Clinical Oncology

[Challenges in Molecular Targeted Therapy for Gastric Cancer: Considerations for Effi cacy and Safety]

KEI Muro

SEPTEMBER 10, 2017

Clinical Oncology - 2017;4(03)

[The Cancer Genome Atlas Research Network recently proposed a molecular classifi cation for gastric cancer (GC) into four subtypes based on comprehensive evaluation. While the mechanisms of molecular targeted therapies in GC were confi rmed by multiple clinical studies, only a limited number of therapeutics for GC have been approved to date. In this systematic review of the available literature, we discuss the completed and ongoing clinical trials of molecular targeted therapies in patients with GC, with a focus on their effi cacy and safety. Results of recent studies clearly demonstrated that trastuzumab and ramucirumab, monoclonal antibodies (mAbs) against human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF), respectively, improved overall survival (OS) in GC with manageable safety profi les. Careful surveillance of ongoing clinical trials and timely profi ling and monitoring of genetic signatures are imperative to establish a strong foundation for precision medicine in GC.]

COMMENTS

0 comments

Further articles in this publication

Clinical Oncology

[News from the World]

Clinical Oncology

[Treatment of the relapsed epithelial ovarian cancer ]

BOÉR Katalin

[Ovarian cancer remains the most lethal gynaecological cancer and most patients present with advanced FIGO stage disease. Despite optimal upfront surgery and the administration of front-line paclitaxel-carboplatin chemotherapy, approximately two-third of ovarian cancer patients will relapse in the fi rst 3 years. In the last years, the goal in the treatment of ovarian cancer has shifted to maintenance therapy, trying to extend the progression free intervals of the patients. Remarkable advances in the knowledge of molecular biology of relapses led to the introduction the combination of antiangiogenic agent bevacizumab and chemotherapy, which showed to be effective in all phases of the disease, in fi rst-line therapy, as maintenance therapy, and in platinum-sensitive and platinum-resistant recurrence as well. Very recently, a new maintenance therapy, olaparib monotherapy has been introduced into clinical practice to treat platinum-sensitive, relapsed, high-grade serous ovarian cancer. Despite progresses in this therapy, are still some areas of controversy on how to manage epithelial ovarian cancer relapses. The aim of this manuscript is to give an overview on the management of relapsed ovarian cancer in the context of new available therapeutic modalities.]

Clinical Oncology

[Targeted therapy in melanoma]

EMRI Gabriella

[The incidence of melanoma is increasing, and although most of the melanomas are diagnosed at low tumour thickness, the number of metastatic cases is also increasing. In systemic treatment of metastatic and/or unresectable melanoma, targeted molecular inhibitor or immunotherapy can be used as fi rst-line option depending on molecular pathological report. Targeted treatment results in rapid decrease of tumour burden in high percentage of cases; however, the loss of effect is also frequent due to acquired drug resistance. Further improvement on prognosis of metastatic disease is expected from proper sequencing and/or combination of targeted and immunotherapy.]

Clinical Oncology

[Targeted therapy of the clear cell renal cancer ]

TORDAY László

[The renal cell cancer is among the ten most frequent cancers in developed countries. Its inci dence rate continuously increased until recently. On the other hand, survival parameters of renal cell cancer patients considerably improved in the last decade due to early diagnosis and developments in the treatment of irresectable disease. Huge progress had been made in understanding of the biological background of this chemo- and radiotherapy resistant disease, leading to the introduction of drugs in fi rst and further line treatment acting on VEGF and mTOR signal transduction pathways. Simultaneously, the era of widespread cytokine treatments had been ended. Recent studies had ensured the introduction of several drugs with new mechanism of action (MET, AXL; FGFR, PD-1 inhibition) into the therapy; these new advances completely changed the treatment landscape of RCC further improving progression free and overall survival. In this publication a review of data regarding the targeted treatment of clear cell renal cancer will be provided and as of our recent knowledge therapeutic positions of different drugs used will be discussed.]

Clinical Oncology

[MEK and ERK - against RAS and RAF ]

KOPPER László

[In most cases, the targeted therapy is able to produce clinical response, but after a certain interval it turns to be ineffective due to secondary resistance against the therapy. One of the most demanding challenge in treatment of cancer is to prevent or inhibit such resistance, which could have several forms, e.g. appearance of new driver activating mutations in the treated tumor, clon(s) existed in minority with different mutations (targets) can grow and replace the temporarely sensitive tumor cells (on the basis of tumor heterogeneity); another pathway takes over the role in cancer progression, etc. Such problems are very common in the RAS-RAF-MEK-ERK pathway. These are very important proteins to collect extracellular signals in order to regular different cell functions, especially proliferation. With activating mutations make the RAS-pathway independent from the normal .regulation. To inhibit the consequence of the mutations is largely still an unsolved problem, with few exceptions (e.g. inhibition of BRAF mutations). Theoretically, the inhibition of the next steps of the pathway, MEK and ERK, may stop the pathologically activated signals, partly due to their inhibition, and party to effi ciently decrease the feedback inside the pathway. This review discusses aspects of this possibilities, especially to overcome resistance and prolong the effectiveness of therapy.]

All articles in the issue

Related contents

Clinical Oncology

[Radiological response evaluation of targeted therapy]

KALINA Ildikó, OSZLÁNSZKY György

[The objective assessment of the changes in the tumor burden along with cancer therapy has essential importance. Recently, the quantitative evaluation of the radiological tumor response was undergone several changes. For conventional chemotherapy of solid tumors the standard procedure has been RECIST since 2000. The targeted therapies trigger other pathophysiological changes in the cells than the cytotoxic agents, accordingly the morphological changes show a new picture. Therefore the targeted therapies require a new evaluation system, that takes into consideration not only the tumor size, but other changes as well, the changes of attenuation that corresponds with the proportion of the viable cells. In case of the targeted therapies in substantial clinical was experienced even without signifi cant morphological changes in the tumour size. As a consequence, the traditional, size-based criteria system can underestimate the effi ciency of the new types of treatments. To eliminate this problem new evaluation systems were created taking the tumortypes and treatment protocolls into consideration. The estimation of the early tumor response to targeted therapy also has high importance. In assessment of the response functional imaging methods are used more frequently. The role of PET has already been defi ned in numerous tumortypes, however the determination of the position of some promising functional examinations still require further studies.]

Clinical Oncology

[Treatment of hepatocellular carcinoma - today]

VÉGH Éva, DEMETER Gyula, BODOKY György

[The hepatocellular carcinoma (HCC) is one of the main causes of cancer-related death globally, and at the same time, it is the main event leading to death in cirrhotic patients. In the etiology of HCC, the non-alcoholic liver disease may be an important cause besides the viral cirrhosis. The HCC’s staging systems (Child-Pugh scores, Cancer of the Liver Italian Programme/CLIP, Barcelona Clinic Liver Cancer/ BCLC) play an important role in predicting the prognosis and determining the appropriate therapy. In Europe, the treatment strategy is based on the BCLC staging system. Screening of cirrhotic patient is also important because curative therapy is available only for the early-stage HCC. Several therapeutic options exist in the intermediate stage disease; among them the radiofrequency ablation (RFA), the transarterial chemoembolization (TACE) and the percutan ethanol injection (PEI) are most important. For the advanced disease, the only approved systemic therapy is sorafenib, which has been well-tolerated and yielded a substantially relative improvement in overall survival. For patient in end-stage disease with impaired liver function or a poor performance status, only supportive care is recommended.]

Clinical Oncology

[Current management of GIST]

LAKATOS Gábor, BODOKY György

[Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs are generally resistant to chemotherapy and radiotherapy. The understanding of pathology at molecular level promised the development of novel treatment modalities. KIT and PDGFRA gene mutations play an important role in the pathogenesis of GIST. IMutational analysis should be considered as standard practice during the diagnostic work-up, since it has a predictive value for sensitivity to molecular-targeted therapy and also has prognostic value. The aim of this review is to summarize recent knowledge about diagnosis, treatment and follow up of GIST.]

Clinical Oncology

[Signaling pathways in cancer stem cells (Notch, Hedgehog, Wnt)]

KOPPER László, NAGY Noémi, SEBESTYÉN Anna

[OThe key regulators in the embryonic life, and later in the differentiation of tissues and organs are the evolutionary reserved signalling pathways, as Notch, Hedgehog and Wnt. Mutations of these pathways have been identifi ed in many tumor types, increasing the risk to the appearance of cancer stem cells (CSC), with very similar geno- and phenotype as normal stem cells have. Such CSCs with stemness functions can be developed not only from normal stem cells, but also from progenitor and differentiated cells. The main characteristics of CSC are the self maintenance, slow growth rate, very effective DNA-repair system, etc. All of these can contribute to the resistance. Further problems are the low number of CSC in the whole tumor mass, which makes rather diffi cult to achieve the effective drug concentration in CSC. The mentioned ancient pathways interact with many other pathways to form a network, which can infl uence the strategy of therapy. No doubt, that these pathways are promising targets, however, till now the clinical effectiveness is very low due to some reasons mentioned above. Nevertheless, some drugs are already in clinical use, either as monotherapy or part of the combinations. Little is known about the relationship between the pathways and the microenvironment, which has an outstanding role in the cellular activities, sometimes resulting opposite output. It is a great challenge to design effective drugs against CSC, similarly to fi nd reliable predictive biomarkers, which unfortunately still missing, since a reasonable drug-marker interactions would speed up the personalized treatment.]

Clinical Oncology

[Immuno(onco)therapy – road to the future]

DANK Magdolna, SZENTMÁRTONI Gyöngyvér, OROSZ Zsuzsanna, TÓTH Andrea, TŐKÉS Tímea

[Our immune system fi ghts effectively against infections, but the same activity exists against invading cancer cells, as well. However, malignant tumors are able to escape from these mechanisms; therefore tumor cells become unrecognizable for the immune system. Immuno-oncology is a novel and innovative discipline, focusing on a long-term purpose: to enhance the immune-response against malignancies. The main goal is to stimulate the immune system to properly recognize and destroy malignant tumor cells. This approach is comprehensive, includes the initiation of antitumor immune-response and enhancing its controlling mechanisms, moreover, provides active, anti-tumor effector cells. Recent results of anticancer research highlighted a new era of oncology, which is based on targeted, personalized medicine over cytotoxic therapies, and mainly focusing on the rapidly evolving discipline of immuno-oncology.]