Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

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Cancer Genome Landscapes

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile.

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The cancer genome atlas pan-cancer analysis project

The Cancer Genome Atlas Pan-Cancer analysis project

Background Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non–small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. Methods After screening tumor samples from approximately 1500 patients with non–small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Results Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. Conclusions The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.)

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Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer

https://www.hal.inserm.fr/inserm-00561753/document

International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society International Multidisciplinary Classification of Lung Adenocarcinoma

Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Common fragile sites (CFSs) are specific chromosome regions that exhibit an increased frequency of breaks when cells are exposed to a DNA-replication inhibitor such as aphidicolin. PARK2 and DMD, the causative genes for autosomal-recessive juvenile Parkinsonism and Duchenne and Becker muscular dystrophy, respectively, are two very large genes that are located within aphidicolin-induced CFSs. Gross rearrangements within these two genes are frequently observed as the causative mutations for these diseases, and similar alterations within the large fragile sites that surround these genes are frequently observed in cancer cells. To elucidate the molecular mechanisms underlying this fragility, we performed a custom-designed high-density comparative genomic hybridization analysis to determine the junction sequences of approximately 500 breakpoints in germ cell lines and cancer cell lines involving PARK2 or DMD. The sequence signatures where these breakpoints occur share some similar features both in germ cell lines and in cancer cell lines. Detailed analyses of these structures revealed that microhomologies are predominantly involved in rearrangement processes. Furthermore, breakpoint-clustering regions coincide with the latest-replicating region and with large nuclear-lamina-associated domains and are flanked by the highest-flexibility peaks and R/G band boundaries, suggesting that factors affecting replication timing collectively contribute to the vulnerability for rearrangement in both germ cell and somatic cell lines.

Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines.

Methods that involve detection of a DSG3 protein for diagnosing cancer are disclosed. In lung cancer, the expression of DSG3 was found to be enhanced at very high frequency at the gene level and protein level. Methods of the present invention can be carried out using an antibody that recognizes a DSG3 protein. Pharmaceutical compositions, cell growth inhibitors, and anticancer agents containing a DSG3-binding antibody as an active ingredient are also disclosed. Methods of inducing cell damage in DSG3-expressing cells and methods of suppressing proliferation of DSG3-expressing cells by contacting the DSG3-expressing cells with DSG3-binding antibodies are also disclosed.

Diagnosis and treatment of cancer using anti-desmoglein-3 antibody

The present invention relates to an antibody binding to a TM4SF20 protein and the diagnosis and treatment of cancer using the antibody. Specifically, the present invention provides an anti-TM4SF20 antibody and a pharmaceutical composition (e.g., an anticancer agent and a diagnostic drug for cancer) comprising the antibody as an active ingredient.

Diagnosis of treatment of cancer using anti-tm4sf20 antibody

[Problem to be Solved] An object of the present invention is to provide novel means for the treatment and diagnosis of cancer. [Solution] The present inventors have obtained a monoclonal antibody against TMPRSS11E and found that this antibody binds to a native form of TMPRSS11E, and TMPRSS11E is highly expressed on the cell membranes of cancer cell lines in flow cytometry. This antibody exhibits antibody-dependent cell-mediated cytotoxicity activity (ADCC activity) and antitumor effect based on internalization activity and is promising as a therapeutic target. Moreover, this antibody has neutralization activity against protease activity and is also expected to have effect brought about by the inhibition of TMPRSS11E functions.

Shunpei Ishikawa

Papers

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer

Mechanisms of genomic instabilities underlying two common fragile-site-associated loci, PARK2 and DMD, in germ cell and cancer cell lines.

Diagnosis and treatment of cancer using anti-desmoglein-3 antibody

Diagnosis of treatment of cancer using anti-tm4sf20 antibody

Diagnosis and treatment of cancer using anti-tmprss11e antibody