On going research projects:
Molecular mechanisms of resistance to PI3K and EGFR inhibitors in HNSCC and ESCC
The role of stromal cells in response to PI3K and EGFR therapies in HNSCC
Biomarkers of response to treatment regimens for HNSCC and ESCC
Develop novel murine head and neck, ovary and cervical cancer models to study drug response including immunotherapy
Molecular mechanisms of resistance to PI3K in gynecological cancers
Resistance to immunocheckpoint inhibitors in HNSCC
The role of LncRNA in resistance to PI3K therapies
Identification of immunomodulators that induce immune-escape in head and neck cancer.
Intrinsic mechanisms of drug resistance
Intra-cellualr rewiring is signalling network process that occurs in the tumor cells following treatment with selective inhibitors of the oncoprotein-activated pathway. This signalling adaptation decreases dependence of the tumor on the oncoprotein by reactivating alternative survival pathways. This dynamic process occurs in hours to days and diminishes the initial effectiveness of the therapy.
Our goal is to elucidate the intrinsic mechanisms of resistance to PI3K and EGFR therapies in squamous cell carcinoma of the esophagus (ESCC) and of the head and neck (HNSCC). Particularly, our laboratory is interested to explore the transcription factors that regulate the expression of genes involved in resistance. These basic information will lead to investigation of new therapeutic alternatives that can be applied back in the clinic.
Extrinsic mechanisms of drug resistance
The cells surrounding the tumor cells provide diverse factors, including cytokines, chemokines, and growth factors, which regulate signaling pathways that are required for invasion and metastasis. Recently, a growing body of evidence has emerged supporting the contribution of the tumor microenvironment to the response of cancer patients to chemotherapy or to molecular targeted therapies. In particular, accumulation of stromal-derived secreted growth factors, which enhance malignant cells proliferation, was reported in pre-clinical models and in patients following treatment with targeted therapies and chemotherapies. In recent work, we measured the activity of over 300 secreted factors on the proliferation of breast and HNSCC cells in the presence of PI3K inhibition. We found that the activation of IGF1R or of HER3 by insulin growth factor 1 (IGF1) or by Neuregulin1 (NRG1), respectively, is sufficient to limit the efficacy of BYL719 in breast cancer. Notably, when we used the same high-throughput screen in HNSCC cancer models, we observed that other ligands and receptors were important for the rescue phenotype from BYL719, underscoring that each tumor type may react differently to the anti-proliferative activity of the PI3K. we speculate that identifying the cell types that express “rescue” factors and uncovering the molecular mechanisms of their migration into the tumors are critical information to improving therapies of PI3K or other targeted therapies.
Biomarker of response to therapy
Innate/de-novo drug resistance results, at least in part, from the heterogeneity of the malignant cells and from the different characteristics of cells in the tumor microenvironment. Comparing tissues from patients with different clinical responses is an approach often employed to suggest plausible biomarkers of sensitivity to therapy.
Molecular analysis of cohort of clinical samples can provide essential information related to response to therapy. Our laboratory collecting tissues from oncologist who treat head and neck and esophageal cancer to perform deep characterization of the tumors (proteomics, genomics and gene expression). Such analysis of well defined cohorts of HNSCC biopsies will provide a trustworthy list of genes, proteins, and genomic alterations associated with responsiveness to therapies. We believe that these findings will improve selection criteria for specific treatment regimen, and will increase response rate for therapy.
Murine cancer model
The lack of murine HNSCC cancer models limiting the possibility to study tumor heterogeneity in response to therapy in cancers in vivo. Our laboratory generating unique murine HNSCC model, which will will help us to understand better the biology of this disease and will serve as pre-clinical HNSCC models to study response to therapies and to explore novel therapies including targeted therapies and immunotherapies.