50% Effort. Dysregulated signaling networks in HNSCC: novel mechanism-based approaches for HSNCC prevention and treatment There is an urgent need for new treatment options for HNSCC patients, considering that their overall 5-year survival is relatively low (50%) and has improved only marginally over the past 3 decades. The emerging knowledge of how the dysregulated function of signaling networks contributes to the initiation, malignant growth, and metastasis of HNSCC can now be exploited to identify novel mechanism-based anti-cancer treatments. mTOR as a novel molecular target for HNSCC treatment. We have shown that the persistent activation of the kinase Akt and its downstream target mTOR is a frequent event in HNSCC, and that inhibition of mTOR by the use of rapamycin causes the rapid apoptotic death of HNSCC tumors in multiple experimental HNSCC models, thereby inducing tumor regression. We have continued our concerted effort to use novel genetically-defined and chemically-induced carcinogenesis models to evaluate the effectiveness of mTOR inhibitors for the prevention and treatment of HNSCC. This includes the demonstration that rapamycin reduces the tumor burden and prolongs the survival of mice harboring mutations in TGF- and Akt-mTOR pathways. In addition, there has been a remarkable increase in the incidence of HNSCC associated with human papillomavirus (HPV) infection. Although HPV+ HNSCCs represent a distinct clinicopathological subset of HNSCC lesions, we observed that these HPV+ lesions also display increased Akt-mTOR activity. mTOR inhibitors induced a rapid tumor collapse and decreased tumor burden concomitant with inhibition of the Akt-mTOR pathway in multiple HPV+ HNSCC xenograft models. In a recent study, we showed that concomitant administration of rapamycin enhances the therapeutic response of HPV+ tumors to standard therapies with cytotoxic agents and the immune recognition of tumor cells in a syngeneic animal model. Thus, mTOR inhibitors may also represent attractive candidates for the treatment of HPV-positive HNSCC lesions. Novel genetically-defined and chemically induced oral-specific animal models to study SCC: We have made significant contributions to the development of genetically engineered mouse models (GEMM) for HNSCC. We have continued with these studies, including the recent analysis of the interplay between the TGFbeta and Akt-mTOR pathway in collaboration with Ashok Kulkarni. We have now focused in the development of oral specific systems enabling the activation/inactivation of genes in the epithelial stem cell compartment. We have also began exploring the use of genetically engineered mice conferring increased susceptibility or resistance to oral cancer, a possibility afforded by our recently developed oral-specific chemical carcinogenesis model. Current studies are aimed at recapitulating HNSCC progression, with emphasis on the activation of the PI3K/mTOR pathway, thus providing a suitable system to investigate targeted anticancer agents. This includes the deletion of the PIP3 phosphatase Pten. Recently, we have shown that mice lacking Pten in the basal layer of the oral epithelium, a frequent event in HNSCC due to epigenetic silencing of Pten, develop oral cancer lesions at very high rate upon carcinogen exposure, resulting in rapid animal cancer-related death. 30% effort. Genomic and proteomic approaches to understand oral cancer We have conducted gene and protein expression analysis of HNSCC by combining laser capture microdissection (LCM), gene arrays, next-gen sequencing and proteomic platforms. These efforts are providing a wealth of information about the dysregulated molecular circuitries driving HNSCC development, hence facilitating the identification of new therapeutic targets and suitable biomarkers for monitoring HNSCC progression and treatment response. Exploiting the head and neck cancer oncogenome. The recent development of deep sequencing approaches to study human cancer genomes in individual tumor lesions is already revolutionizing medical oncology and translational medicine. This large and growing body of information is now contributing to the elucidation of aberrant molecular mechanisms driving tumor progression, hence revealing novel druggable targets for therapeutic intervention to prevent and treat human cancers. The emerging picture is that despite the remarkable complexity of genomic alterations found in HNSCC, most of them fall within few major driver-signaling pathways, with the majority of the HNSCC lesions harboring genetic and epigenetic alterations that converge on the persistent activation of the PI3K-mTOR pathway. While representing a major HNSCC driver, this likely overreliance on the PI3K-mTOR signaling route for tumor growth can in turn expose a cancer vulnerability that can be exploited for therapeutic purposes. Indeed, the have documented the sensitivity of HNSCC to mTOR inhibition in multiple experimental models and encouraging recent clinical studies. The presence of genomic alterations in the PI3K pathway may also represent a suitable biomarker predicting a clinical response to its pharmacological inhibitors. Nanoparticle-based immunosensensors for cancer biomarkers and drug delivery systems for cell-surface receptor-guided cancer therapy: The genomic and proteomic analysis of HNSCC may now allow the development of novel biomarkers of diagnostic and prognostic value. We continued developing nanoparticle-based systems for the detection of HNSCC biomarkers. In particular, we have now developed an ultrasensitive immunosensor based on a glutathione-protected gold nanoparticle sensor surface. When combined with novel massively labeled paramagnetic particles for the electrochemical detection of a panel of cancer biomarkers, we obtained an unprecedented detection limit in the attomolar range, with high level of reproducibility and accuracy. This nanoparticle-based strategy for single-protein sensors has great promise for the future development of nanodetection arrays for clinical cancer screening and therapy monitoring. 20% effort. The role of signaling circuitries in epithelial stem cell function, tissue regeneration, and malignant reprogramming In prior studies we have shown that epithelial stem cells are endowed with a protective mechanism that results in cell senescence upon the persistent stimulation of proliferative pathways that activate mTOR, ultimately suppressing tumor formation. These studies and ongoing activities in the branch prompted us to begin investigating the molecular events controlling epithelial stem cell function, with emphasis on the preservation of the stem cell pool, or its demise by death, differentiation, and senescence (DDS response). Targeting mTOR and TGFbeta to prevent epithelial stem cell senescence and radiation-induced mucositis. We have recently found that whereas inhibition of mTOR does not affect the radiosensitivity of a collection of HNSCC cells, blockade of mTOR protects epithelial stem cells from radiation-induced senescence, thereby preserving their tissue repopulating capacity. We also observed that blocking mTOR leads to the decreased expression of p16INK4a, a key senescence gene that mediates the demise of epithelial stem cells from the tissue regenerating pool. This results in a dramatic decrease in radiation-induced mucositis, which may have a direct impact for thousands of cancer patients that develop this debilitating oral disease as a side effect of cancer treatment. As part of a collaborative effort, we have also shown that TGFbeta expression by epithelial and stromal cells contributes to mucositis, and that its blockade can reduce the epithelial damage upon ionizing radiation of the oral cavity.

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