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The TP53 mutation (R175H) is one of the most common mutations in human cancer. It is a highly attractive strategy for cancer therapy to find the genes that lead the R175H-expressing cancer cells. The aim of this study was to identify the synthetic sick/lethal gene interacting with R175H. Using lentiviral bar-coded comprehensive shRNA library and a tetracycline-inducible R175H expressed in the SF126 human glioblastoma cell line (SF126-tet-R175H), we conducted high-throughput screening to identify the candidate genes that induce synthetic sickness/lethality in R175H-expressing cells. We identified 906 candidate gene suppressions that may lead to accelerated cell growth inhibition in the presence of R175H. Inhibitor of differentiation 1 (ID1) was one of the candidate genes, and its suppression by siRNA resulted in the acceleration of growth inhibition in cell lines both transiently and endogenously expressing R175H but not in TP53-null cell lines or other common p53 mutants (such as R273H). Flow cytometry analysis showed that ID1 suppression resulted in G1 arrest, and the arrest was accelerated by the expression of R175H. ID1 is a synthetic sick/lethal gene that interacts with R175H and is considered to be a novel molecular target for cancer therapy in R175H-expressing cells.

The epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, triggers a downstream signaling cascade through areas such as the RAS-RAF-MAPK and PI3K-AKT pathways, which are involved in cell proliferation, survival and motility.Inhibiting EGFR activation has demonstrated significant promise as a molecular targeting therapy for various solid tumors. Two monoclonal antibodies (mAbs) targeting EGFR, cetuximab and panitumumab, are established to be new treatment options for metastatic colorectal cancer (mCRC). Among activating mutations in downstream of EGFR, the KRAS mutation, which is present in 40% of mCRC patients, has shown to be a predictive biomarker for resistance to anti-EGFR antibody therapy based on Caucasian studies. However, only a small proportion of patients achieved an objective response and benefit from anti-EGFR antibody, even among those with wild-type KRAS tumors. Other downstream factors in EGFR signaling are now being explored, such as the BRAF, PIK3CA, PTENgenes. Cetuximab, a chimeric immunoglobulin 1 (IgG1) monoclonal antibody, may also exert antitumor effects through antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC is influenced by FCrR1 a-H131R and FC7RIKa-V158F polymorphisms. Additional analysis of BRAF, PIK3CA, PTEN and FcqR genes in KRAS wild-type patients could narrow down the selection of patients who are most likely to benefit from anti-EGFR antibody therapy.

EGFR constitute an attractive target for tumor therapy, because it is a transmembrane receptor tyrosine kinase which is critically involved in tumorigenesis by stimulating cell proliferation and inhibiting apoptosis or other biological functions. The anti-tumor effects of targeted therapy by anti-EGFR monoclonal antibodies are mainly based on direct inhibition of the EGFR signal transduction pathway. In addition, monoclonal antibody has the potential advantage of recruiting immune effect or mechanisms to kill tumor cells. The pre-clinical and clinical data indicated that antibody-dependent cellular cytotoxicity (ADCC) contributes to tumor cell lysis by anti-EGFR monoclonal antibodies. Some polymorphisms in Fc gamma receptor genes have been shown to be a predictive marker for the efficacy of anti-EGFR antibodies. Continued research on the immunotherapeutic mechanisms of monoclonal antibodies will improve the efficacy of antibody-based targeted therapy for cancer.

Anti-EGFR antibodies were designed to inhibit the receptor tyrosine kinase activity of EGFR by directly binding to the extracellular domain. Anti-EGFR antibodies have been approved or will be approved for use in Japan, the USA or Europe. Recently, many studies have investigated molecular markers can predict the response to anti-EGFR antibodies so as to discriminate responders and non-responders. Activating KRAS mutation has been shown to be a potent predictive marker of resistance to anti-EGFR antibodies. Moreover, BRAF mutations, PIK3CA mutations or loss of PTEN have also been shown to be other molecular markers to predict resistance to anti-EGFR antibodies. Further studies must integrate these markers into clinical decisions to use or not use anti-EGFR antibodies.

Cancer of unknown primary site (CUP) is not a rare entity and accounts for 3-5% of all malignant neoplasias. CUPs are diagnosed with metastatic lesion so they are all in the advanced stage. Systemic chemotherapy is applied in many cases, but the ideal therapeutic strategy has not yet been determined. CUP shows much histological and therapeutic heterogeneity. Histologically, half of CUPs are adenocarcinoma and the rest are undifferentiated carcinomas. We analyzed the clinical and therapeutic characteristics 22 cases of CUP patients. Most CUP patients are found from lymph node swelling. There is no significant tendency as to the site of lymph node metastasis. Bone metastases are frequently encountered. It seems undifferentiated carcinomas are more responsive to chemotherapy. Chemo-sensitive patients are likely to have a longer life expectancy. In our experience all of the chemo-responsive cases are treated with platinum-based chemotherapy. Today several platinum-based combination chemotherapies are reported, but there is no large-scale randomized study. Because of its variety, individualized therapy may be ideal for CUP.

A 44-year-old man had a tumor in the lower thoracic esophagus at a health check, and was initially diagnosed as an undifferentiated carcinoma of the esophagus by the esophago-gastric endoscope. Although curative chemoradiotherapy was scheduled after the diagnosis, the interim evaluation revealed that the tumor was malignant melanoma of the esophagus with right renal metastasis. Since then, CVD (cisplatin, vindesine and dacarbazine) therapy, palliative radiotherapy and DAC-Tam (dacarbazine, nimustine, cisplatin and tamoxifen) therapy were carried out, but all of them proved ineffective, and multiple newly metastatic lesions appeared in liver and lymph nodes. Oral intake was impossible because of progressing stricture of the esophagus. As a fourth-line therapy, weekly paclitaxel therapy was started, and his oral intake was improved after the second course. He received the therapy as an outpatient for four months. After the third course, tumor lesions were evaluated as a partial response by CT. Consequently, five courses of the therapy were performed with modest adverse effects. Weekly paclitaxel therapy was reasonably safe as reported in other reports and considered to be a promising regimen for malignant melanoma of the esophagus.

During the last two decades, many genes responsible for hereditary cancer syndromes have been isolated. Based on the accumulating genetic information, genetic testing for both patients and the relatives is carried out in hospitals and clinics, and the clinical significance has been investigated. In addition to the genetic analyses of known genes and the functional analyses of the gene products, the recent research trends in hereditary cancer studies tend to move into the second era of research strategies including the isolation of novel genes responsible for remaining hereditary cancers, associated studies for finding cancer-susceptibility variants and the comprehensive analyses of expression profiles in tumors. Such new strategies are not only important to elucidate the pathophysiological mechanism of each hereditary cancer but may provide a potential application of tailor-made cancer therapy depending on the mutation status because many of the gene products seem to participate in the chemosensitivity of cancer cells. Furthermore, the research efforts have been expected to develop novel strategies for cancer prevention, diagnostics and therapeutics. In this paper, we have outlined the state of the art of studies on hereditary cancer syndrome, focusing on familial breast cancer and hereditary non-polyposis colorectal cancer.