Multiple Myeloma: Translational and Emerging Therapies (Translational Medicine)

Preclinical Strategies, Models & Tools in Oncology
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Melanoma Sanjiv S. Diabetes Carla J. Of these, 96 transcripts were scored as overrepresented fourfold or more in tumors and 30 transcripts were overrepresented fold or more in tumors. The possible role of these genes in the etiology and therapy of lung cancer is now being assessed. Another microarray study reported on the effect of smoking on gene expression in normal bronchial epithelial samples from 75 individuals without cancer Differential analysis of transcripts revealed that smoking induced the transcription of several putative oncogenes and reduced transcription of several putative TSGs.

Importantly, the study indicated, which changes were irreversible after cessation of smoking. Thirteen gene transcripts did not return to normal levels in former smokers, even in those who had discontinued smoking 20 years before testing. For example, transcript expression of carcinoembryonic antigen CEA -related cell adhesion molecule 6 and HN1 a member of the human Notch family was permanently increased, whereas expression of TU3A a gene previously isolated from renal cell cancer and CX3CL1 a chemokine ligand was permanently decreased.

These results are interesting, because these genes were not previously associated with lung carcinogenesis. Gene expression microarrays are also being developed to predict lung cancer histology and outcome A panel of 50 transcripts, including HER2 and vascular endothelial growth factor VEGF mRNA, was reported to separate patients with early stage lung adenocarcinoma into two groups with different prognosis As discussed in the section on CCND1, splicing is an important regulatory mechanism that can vary the primary mRNA structure and therefore the encoded protein from a given gene.

Multiple Myeloma Symposium: Emerging Treatment Options - Dana-Farber Cancer Institute

Another regulatory mechanism at the RNA level has been discovered recently. The human genome encodes approximately miRs, produced as long precursors, which are cleaved into 20 to 25 nucleotide long oligomers that are bound into an active miR-induced silencing complex. These complexes have important functions in normal and cancer cells.

In lung cancer, let-7 miRs are downregulated, which is associated with poor prognosis Downregulation of let-7 in lung cancer was confirmed by 12 Gautschi et al.

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Figure 4 Function of the let-7 microRNA. In lung cancer cells, let-7 is downregulated, leading of increased production of potentially oncogenic RAS protein.

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Interestingly, it is known that viruses use miR for gene regulation in host cells and increased expression of miR is found in Epstein—Barr virus—transformed lymphoblastoid cells A viral cause of human lung cancer has been suggested in the past and although this hypothesis is highly speculative, miR may be the key that could lead to further advances in this field.

The predicted targets of these miRs are significantly enriched for proto-oncogenes and TSGs, suggesting that a large number of miRs are dominant or recessive lung cancer genes. The discovery of miR may have implications for lung cancer therapy. It was speculated that augmentation of let-7 miR may benefit lung cancer patients, but pharmacological delivery of miR may be challenging and inhibition of overexpressed miRs could be more efficient Antagomirs, cholesterol-conjugated single-stranded RNA analogues, are efficient and specific inhibitors of endogenous miRs in mice, and the safety and activity of these compounds in cancer patients must now be tested Large-scale technologies proteomics are being developed to broadly measure changes at the protein level in lung cancer The therapeutic implications of proteomics research are considerable, because mRNA and protein levels can be discordant and this approach allows the study of posttranslational protein modifications.

Two-dimensional gel electrophoresis or protein microarrays can separate complex protein mixtures and individual proteins can then be identified by mass spectrometry. More recently, chromatography has been added to these methods in order to measure changes at the enzyme substrate level metabolomics The advantage of metabolomics is that the consequences of protein function and drug treatment can be observed.

At present, the reproducibility and global measurement capability of both proteomics and metabolomics are not as high as with genomics, in part because of the additional technical complexity involved in measurement, in part due to the lack of a specific amplification system similar to the PCR. For the moment, only restricted classes of proteins are considered to be targetable by small molecule inhibitors.

Research on one such class, the protein kinases PKs , has yielded significant success in lung cancer therapy. Today, it is known that the human genome contains approximately genes, which encode PKs. PKs transfer phosphate groups from high-energy donor molecules such as adenosine triphosphate ATP to target proteins.

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Because of this central role, PKs are tightly controlled by many mechanisms, including phosphorylation sometimes by the PK itself, referred to as autophosphorylation , binding of regulatory proteins, control of their localization in the cell relative to their substrates, and removal of phosphate groups from target proteins by their functional antagonists, the protein phosphatases Activation of PKs is frequent in cancer and new drugs, which inhibit specific kinases, are discussed elsewhere in this book The three-dimensional 3-D structure of a protein is an important determinant of its interaction with other molecules, but the process of protein folding is not well understood.

Methods of analysis include X-ray diffraction, nuclear magnetic resonance, and prediction by comparison of the amino acid sequence with proteins of known structure and similar sequence. Recent studies in this field revealed the structural features of HER family dimerization It was shown that these receptors, which are produced as inactive monomers, could switch between a tethered and an extended conformation Fig.

Only the extended conformation of the monomer can undergo dimerization with another HER family member. In the case of EGFR, binding of the ligand leads to the receptor adopting the extended conformation, resulting in dimerization and activation of the receptor 14 Table 3 Gautschi et al. Cetuximab, an EGFR-targeted therapeutic monoclonal antibody, inhibits this process, both blocking ligand binding and also sterically preventing the receptor from adopting the extended conformation necessary for dimerization These results show that proteins can undergo dynamic conformational changes that are functionally and therapeutically relevant.

Knowledge of 3-D protein structure was also important for the discovery of the proteasome, its function, and subsequent development of proteasome inhibitors Proteasomes are intracellular, barrel-shaped macromolecules that specifically digest other proteins into short polypeptides and amino acids. Target proteins are recognized by the proteasome based on a ubiquitin tag, which is added by the ubiquitin ligases.

The proteasome removes the ubiquitin tag and degrades the target protein in an ATP-dependent process. Many important proteins involved in cell cycling and apoptosis are degraded by the proteasome complex, including the cyclins and IKB. The elucidation of this system led to the development of the proteasome inhibitor bortezomib Velcade, PS , which is clinically active as a single agent and in combination with cytotoxic drugs in many tumor types, including lung cancer 79, The proposed mechanism of action of bortezomib in lung cancer cells rests on the induction of G2-M arrest and apoptosis.

Transition between two EGFR structures is shown in both ribbons and cartoon representation. The inactive, tethered structure is shown on the left. A model of the EGF-induced dimer is shown on the right. The speculated position of the plasma membrane is depicted as a gray bar. This exposes the dimerization arm and allows dimerization of EGFR, as depicted on the right. Abbreviation: EGF, epidermal growth factor. Large-cell carcinoma and adenocarcinoma are typically located in the Molecular Biology of Lung Cancer 17 periphery of the lung, whereas squamous cell carcinoma often presents as a central tumor with necrosis and endobronchial growth.

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Squamous cell carcinoma tends to grow more slowly and has a slightly better prognosis than adenocarcinoma and large-cell carcinoma. Squamous cell carcinoma is often necrotic and may invade large blood vessels. The therapeutic consequence of this characteristic is that squamous carcinoma is significantly associated with fatal tumor bleeding in patients treated with the anti-VEGF antibody bevacizumab Bronchioloalveolar carcinoma BAC is another histopathological diagnosis of interest.

Translational bioinformatics and biomarkers

Multiple Myeloma: Translational and Emerging Therapies - CRC Press Book. and individualization of treatment and the development of novel therapeutic. Multiple Myeloma: Translational and Emerging Therapies (Translational Medicine): Medicine & Health Science Books @ newscongsytacva.ml

Despite the World Health Organization designation of this disease as a subtype of adenocarcinoma, BAC has features that are distinct, such as relatively slow and multifocal growth SCLC belongs to the class of neuroendocrine tumors, which also includes typical carcinoid, atypical carcinoid, and large-cell neuroendocrine carcinoma Recent data suggest that activating mutations of KIT are not common in SCLC, likely explaining the lack of clinical activity of imatinib SCLC cells also express multidrug resistance-related protein-1 and p-glycoprotein encoded by the multidrug resistance gene one , which are ATP-binding cassette transporter proteins that confer resistance by enhancing drug efflux Although inhibitors to these proteins have been developed, clinical studies have met with little success and the concentrations required to block multidrug resistance proteins in humans may not have been reached As an alternative resistance mechanism, SCLC cells exposed to cisplatin upregulate survival pathways that directly protect them from cell death.

Several small molecule inhibitors of PI3K and Akt are currently being tested in clinical trials.

Markers can be prognostic for patient outcome general effect which is 18 Gautschi et al. Other markers have been isolated from patient sputum and peripheral blood and were associated with lung cancer diagnosis and outcome Interpretation of these preliminary studies has often been limited by small sample size and lack of validation, with the consequence that there is at present no Food and Drug Administration— approved biomarker specific for lung cancer.

One biomarker of interest is the uridine diphosphate UDP -glucuronosyltransferase isoform 1A1 UGT1A1 gene polymorphism, which has been associated both with cancer risk and also toxicity, time to progression, and survival in patients treated with irinotecan Irinotecan is a prodrug, which is converted into its active metabolite SN by the UDP-glucuronosyltransferases in the liver. The observation that the EGFR tyrosine kinase inhibitors, gefitinib or erlotinib, show dramatic responses in a small subset of NSCLC patients and that EGFR mutation status and gene copy number are predictive of clinical benefit has been pivotal to current efforts to develop methods for prospective patient selection for treatment with these agents 19,99, These data are now being incorporated into clinical trial design in advanced stage NSCLC, exemplified by trials using molecular screening to identify patients appropriate for randomization to front line erlotinib or chemotherapy.

Multiple Myeloma: Translational and Emerging Therapies (Translational Medicine)

Other targeted agents are emerging and two different strategies have been developed to predict the sensitivity of tumors to these novel agents: i hypothesisdriven analyses of the target and a limited number of associated molecules; and ii large-scale gene expression microarrays to determine the type of deregulated oncogenic pathway in a given tumor , This process is supported by the NCI, which has awarded six grants to collaborative research groups to explore how information derived from comprehensive molecular analyses can be used to impact the care of cancer patients and Molecular Biology of Lung Cancer 19 ultimately improve outcome.

The Strategic Partnering to Evaluate Cancer Signatures program in lung cancer will thus facilitate the development of robust and reproducible assays for specific molecular signatures that can be tested in clinical trials. We encourage the reader to take advantage of advances in other areas as well — The following chapters will discuss specific examples translating this increased knowledge to the clinic.

Despite these advances, lung cancer remains a multimolecular and heterogeneous disease, both in the laboratory environment and in the clinic. It is likely that additional new technologies and new clinical trial designs capable of integrating this complexity into the treatment decision making process will be required to make further progress in this malignancy. Hardy PA, Zacharias H.