• Advances in Targeting Signal Transduction Pathways.

     
    Advances in Targeting Signal Transduction Pathways.

    ABSTRACT

    Over the past few years, significant advances have occurred in both our understanding of the complexity of signal transduction pathways as well as the isolation of specific inhibitors which target key components in those pathways. Furthermore critical information is being accrued regarding how genetic mutations can affect the sensitivity of various types of patients to targeted therapy. Finally, genetic mechanisms responsible for the development of resistance after targeted therapy are being discovered which may allow the creation of alternative therapies to overcome resistance. This review will discuss some of the highlights over the past few years on the roles of key signaling pathways in various diseases, the targeting of signal transduction pathways and the genetic mechanisms governing sensitivity and resistance to targeted therapies.

    Mutations Alter the Activity of the Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways.

    The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways are often activated by mutations within individual components of these pathways, as well as the aberrant activation of upstream growth factor receptors. The genetic basis of sensitivity and resistance to various small molecule inhibitors which target these pathways as well a comprehensive list of small molecule inhibitors as a well as their use in clinical trials have recently been published [1-7].

    Predicting Sensitivity to Small Molecule Inhibitors.

    Extensive panels of human cell lines have been examined for mutations in genes implicated in cancer as well as for their sensitivity to various inhibitors and chemotherapeutic drugs commonly used to treat cancers [8,9].

    The cell lines were intensively interrogated by expression profiling, chromosome copy number, deep sequencing, biostatistical and systems analyses. Both studies indicated that sensitivity to inhibitors was often linked with genetic mutations at key elements in the Ras/Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and some other pathways. Sensitivity to MEK and Raf inhibitors was often investigated in these studies. Sensitivity to the B-Raf inhibitor PLX4720 was highly associated with particular mutations at BRAF (V600E). Sensitivity to MEK inhibitors was shown to be associated with BRAFNRAS as well as PTENPTPN5SPRY2DUSP4DUSP6 mutations and to a lesser extent mutations at KRAS. Sensitivity to MEK inhibitors in NRAS mutant lines was linked with aryl hydrocarbon receptor (AHR) expression [9].

    Mutation of BRAF or RAS can contribute to the pathogenesis of many cancers, including, melanoma and colo-rectal cancer [10]. BRAF mutations have also been implicated in the pathogenesis of papillary thyroid cancer [11].

    Mutation of BRAF and KRAS can result in aberrant c-Myc and SIRT1 protein deacetylase expression in the colorectal cancer [12]. Mutations at KRAS which result in increased mutant Ras activity can interact with increased Wnt expression in lung cancer and lead to a worse prognosis as the tumors arise at an increased incidence and tumors which are also larger [13]. Interesting it was observed that in those tumors where there was increased KRAS and Wnt activities they had a distinct phenotype which was similar to embryonic progenitors found in the developing lung, consistent with the previously described effects of the Wnt pathway on developmental processes. https://www.oncotarget.com/article/802/text/


    Mikhail (Misha) V. Blagosklonny graduated with an MD and PhD from First Pavlov State Medical University of St. Petersburg, Russia. Dr. Mikhail V. Blagosklonny has then immigrated to the United States, where he received the prestigious Fogarty Fellowship from the National Institutes of Health. During his fellowship in Leonard Neckers’ lab at the National Cancer Institute (NCI), he was a co-author of 18 publications on various biomedical themes, including targeting HSP90, p53, Bcl2, Erb2, and Raf-1. He also was the last author for a clinical phase I/II trial article. 
    After authoring seven papers during a brief yet productive senior research fellowship in the El-Deiry Cancer Research Lab at the University of Pennsylvania, Dr. Blagosklonny returned to NCI to work with Tito Fojo. Together, they published 26 papers. Moreover, Dr. Blagosklonny published many of experimental research papers and theoretical papers as sole author. The abovementioned sole-author articles discussed two crucial topics. The first of these discussed selectively killing cancer cells with deregulated cell cycle or drug resistance via verifying their resistance. The outcomes and underlying notion were so revolutionary that they were incorrectly cited by other scientists as “reversal of resistance,” even though the publication was titled, “Exploiting of drug resistance instead of its reversal.” One big supporter of this concept was the world-famous scientist Arthur Pardee, with whom Dr. Blagosklonny co-authored a joint publication in 2001.
    The second theme throughout Dr. Blagosklonny’s sole-author articles is a research method to develop knowledge by bringing several facts together from seemingly irrelevant areas. This results in new notions with testable forecasts, which in turn can be “tested” via analyzing the literature further. Likewise, the concept was co-authored by Arthur Pardee in a 2002 article in Nature. The first success of the new research methodology was the description of the feedback regulation of p53, as confirmed by the discovery of mdm2/p53 loop; and the explanation why mutant p53 is always overexpressed, published in 1997. The most important result revealed by Dr. Blagosklonny’s research methodology is the hyperfunction (or quasi-programmed) theory of aging and the revelation of rapamycin as an exclusively well-tolerated anti-aging drug, published in 2006. As mentioned in Scientific American, Michael Hall, who discovered mTOR in 1991, gives Dr. Blagosklonny credit for “connecting dots that others can’t even see.”
    In 2002, Dr. Blagosklonny became associate professor of medicine at New York Medical College. He agreed to accept responsibilities as a senior scientist at Ordway Research Institute in Albany, New York, in 2005, before receiving another position at Roswell Park Cancer Institute as professor of oncology in 2009.
    Since coming to Roswell Park Comprehensive Cancer Center in 2009, Dr. Blagosklonny has studied the prevention of cancer (an age-related disease) via stopping organism aging - in other words, “preventing cancer via staying young.” His laboratory closely worked together with Andrei Gudkov’s and conducted research on the suppression of cellular senescence, namely suppression of cellular conversion from healthy quiescence to permanent senescence. This led to the discovery of additional anti-aging medicines beyond rapamycin. The cell culture studies were complemented by studies in mice, including several models like normal and aging mice, p53-deficient mice, and mice on a high-fat diet.
    Dr. Blagosklonny has also published extensively on the stoppage of cellular senescence via rapamycin and other mTOR inhibitors, life extension and cancer stoppage in mice, and combinations of anti-aging medicines to be taken by humans. A rapamycin-based combination of seven clinically available medications has been named the “Koschei Formula” and is now used for the treatment of aging in patients at the Alan Green Clinic in Little Neck, New York. 
     

     


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