Preclinical models for the evaluation of targeted therapies of metastatic disease

It has been estimated that approx 60–70% of cancer patients harbor overt or subclinical metastases at diagnosis, and it is the eradication of such systemic disease that largely determines survival. Preclinical tumor model systems employed to evaluate potential new treatment strategies should aim to represent the process and patterns of metastasis of their clinical counterparts as closely as possible. Severe combined immune-deficient (SCID) andnu/nu mice have been extensively used as hosts for the growth of human tumor cell lines and in some cases fresh tumor material. However, in most instances the resulting neoplasms fail to metastasize, and the aberrant immune systems of such animals has limited their use mainly to passive therapies of localized disease. Recently, the development of specially selected tumor variants and the use of appropriate orthotopic sites for implantation has provided several models in which dissemination can be demonstrated. Where the gene coding for a potential target antigen has been cloned, and where its overexpression or mutation is associated with malignancy (e.g., c-erbB-2, H-ras), transgenic mice may yield tumors that will develop in these immunocompetent hosts. In some cases such tumors exhibit metastasis. A third approach is to transfect human genes of interest into appropriate rodent tumors expressing the desired metastatic phenotype. These various approaches are compared with particular reference to mammary carcinoma biology.     

A Monte Carlo approach to small-scale dosimetry of solid tumour microvasculature for nuclear medicine therapies with 223Ra-, 131I-, 177Lu- and 111In-labelled radiopharmaceuticals

The small-scale dosimetry of radionuclides in solid-tumours is directly related to the intra-tumoral distribution of the administered radiopharmaceutical, which is affected by its egress from the vasculature and dispersion within the tumour. The aim of the present study was to evaluate the combined dosimetric effects of radiopharmaceutical distribution and range of the emitted radiation in a model of tumour microvasculature.We developed a computational model of solid-tumour microenvironment around a blood capillary vessel, and we simulated the transport of radiation emitted by ²²³Ra, ¹¹¹In, ¹³¹I and ¹⁷⁷Lu using the GEANT4 Monte Carlo. For each nuclide, several models of radiopharmaceutical dispersion throughout the capillary vessel were considered.Radial dose profiles around the capillary vessel, the Initial Radioactivity (IR) necessary to deposit 100 Gy of dose at the edge of the viable tumour-cell region, the Endothelial Cell Mean Dose (ECMD) and the Tumour Edge Mean Dose (TEMD), i.e. the mean dose imparted at the 250-μm layer of tissue, were computed. The results for beta and Auger emitters demonstrate that the photon dose is about three to four orders of magnitude lower than that deposited by electrons. For ²²³Ra, the beta emissions of its progeny deliver a dose about three orders of magnitude lower than that delivered by the alpha emissions.Such results may help to characterize the dose inhomogeneities in solid tumour therapies with radiopharmaceuticals, taking into account the interplay between drug distribution from vasculature and range of ionizing radiations.     

Engineering nuclear localization signals in modular protein vehicles for gene therapy

Amino acids from 126 to 135 of the SV40 virus T antigen act as efficient nuclear localization signal during infection but also when fused to recombinant proteins. This peptide has been inserted into two alternative acceptor sites of a modified Escherichia coli beta-galactosidase which also displays a DNA-binding domain, a cell-binding motif for integrin alpha(v)beta(3) targeting and cell internalization, and a cryptic nuclear targeting signal naturally present in the bacterial enzyme. In cultured cells, the presence of the SV40 peptide enhances the expression of a delivered DNA up to 30-fold. However, the DNA expression levels are largely depending on the chosen insertion site for the SV40 segment concomitant to the structural impact of peptide accommodation on the protein vehicle. The structural stability of the hybrid protein, apparently critical for efficient gene transfer, is discussed in the context of modular protein engineering to develop non-viral vectors for gene therapy.     

Biomarkers for early detection of high risk cancers: From gliomas to nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NpC) is a malignant disease associated with Epstein-Barr virus infection, and often diagnosed at anadvanced stage. This significantly curtails patient survival. We hypothesize that a panel of biomarkers can be assembled to assessNpC incidence, early detection, and tumor progression during therapeutic intervention. Our thesis rests on a model ofsuccessfully predicting high-risk gliomas by means of a carefully crafted panel of molecular mitotic biomarkers (i.e., securin,survivin and MCM2). The strategy we propose holds strong promise for prevention and cure of NpC. The approach we proposeseeks to identify certain biomarkers from viral materials, patient tissues and assessment of related diseases, whose signatures,taken together, will be endowed with some degree of congruency, or sense of a coordinated language (i.e., “votes”). Biomarker“voting” will then permit to outline a broad coordinated molecular map for the molecular and epigenetic characterization of eachindividual patient''s NpC tumor. We will draw on the process of contrasting biomarkers in health and disease, which rests on theauto-proteomic concept particularly relevant in high-risk cancer individuals, such as is the case for NpC. In brief we defend,current advances in human proteome profiling proffers the possibility of having individual baseline proteomic profiles using localbody fluids (e.g., saliva, nasal secretions, sputum) or systemic fluids (e.g., plasma, serum, cerebrospinal fluid) to unravel apersonalized molecular map for high-risk NpC individuals. Regular check-up will monitor for new or impending manifestationsof NpC, and provide a secure assessment of incidence and early detection.