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American Journal of Nuclear Medicine and Molecular Imaging (1)
PLoS ONE (1)
Ray, Pritha (2)
Astanehe, Arezoo (1)
Gaikwad, Snehal M (1)
Gaikwad, Snehal M. (1)
Gambhir, Sanjiv Sam (1)
Gunjal, Lata (1)
Junutula, Anitha R. (1)
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author:("Gaikwad, sneha M")
Non-Invasive Imaging of Phosphoinositide-3-Kinase-Catalytic-Subunit-Alpha (PIK3CA) Promoter Modulation in Small Animal Models
Junutula, Anitha R.
Gambhir, Sanjiv Sam
Activation of the PI3K/Akt pathway, a critical step for survival in cancer cells is often associated with decreased sensitivity to several chemotherapeutic drugs. PIK3CA gene amplification is observed in 16–24% of epithelial ovarian cancer (EOC) patients in conjunction with p53 mutations. A 900 bp long PIK3CA promoter is shown to be negatively regulated by p53 in ovarian surface epithelial cells but the consequence of chemotherapeutic drug treatments on this promoter in ovarian cancer cells is largely unknown. We aim to study the modulation of this promoter by cisplatin using an improved fusion reporter in ovarian cancer cells and tumor xenografts by non-invasive imaging approach. A PIK3CA sensor was developed using a bi-fusion reporter from a newly constructed library of bi- and tri-fusion vectors comprising of two mutant far red fluorescent proteins (mcherry/mch and tdTomato/tdt), a mutant firefly luciferase (fluc2), and a PET reporter protein (ttk). In vivo imaging of mice implanted with 293T cells transiently expressing these bi- and tri-fusion reporters along with respective controls revealed comparable activity of each reporter in the fusion background and fluc2-tdt as the most sensitive one. Repression of the PIK3CA sensor by drugs was inversely proportional to cellular p53 level in a germline (PA1) and in an EOC (A2780) cell line but not in a p53 deficient EOC (SKOV3) cell line. Bioluminescence imaging of tumor xenografts stably expressing the PIK3CA sensor in PA1 and A2780 cells exhibited attenuating activity without any change in SKOV3 tumors expressing the PIK3CA sensor after cisplatin treatment. Sequential mutation at p53 binding sites showed gradual increase in promoter activity and decreased effects of the drugs. These newly developed PIK3CA-fluc2-tdt and the mutant reporter sensors thus would be extremely useful for screening new drugs and for functional assessment of PIK3CA expression from intact cells to living subjects.
Non-invasive imaging of PI3K/Akt/mTOR signalling in cancer
American Journal of Nuclear Medicine and Molecular Imaging
Platinum based drugs are widely used to treat various types of cancers by inducing DNA damage mediated cytotoxicity. However, acquirement of chemoresistance towards platinum based drugs is a common phenomenon and a major hurdle in combating the relapse of the disease. Oncogenesis and chemoresistance are multifactorial maladies which often involve deregulation of one of the prime cell survival pathways, the PI3K/Akt/mTOR signalling cascade. The genetic alterations related to this pathway are often responsible for initiation and/or maintenance of carcinogenesis. Molecular components of this pathway are long being recognized as major targets for therapeutic intervention and are now also have emerged as potential tools for diagnosis of cancer. To develop novel therapeutics against the key molecules of PI3K pathway, stringent validation is required using both in-vitro and in-vivo models. Repetitive and non-invasive molecular imaging techniques, a relatively recent field in biomedical imaging hold great promises for monitoring such diagnosis and therapy. In this review, we first introduced the PI3K/Akt/mTOR pathway and its role in acquirement of chemoresistance in various cancers. Further we described how non-invasive molecular imaging approaches are sought to use this PI3K signalling axis for the therapeutics and diagnosis. A theranostic approach using various imaging modalities should be the future of PI3K signalling based drug development venture.
PI3K signalling; platinum based chemoresistance; repetitive and non-invasive molecular imaging techniques; PET imaging; bioluminescence imaging; Akt sensor; fluorescence imaging
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