Silvia Lapenna & Antonio Giordano on Cell Cycle Kinases
Fast Breaking Commentary, August 2010
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Article Title: Cell cycle kinases as therapeutic targets for cancer
Authors: Lapenna, S;Giordano, A |
Silvia Lapenna & Antonio Giordano talk with ScienceWatch.com and answer a few questions about this month's Fast Breaking Paper paper in the field of Pharmacology & Toxicology.
Why do you think your paper is highly
cited?
Our review article focuses on cell cycle kinases as cancer therapeutic targets. More specifically, it provides an overview of the complex mechanisms involved in the regulation of the cell cycle, and the disruption of cell cycle control in cancer.
The article illustrates the current knowledge on the actions and functions of specific families of protein kinases that orchestrate several distinct, but intertwined pathways in cell cycle regulation, including the irreversible switch from cell quiescence to division, the response to DNA damage, the assembly of the mitotic spindle, and, finally, cell division.
The paper summarizes the state of the art, in early 2009, for cancer drug discovery and development targeting cell cycle kinases, and reviews over 60 small-molecule inhibitors currently in clinical trials or preclinical screening, including their structure (when disclosed), known biological targets, and potency and selectivity evaluation both in vitro and in vivo.
The collected chemical and biological data may be useful to undertake new biological chemistry studies aimed at unraveling the functions of key human regulatory proteins such as the cell cycle kinases. Thus, the paper is a valuable source of information for researchers in the fields of cancer drug discovery, molecular pharmacology and toxicology, and chemical biology.
Coauthor Antonio Giordano.
This review is not a mere list of research articles on the cell cycle, but rather a critical review on the current understanding of the mechanisms of regulation of the human cell cycle, the links between the various pathways involved, and their dysfunctions in cancer. We also discussed the failures and successes in targeting various protein kinases for cancer treatment so far, and what may be learned from such efforts.
In writing the article, we tried to provide a reference paper not only for experts in the field, but also for clinicians and students approaching this topic for the first time.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
As the search for synthetic inhibitors of protein kinases as anticancer drugs has been invigorated by the successful approval of the BCR-ABL protein kinase inhibitor imatinib and related compounds, a high number of molecules that specifically inhibit cell cycle kinases have been developed. Still, none of these has been approved for commercial use and the exploitation of cell cycle protein kinase inhibitors in clinical oncology has not yet achieved proof of concept.
Although an effective strategy to specifically control malignant cell proliferation has yet to be established, in this article we speculated on promising future approaches and strategies. For example, we described the potential of SPA310, a short peptide derived from the tumor suppressor retinoblastoma-like protein 2 (RBL2), which was discovered in our lab, as a candidate template molecule for the design of novel cyclin-dependent kinase (CDK) inhibitors that function as tumor growth suppressors.
We also share our thoughts on the potential scope of exploring alternative docking sites for kinase inhibitors, including allosteric sites of mitotic kinases, regulatory subunits of CDKs, and molecules that target non-catalytic domain of Polo-like kinases.
Would you summarize the significance of your paper
in layman’s terms?
One of the objectives of our paper was to provide insights to support the rational, mechanism-based design of new anticancer drugs. In this article, we discuss the potential and limitations of therapeutically targeting the different protein kinases that control the mammalian cell cycle. These kinases orchestrate the distinct but intertwined pathways that drive cell proliferation, response to DNA damage and mitosis.
We believe that the recent progresses made in unraveling these molecular pathways as well as the identification of several tumor suppressor genes (i.e., genes which help to control cell proliferation) may facilitate a paradigm shift in cancer drug discovery, where traditional medicinal chemistry and structure-activity relationship studies are combined with knowledge of the biological responses to the chemical/drug in the context of the multiple molecular pathways which may be affected.
How did you become involved in this
research?
Silvia Lapenna: My background is in medicinal chemistry and pharmacology. As a Ph.D. student and post-doc researcher, I worked in the field of drug discovery in both academia and industry.
"...a critical review on the current understanding of the mechanisms of regulation of the human cell cycle, the links between the various pathways involved, and their dysfunctions in cancer..."
While I was a post-doc at the CROM Research Centre, and the University of Siena, I used computational chemistry methods to help to explain the tumor-growth arrest properties of the CDK inhibitor, SPA130, in terms of its peptide-protein interactions and its ability to modulate cell cycle pathways. The observations from the models served as the basis for an initial study aimed at discovering new anticancer drugs targeting cell cycle proteins and for designing relevant biological assays to test the hypotheses from the models.
Antonio Giordano: My early research includes seminal work demonstrating the importance of cell cycle proteins in the functioning of DNA tumor viruses. The transforming gene products of these viruses, such as the E1A oncoproteins of adenovirus 5, helped me in the identification of cellular factor p60, later shown by others to be cyclin A.
This research led to the first demonstration, in 1989, of a physical link between cellular transformation and the cell cycle, thereby paving the way for the melding of these two areas of research. It also helped to open a very exciting avenue of research involving investigators with expertise in different aspects of growth control and cancer.
My lab also discovered the tumor suppressor gene RB2/p130 and the cell cycle kinases CDK9 and CDK10 and Novel Structure Proteins (NSPs), a new family of structural proteins with a possible role in nuclear dynamics during cell division.
Where do you see your research leading in the
future?
We believe that progress in cancer research is to be expected if a multidisciplinary approach is pursued so that early drug-discovery efforts are paralleled with an increased understanding of the complex molecular pathways that control cell cycle deregulation in cancer.
In our opinion, the emerging fields of biological chemistry (where synthetic chemicals are used to modulate the activity of biological macromolecules) and systems biology (involving reconstruction of signaling networks followed by the synthesis of in silico models describing their functions as well as chemical-induced alterations) will have a crucial impact on future drug discovery initiatives.
Do you foresee any social or political
implications for your research?
Over the past two decades, there has been an intensive search for small
molecules that target cell cycle regulatory proteins. However, in the
clinical setting, these molecules simply failed. Considering the high
impact of cancer in our society, and the increasing challenges that drug
discovery and development is facing today, as well as the cost-constrained
health care systems, it is very important to consider the mechanism-based
hypotheses derived from preclinical studies when planning clinical trials
for new candidate drugs.
Silvia Lapenna
European Commission Joint Research Centre
Institute for Health and Consumer Protection
Systems Toxicology - Computational Toxicology and
Biostatistics
Ispra (VA), Italy
Web
Antonio Giordano
Sbarro Institute for Cancer Research and Molecular
Medicine
Center for Biotechnology
Temple University
Philadelphia, PA, USA
and
Department of Human Pathology and Oncology
University of Siena
Siena, Italy
and
Oncology Research Centre of Mercogliano (CROM)
Mercogliano (AV), Italy
KEYWORDS: CELL CYCLE KINASES, THERAPEUTIC TARGETS, CANCER, REVIEW, SMALL-MOLECULE INHIBITOR, AURORA-B KINASE, CHRONIC LYMPHOCYTIC LEUKEMIA, PRB2/P130 SPACER DOMAIN, TUMOR GROWTH INHIBITOR, ADVANCED SOLID TUMORS, IN-VIVO ACTIVITY, DEPENDENT KINASE, SELECTIVE INHIBITOR, PHASE I.