patients with metastatic colorectal cancer. The integration of targeted therapies in the treatment of colon cancer has resulted in significant improvements in efficacy outcomes. Bevacizumab was the first antiangiogenic therapy approved for use in cancer and received accelerated FDA approval for the treatment of recurrent glioblastoma multiform in 2009. The efficacy of Bevacizumab in the treatment of metastatic colorectal cancer and recurrent glioblastoma multiform is presented in this review article. The structural characteristics and selectivity profiles of this antiangiogenic drug and those disclosed in related patent applications are also summarised in this article.     

Targeted-therapy in advanced renal cell carcinoma

Surgery has been the mainstay of renal cell carcinoma (RCC) treatment for resectable tumours. In stages I-III disease, nephrectomy is the standard of care and may be curative. Historically, patients presenting with stage IV disease may achieve improved survival with debulking nephrectomy, which is commonly performed prior to systemic therapy. The response rate of immunotherapy is low, with a smaller percentage exhibiting complete remission upon treatment. Therefore, new therapeutic approaches against metastatic RCC are necessary. Recently, molecular mechanisms responsible for the proliferation of RCC have been identified, and molecular targeted therapy has developed. Clear cell RCC commonly features mutation or inactivation of the von Hippel- Lindau (VHL) gene and resultant over-expression of vascular endothelial growth factor (VEGF). The first drug to validate VEGF as a target in the treatment of clear cell RCC was the monoclonal antibody bevacizumab. Sunitinib is now a standard first-line therapy for advanced disease and sorafenib is among the second-line treatment options. Mammalian target of rapamycin (mTOR) is a second validated therapeutic target as the mTOR inhibitor temsirolimus has been shown to prolong survival in first-line treatment of poor prognosis RCC of all histologies. Everolimus is an oral mTOR inhibitor and has been shown to prolong progression-free survival (PFS) when used in second-line treatment. This review describes recent advances in molecular targeted therapy for metastatic RCC, focusing on chemical structure and mechanism of action of VEGFR and mTOR inhibitors.     

Antiangiogenic agents targeting vascular endothelial growth factor and its receptors in clinical development

There is ample therapeutic opportunity for the use of antiangiogenic inhibitors in the clinic, as there are several human diseases that are dependent upon angiogenesis [1]. However, no disease has attracted as much attention as a target for antiangiogenic therapy as malignant disorders. There is a vast amount of literature acting as proof-of-principle for the use of angiogenic inhibitors as effective agents for blocking tumour-induced angiogenesis and subverting tumour growth and disease dissemination. One of the unique attractions of targeting tumour angiogenesis is that vascular endothelial cells are a genetically stable population in which acquisition of therapeutic resistance might be less efficient than in genetically unstable tumour cells [2,3]. This review covers inhibitors that target the tumour angiogenic agent vascular endothelial growth factor and its receptors as one such antiangiogenic approach. Many agents in this class are in clinical trials with limited reports of toxicity and some early evidence of clinical benefit.     

Antiangiogenic agents targeting vascular endothelial growth factor and its receptors in clinical development

There is ample therapeutic opportunity for the use of antiangiogenic inhibitors in the clinic, as there are several human diseases that are dependent upon angiogenesis [1]. However, no disease has attracted as much attention as a target for antiangiogenic therapy as malignant disorders. There is a vast amount of literature acting as proof-of-principle for the use of angiogenic inhibitors as effective agents for blocking tumour-induced angiogenesis and subverting tumour growth and disease dissemination. One of the unique attractions of targeting tumour angiogenesis is that vascular endothelial cells are a genetically stable population in which acquisition of therapeutic resistance might be less efficient than in genetically unstable tumour cells [2,3]. This review covers inhibitors that target the tumour angiogenic agent vascular endothelial growth factor and its receptors as one such antiangiogenic approach. Many agents in this class are in clinical trials with limited reports of toxicity and some early evidence of clinical benefit.     

Present and future therapeutic options for locally advanced and metastatic renal cell carcinoma

INTRODUCTION: Locally advanced or metastatic renal cell carcinoma (RCC) is notoriously chemo- and radioresistant, leaving immunotherapy as the only treatment option. In recent years, targeted therapies have offered significant increases in progression-free survival (PFS). Despite this, the majority of patients soon develops resistant disease and finally succumbs. The need to implement treatment strategies that improve overall survival while having an acceptable safety profile is imperative. AREAS COVERED: This review provides information on the efficacy of recently studied treatment strategies for advanced RCC. These include sequential and combination therapy of established drugs as well as data on agents in early clinical development. The Medline and ASCO database were searched for clinical trials on medical therapy of advanced RCC from 2004 until May 2010. Data on targeted therapies, including tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, mammalian target of rapamycin inhibitors, and antiepidermal growth factor receptor agents are summarized. EXPERT OPINION: Improvements in response rates and PFS in patients with advanced RCC have been observed with new treatment strategies. The benefit in overall survival is less clear and needs further evaluation. Toxicity represents a concern especially in combination regiments.     

Clinical experience with antiangiogenic therapy in leukemia

The pathological role of bone marrow angiogenesis in human leukemias has been clearly established. Bone marrow neoangiogenesis is mediated by several growth factors, such as VEGF-A, VEGF-C, angiopoietin-1 and -2, FGF, HGF, TGF-β and others secreted by leukemic cells. The prognostic relevance of microvessel density, and expression of VEGF-A and -C has been demonstrated especially in acute myeloid leukemia. In the last years, several classes of angiogenesis inhibitors have been developed blocking several angiogenic pathways. These include drugs that inhibit the VEGF (with or without blockade of FLT3) and the mTor signalling cascade. Besides, thalidomide and lenalidomide although possessing a pleiotrophic mode of action including antiangiogenic properities have been evaluated in the treatment of human leukemias. In the current review we analyze the results of clinical trials employing these antiangiogenic drugs. Since the clinical efficacy of these compounds used as monotherapy is often limited, confined to certain subgroups of patients and frequently short lived, several trials combining standard chemotherapy with these agents have been initiated in order to demonstrate an additional benefit to standard therapy. Furthermore the introduction of new antiangiogenic drugs such as inhibitors of the angiopoietin and HGF/cMET pathway is on the horizon. Utilizing cocktails of inhibitors of several angiogenic pathways may represent a new possibility to augment the efficacy of antiangiogenic therapy in the future.