Recent advances of novel targeted therapy for squamous cell carcinoma of the head and neck

Targeted therapies have proven beneficial for patients suffering from a number of different malignancies, including cancers of the head and neck. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor has shown benefit in combination with radiation for untreated patients or as a single agent for patients with platinum resistant disease. Cetuximab is the only targeted agent currently approved by the Federal Drug Administration for the treatment of head and neck cancer. A number of other agents have shown promising initial results including intracellular tyrosine kinase inhibitors, agents targeting vascular endothelial growth factor receptor, as well as other classes of novel therapies. Some of the data supporting the use of targeted therapy, including agents not yet approved in head and neck cancer, will be presented in this review. As our understanding of the cancer cell signaling pathways and novel targeted agents increases, the potential for treatment with reduced toxicity and improved clinical outcomes will become a reality.     

Cetuximab, a chimeric human mouse anti-epidermal growth factor receptor monoclonal antibody, in the treatment of human colorectal cancer

The recent successful development of monoclonal antibodies that target key components of biological pathways has expanded the armamentarium of treatment options for patients with colorectal cancer (CRC). In particular, the epidermal growth factor receptor (EGFR), a tyrosine kinase growth factor receptor involved in CRC development and progression, is exploited by the newest monoclonal antibody that is available for use in CRC patients. Cetuximab, the first chimeric monoclonal antibody, which has been generated against the EGFR, is currently registered in USA, Europe and worldwide, in combination with irinotecan in the treatment of metastatic CRC patients who have progressed on irinotecan containing chemotherapy. Cetuximab is well tolerated and does not exacerbate the toxicity of concomitant chemotherapy. Furthermore, a series of phase III clinical trials are currently evaluating the combination of cetuximab with standard chemotherapy regimens in the first-line treatment chemotherapy-na?ve patients with metastatic CRC.     

结直肠癌抗ＥＧＦＲ单克隆抗体疗效预测靶标的研究进展

分子靶向治疗成为结直肠癌治疗的新突破,其中包括抗表皮生长因子受体（ＥＧＦＲ）单克隆抗体。如何寻找使用抗ＥＧＦＲ单抗的优势人群,从而避免不必要的毒副作用和无效治疗是目前研究的热点。本文就目前国内外研究较多的预测抗ＥＧＦＲ单抗疗效的生物靶标作一综述。     

Targeted Therapies for Adrenocortical Carcinoma: IGF and Beyond

Standard chemotherapy for adrenocortical cancer currently is under evaluation in the context of the recently completed FIRM-ACT evaluating the combination of mitotane with either streptozocin or etoposide, cisplatin, and doxorubicin. New agents are eagerly sought by the ACC community that hopes to make progress against this deadly disease. Investigators have begun to dissect the molecular and genomic context of ACC with a goal of identifying potential novel therapeutic agents. One gene consistently overexpressed in ACC is insulin growth factor type 2. Targeting its receptor IGF1R has shown encouraging results in ACC cell lines and against murine xenografts. As a result, clinical trials to evaluate agents targeting the IGF1R have been done including mitotane and IMC-A12 (a monoclonal antibody) and the GALACCTIC trial that has just completed accrual to evaluate OSI-906, a small molecule IGF1R antagonist. On the horizon are other agents targeting other tyrosine kinases, including EGF and FGF, and novel strategies such as individualized tumor analysis to select treatment.     

Molecularly Targeted Therapy for Metastatic Colon Cancer: Proven Treatments and Promising New Agents

There has been a dramatic upsurge in the investigation of molecularly targeted therapy in colorectal cancer over the past two decades, with the first success being bevacizumab, a monoclonal antibody directed at vascular endothelial growth factor (VEGF). The latest additions to our armament are epidermal growth factor receptor (EGFR) inhibitors and the discovery of K-ras mutation’s impact on treatment efficacy. This review summarizes the new therapies targeting established pathways, such as VEGF and EGFR, and introduces tyrosine kinase inhibitors and monoclonal antibodies, as well as exciting novel agents targeting insulin-like growth factor, tumor necrosis factor, the Sonic Hedgehog pathway, Src kinase, mammalian target of rapamycin, and protein kinase C, which already have shown activity in other cancers and are currently being studied in phase 1/2 trials in metastatic colorectal cancer.     

Differential binding patterns of monoclonal antibody 2C4 to the ErbB3-p185her2/neu and the EGFR-p185her2/neu complexes

2C4 (Pertuzumab, Omnitarg) is a monoclonal antibody targeting p185(her2/neu), which is overexpressed in 30% of invasive breast cancer. 2C4 is currently in phase II clinical trials for several types of cancers. This antibody has been reported to disrupt the association between p185(her2/neu) and ErbB3. In our studies of epidermal growth factor receptor (EGFR)-p185(her2/neu) heterodimerization, we noted that 2C4 formed associations with the EGFR-p185(her2/neu) receptor complex. Our data argue against 2C4 as a universal heterodimerization blocker for p185(her2/neu), but indicate that cocktails of monoclonal antibodies binding distinct interaction surfaces of p185(her2/neu) will emerge as the most potent targeted therapy.     

胰腺癌的靶向治疗

放化疗联合靶向药物治疗是晚期胰腺癌的主要治疗手段.目前与胰腺癌治疗相关的靶向药物主要有表皮生长因子受体(EGFR)阻断剂、抗血管内皮生长因子(VEGF)单克隆抗体等.其中,厄洛替尼与吉西他滨(GEM)联合已被证实具有延长胰腺癌患者生存期的作用.     

Synergy between cetuximab and chemotherapy in tumors of the gastrointestinal tract

Cetuximab is a recently approved monoclonal antibody that targets the epidermal growth factor receptor, a receptor tyrosine kinase involved in the development and progression of colorectal cancer (CRC) and other solid tumors. Cetuximab, as a single agent or in combination with chemotherapy, has demonstrated significant clinical efficacy against CRC. Combinations of cetuximab with chemotherapy have proven to be well tolerated, with minimal overlap of toxicities between agents; and the anticancer synergy between cetuximab and traditional chemotherapy agents has made cetuximab a vital treatment for patients who are no longer responsive to chemotherapy alone. The U.S. Food and Drug Administration approved cetuximab in combination with irinotecan for the treatment of irinotecan-refractory metastatic CRC or as monotherapy for treating patients intolerant to irinotecan. Combination chemotherapies involving cetuximab as well as combinations involving cetuximab and other targeted agents, such as bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, constitute powerful new treatment options for the management of CRC. This review discusses recent clinical studies that have further defined this synergy, focusing primarily on tumors of the gastrointestinal tract.     

与晚期结直肠癌EGFR单克隆抗体靶向药物选择相关的分子标志物

对于转移性结直肠癌而言,如何在标准化疗的基础上进行个体化靶向治疗是目前关注的热点。KRAS基因突变被认为是转移性结直肠癌对抗表皮生长因子受体(epidermal growth factor receptor,EGFR)单克隆抗体(anti-EGFR monoclonal antibody,anti-EGFR)靶向治疗反应不佳的独立预测因素。35%～45%的转移性结直肠癌患者存在KRAS基因的突变,且对anti-EGFR治疗抵抗;同时只有50%的野生型KRAS患者对anti-EGFR治疗有效,提示EGFR下游信号通路其他分子的激活和变异可能影响了其治疗反应。EGFR依赖的2条主要信号通路RAS-RAF-MAPK和PI3K-PTEN-AKT均与anti-EGFR治疗失败有关。EGFR基因拷贝数(gene copy number,GCN)增加与结肠癌anti-EGFR的疗效相关,但EGFR GCN增加并不意味着EGFR蛋白表达增加,且EGFR表达与anti-EGFR疗效无相关性。在野生型KRAS转移性结直肠癌患者中增加对BRAF和PIK3CA基因突变以及PTEN基因表达缺失的检测可能有助于筛选anti-EGFR抵抗患者。本研究对近年来转移性结直肠癌研究中所涉及的疗效预测和预后分子标志物进行综述,以进一步指导转移性结直肠癌的个体化分子靶向治疗。     

Targeted therapy in colorectal cancer

Adjuvant therapy can reduce the risk of disease recurrence in patients with stage II-IV colorectal cancer. Recently, 3 monoclonal antibodies have been shown to improve clinical outcome in this group of patients. Bevacizumab is an antiangiogenesis agent that has been shown in clinical and preclinical models to reverse the effects of proangiogenic molecules. Bevacizumab is active in the adjuvant setting and in the treatment of metastatic disease. Cetuximab is targeted to the epidermal growth factor receptor. Panitumumab is a fully human immunoglobulin G2 antibody that also binds to the epidermal growth factor receptor. Combination therapies of monoclonal therapies and chemotherapy have resulted in better clinical outcomes than with either modality alone.     

Targeted therapies in the treatment of colorectal cancers.

BACKGROUND: In solid organ malignancies, no tumor type has seen a greater impact from the development of novel targeted therapies in 2004 than metastatic colorectal cancer. METHODS: We review the current progress to date with the use of monoclonal antibodies in colorectal cancer and look at newer therapies under investigation. RESULTS: Two monoclonal antibodies received Food and Drug Administration approval in early 2004, both for the indication of advanced, metastatic colorectal cancer. A large, randomized, placebo-controlled study demonstrated that the addition of a monoclonal antibody to vascular endothelial growth factor, bevacizumab, led to a statistically significant improvement in overall survival, with tolerable additional toxicity. Chimeric monoclonal antibody therapy directed at the epidermal growth factor receptor was associated with radiographic responses in a significant minority of patients with irinotecan-refractory colon cancer in a randomized phase II study of patients with irinotecan-refractory disease. CONCLUSIONS: These dramatic successes have led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research.     

Therapeutic application of noncytotoxic molecular targeted therapy in gliomas: growth factor receptors and angiogenesis inhibitors

Growth factor receptors and angiogenesis play major roles in the oncogenesis of gliomas. Over the last several years, several noncytotoxic molecular targeted therapies have been developed against growth factor receptors and tumor angiogenesis. In gliomas, two main anti-growth factor receptor strategies have been evaluated in phase I/II clinical trials: (a) small molecule tyrosine kinase inhibitors (TKIs) and (b) monoclonal antibodies that target growth factors or growth factor receptors other than vascular endothelial growth factor (VEGF). Up to now, few glioma patients have responded to small TKIs (0%-14%) or monoclonal antibodies (three case reports) delivered as a single agent. Greater doses, combined therapies, as well as the identification of molecular biomarkers predictive of response and resistance are important in order to optimize drug delivery and improve efficacy. Antiangiogenic therapies are promising for the treatment of gliomas. Thalidomide and metronomic chemotherapy were the first antiangiogenic strategies evaluated, but they have shown only modest activity. Recent studies of bevacizumab, an anti-VEGF antibody, and irinotecan, a topoisomerase I inhibitor, have demonstrated a high response rate, suggesting that targeted antiangiogenic therapies may play a significant role in the management of high-grade gliomas in the future. However, the toxicity profiles of these agents are not fully defined and the radiological evaluation of possible tumor response is challenging. Clinical evaluation of several VEGF receptor TKIs is currently ongoing; one of these inhibitors, cediranib, has already demonstrated interesting activity as a single agent. The integrin inhibitor cilengitide represents another promising strategy.     

Place des thérapeutiques moléculaires ciblées dans les carcinomes épidermoïdes des voies aérodigestives supérieures

The development of molecular targeted therapies in oncology is currently experiencing rapid growth, focusing primarily on two large categories of molecules, monoclonal antibodies and tyrosine-kinase inhibitors. Their action is directed at different molecular targets, particularly receptors of the HER family such as the epidermal growth factor receptor (EGFR or HER1) and biological factors involved in the neoangiogenesis process such as VEGF. Cetuximab, an anti-EGFR monoclonal antibody, has been shown to be effective in the treatment of epidermoid carcinoma of the upper aerodigestive tract in association with radiotherapy (locally advanced tumors) or with conventional cytotoxic agents (recurrent or metastatic tumors). Intensive research efforts are currently ongoing to develop new molecules with original specific biological targets or able to interact with several molecular pathways, to combine these therapies either amongst themselves or with conventional therapeutic agents (radiotherapy and chemotherapy) and, above all, to determine the predictive factors of their efficacy and toxicity.     

EGFR inhibitors in lung cancer

Targeted therapies inhibiting the epidermal growth factor receptor (EGFR) have been introduced in the treatment of patients with advanced non-small-cell lung cancer (NSCLC). Many inhibitors of the EGFR have been developed, targeting either the extracellular receptor domain with antibodies or the intracellular tyrosine kinase binding domain with small molecules. The tyrosine kinase inhibitor (TKI) gefitinib (Iressa) was the first targeted drug to be registered for the treatment of NSCLC after failure of chemotherapy. Given concurrently together with platinum combination chemotherapy both TKIs gefitinib and erlotinib (Tarceva) failed to increase activity. Sequential targeted therapy after chemotherapy is currently being investigated further. Studies with the monoclonal antibody cetuximab (Erbitux) combined with chemotherapy are ongoing. Side effects of the small molecules are mainly skin rash and diarrhea, whereas the antibodies do not give diarrhea. Selection of patients, based on molecular markers and patient characteristics, has become an important issue for the further development of these drugs, given there is activity in a relatively small group of patients with NSCLC. Newer drugs inhibiting more than one receptor pathway are being investigated in order to find activity in a broader group of patients.     

A mechanistic perspective of monoclonal antibodies in cancer therapy beyond target-related effects

Several monoclonal antibodies are now in clinical use for cancer therapy, and many others are currently undergoing clinical evaluation. These agents offer unique specificity against key molecular targets on tumor cells or in the tumor microenvironment. The clinical efficacy of monoclonal antibodies is generally attributed to target-specific mechanisms resulting from neutralizing or inhibiting a growth factor or receptor that drives cell proliferation and tumor growth. Several targets, including CD20, human epidermal growth factor receptor 2, vascular endothelial growth factor, and epidermal growth factor receptor, have been validated in specific malignancies on the basis of monoclonal antibody efficacy. However, monoclonal antibodies also have the potential to activate immune-mediated effector functions, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. These functions result from interactions involving the Fc domain of the antibody, and, consequently, may vary by antibody, isotype, and Fc modification, such as changes in glycosylation. Accordingly, all monoclonal antibodies directed against a given target should not be considered equivalent in their ability to stimulate immune-mediated effector functions.     

Ramucirumab (IMC-1121B): Monoclonal Antibody Inhibition of Vascular Endothelial Growth Factor Receptor-2

Angiogenesis, a well-recognized characteristic of malignancy, has been exploited more than any other pathway targeted by biologic anti-neoplastic therapies. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the critical receptor involved in malignant angiogenesis with its activation inducing a number of other cellular modifications resulting in tumor growth and metastases. Ramucirumab (IMC-1121B; ImClone Systems Corporation, Branchburg, NJ) is a fully human monoclonal antibody developed to specifically inhibit VEGFR-2. Ramucirumab is currently being investigated in multiple clinical trials across a variety of tumor types. Herein, angiogenesis inhibition in cancer is reviewed and up-to-date information on the clinical development of ramucirumab is presented.     

Cetuximab in metastatic colorectal cancer

Management of metastatic colorectal cancer has evolved in the last 10 years, with the availability of targeted therapies resulting in improvement in quality of life and overall survival. Cetuximab is a chimeric monoclonal antibody that binds to the EGF receptor, and the net effects are inhibition of tumor growth, invasion, angiogenesis and metastasis. Cetuximab binding to the EGF receptor is also known to augment the effects of chemotherapy and radiotherapy. Only tumors expressing wild-type KRAS respond to cetuximab and improvements in progression-free survival and overall survival are seen, whereas patients with mutant KRAS are considered to be resistant. Cetuximab is currently available worldwide for use as monotherapy or in combination with chemotherapy in first-, second- or third-line settings in metastatic colorectal cancer patients with wild-type KRAS.     

Triple negative breast cancer: unmet medical needs

Triple negative breast cancer (TNBC) is an aggressive clinical phenotype characterized by lack of expression (or minimal expression) of estrogen receptor (ER) and progesterone receptor (PR) as well as an absence of human epidermal growth factor receptor-2 (HER2) overexpression. It shows substantial overlap with basal-type and BRCA1-related breast cancers, both of which also have aggressive clinical courses. However, this overlap is not complete, and the expression of ER, PR, and HER2 has been noted in basal-like tumors. TNBC also includes the normal-like subtype, and not all patients with TNBC harbor BRCA1 mutations. Because of its expression profile, TNBC is not amenable to treatment with hormone therapy or the anti-HER2 monoclonal antibody trastuzumab, and systemic treatment options are currently limited to cytotoxic chemotherapy. Overall survival, whether in early-stage or advanced disease, is poor compared with that in patients who have other phenotypes. A number of targeted approaches to TNBC are undergoing clinical evaluation, including the use of agents with poly(ADP-ribose) polymerase inhibitory properties such as iniparib (the United States Adopted Name for the investigational agent BSI-201), olaparib (AZD2281), and veliparib (ABT-888), antiangiogenic agents such as bevacizumab and sunitinib, and epidermal growth factor receptor blockers such as cetuximab and erlotinib. Encouraging results with some of these agents have been reported, thereby offering the promise for improved outcomes in patients with TNBC. The clinical characteristics of TNBC and clinical experience to date with novel targeted agents under development for this aggressive phenotype is reviewed.     

Targeted therapies in the treatment of non-small cell lung cancer

New targeted treatments offer an important opening towards the improvement of the results in the treatment of lung cancer. Currently two types of therapeutic targets are developed successfully in the treatment of advanced non-small cell lung cancer: tumour angiogenesis and growth factor receptors. Therapeutic drugs are small molecules inhibitors and the monoclonal antibodies. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor receptor, VEGF, an important molecule in tumour angiogenesis. The combination of bevacizumab with first line chemotherapy increases the median survival of advanced NSCLC with a few weeks. At this moment no biomarker predicting efficacy that can help in the selection of patients is unfortunately available for this expensive treatment, although it is important to select patients based on specific contra-indications. The epidermal growth factor receptor (EGFR or HER1) is activated in NSCLC by several mechanisms. The small molecules erlotinib and gefitinib are targeting the intracellular kinase domain of the EGF receptor, thus inhibiting the signal transduction cascade. Erlotinib is currently registered and reimbursed in Belgium. The concomitant use of these small molecules with chemotherapy is ineffective in non-selected NSCLC patients. On the other hand, these molecules have great activity in patients with tumours having a constitutionally activated EGFR. Changes in the kinase domain of the receptor give rise to extremely high response rates and unexpectedly improved survival duration in patients with NSCLC. Currently studies are exploring whether erlotinib should be employed in the first line treatment of NSCLC. The FIELT study is a translational academic and multicentre phase II study in Belgium and Luxemburg addressing this issue. Specific mechanisms of resistance for these agents are gradually discovered and the new drugs being able to overcome these resistances are at the horizon.     

The role of adjuvant monoclonal antibody therapy for breast cancer: rationale and new studies

HER2 is a member of the epidermal growth factor receptor (EGFR) family of tyrosine kinases and is involved in the growth, invasion, metastasis, and prognosis of breast cancer. The rationale for prospective trials evaluating the role of anti-HER2 monoclonal antibody therapy for patients with high-risk HER2-positive resected breast cancer is based on several factors. These include 1) the relative and absolute poor prognosis of patients with node-positive, HER2-positive breast cancer; 2) the emerging data of potential importance concerning anthracyclines as a component of adjuvant therapy for patients with HER2-positive breast cancer; 3) the role of taxanes in the management of patients with HER2-positive metastatic breast cancer; and 4) the feasibility and efficacy of molecularly targeted anti-HER2 monoclonal antibody treatment alone or in combination with chemotherapy for patients with advanced breast cancer.