Marcos Malumbres on CDK Inhibitors in Cancer Therapy
Fast Moving Front Commentary, July 2010
|
Article: CDK Inhibitors in Cancer Therapy: what is next?
Authors: Malumbres, M;Pevarello,
P;Barbacid, M;Bischoff, JR |
Marcos Malumbres talks with ScienceWatch.com and answers a few questions about this month's Fast Moving Fronts paper in the field of Pharmacology & Toxicology.
Why do you think your paper is highly
cited?
This paper discusses biological and preclinical data on the relevance of small-molecule cyclin-dependent kinase (CDK) inhibitors for cancer therapy. There are multiple reviews on the same subject, but I think this manuscript contains two features that may contribute to the high number of citations.
First, it is written by a team formed of basic biologists together with chemical pharmacologists. Thus, the text uses a combination of languages that may be attractive to a wide spectrum of scientists from different backgrounds interested in the area. The manuscript elaborates on diverse data relevant for new therapeutic approaches by inhibiting CDKs in cancer; from the phenotype of mouse knock outs to the problems regarding the delivery of the corresponding drugs.
Figure 1:
CDKs and the cell cycle. Schematic representation of
some of the mammalian CDKs involved in progression throughout the different
phases of the cell cycle. Some of these kinases are required for DNA
replication (S-phase) whereas other participate in the preparation for
chromosome segregation during mitosis. Their therapeutic validation,
however, requires proper analysis of this basic version of the cell cycle
in different cell types and under different oncogenic backgrounds in
vivo.
View larger image in tab below.
Second, it is a timely review. It was published at a moment where the results of clinical trials using first- and/or second-generation CDK inhibitors were published. Despite the great expectation these inhibitors had, their outcome in clinical trials was not too enthusiastic. However, third-generation or more specific compounds were ready and a discussion of what we had learned was necessary.
In addition, some data from mouse models were suggesting a change in the strategy for selecting tumors or patients based on genetic background or tumor type. It was probably the right time to discuss all these topics and try to optimize the analysis of the following rounds of available inhibitors.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The manuscript contains a synthesis of the current knowledge about CDK inhibitors, their targets, and their clinical relevance. But not only that, it also tries to propose a framework to advance the therapeutic uses of these molecules.
As the title indicates ("CDK inhibitors in cancer therapy: what is next?"), the goal of the manuscript was not only to synthesize the current knowledge but try to find practical recommendations, or at least to select the more relevant questions that need to be addressed.
The questions and the discussions among the authors in the elaboration of the manuscript are likely to be similar to the discussions that readers—whether biologists, clinicians, chemists, or pharmacologists—are having when discussing in the lab "what is next." These questions are probably still valid today.
Would you summarize the significance of your paper
in layman's terms?
Since the discovery of the critical regulators of the cell division cycle, scientists have tried to select which of these molecules may have therapeutic relevance. One of the first targets selected were the cyclin-dependent kinases. The reasons are three-fold.
First, these molecules are critical drivers of progression throughout the cell cycle. Second, they are upregulated in the vast majority of human cancers. Third, they have kinase activity and they are therefore druggable targets.
Several CDK inhibitors have been identified and the first and second generations of CDK inhibitors have been tested in clinical trials. The results were not too good, probably as a consequence of lack of specificity but also as a consequence of the poor understanding of the requirements for these kinases in vivo.
The manuscript first discussed the new data obtained from in vivo mouse models deficient in individual CDKs. These data suggest that the individual CDK to be targeted (the CDK family includes about 20 family members in mammals) depends on the cell type and the genetic background of the tumoral cell and, thus, specific drugs are required to avoid general toxicity.
The manuscript then described the most recent specific drugs identified in some pharmaceutical companies and their preclinical data. Some general questions about the right delivery procedures or additional kinases to be considered in the future are also included in the text.
How did you become involved in this research, and
how would you describe the particular challenges, setbacks, and
successes that you've encountered along the way?
"This paper discusses biological and preclinical data on the relevance of small-molecule cyclin-dependent kinase (CDK) inhibitors for cancer therapy."
I got involved in cell cycle research first during my postdoctoral training at the New York University Medical Center, and then when I joined Mariano Barbacid’s lab at the recently created Spanish National Cancer Research Center (CNIO) in Madrid. In 2004, I got a position as an independent researcher and I am still working on the validation of cell cycle kinases as cancer targets.
To obtain in vivo data, we use genetically modified mouse models. This approach takes long time, it is expensive, and requires good core services to take the best from these models. However, you get in vivo data, you can analyze all cell types and tissues in the organism, and you can challenge real tumors using genetic or chemical approaches.
Where do you see your research leading in the
future?
We realized in our previous studies that clinical trials with kinase inhibitors are usually justified by biological assays in cells (including xenografts), but not in vivo. We think that the right therapeutic approaches must consider that the cell cycle is different in the various cell types in our organism.
We also need to take into account that the cell cycle in tumor cells may be modified by the oncogenic signals in those cells. Thus, we are currently analyzing the requirements for cell cycle kinases in vivo using genetically modified mouse models.
We need to understand the requirements for these kinases in different cell types and different tumors using these mouse models before the corresponding inhibitors are used in the hospital and before patients are treated with these drugs in clinical trials. We hope our work will be able to suggest the right therapeutic benefits of kinase inhibitors before patients are treated based on the information generated in cells cultured in vitro.
Do you foresee any social or political
implications for your research?
Kinase inhibitors are currently one of the favorite drugs in development by many pharmaceutical companies. It is relatively easy to find potent inhibitors and modify them to generate substances that can enter clinical trials.
Thus, any knowledge on the expected toxicities, biomarkers, or the possibility to select the patients that are most likely to respond to these molecules is crucial to facilitate the successful application of these new therapies. We believe that our research efforts can participate in this area by helping to understand the biological function of some of these targets in vivo.
In addition to these CDKs, there are many other new targets to be analyzed. Hopefully, we can do this biological analysis at the same speed as chemists and pharmacologists generate useful specific inhibitors and oncologists use them in clinical trials.
Marcos Malumbres
Group Leader
Cell Division and Cancer Group
Spanish National Cancer Research Center
(CNIO)
Madrid, Spain
KEYWORDS: CYCLIN-DEPENDENT KINASES (CDKs), INHIBITORS, CANCER, FLAVOPIRIDOL, CY-202, FIRST-GENERATION, SECOND-GENERATION, CELL CYCLE, TUMOR GROWTH, PRECLINICAL MODELS, APOPTOSIS, CLINICAL UTILITY.
Figure 1:
Figure 1: CDKs and the cell cycle. Schematic representation of some of the mammalian CDKs involved in progression throughout the different phases of the cell cycle. Some of these kinases are required for DNA replication (S-phase) whereas other participate in the preparation for chromosome segregation during mitosis. Their therapeutic validation, however, requires proper analysis of this basic version of the cell cycle in different cell types and under different oncogenic backgrounds in vivo.