OPPORTUNITY 2
Preclinical Models of Cancer
Technical advances have always played a key role in improving our ability
to manage and treat disease. This link between new technical advances and
rapid progress is equally true for the discovery process in cancer research.
Recently developed methods in animal genetics now allow the study of cancer
in ways that were impossible even a few years ago. These techniques provide
an unprecedented opportunity to study cancer in settings that closely mimic
human disease. They allow us to manipulate the genome of laboratory animals,
particularly mice, and provoke tumors in natural settings in ways that tie
tumor development to the same mutations that drive human disease. These
are powerful tools. It is now time to exploit these advances.
The Goal
Create animal models for human cancer based on knowledge of human cancer
genes.
The Opportunity
Cancers arise through multiple steps of selection. Cells are constantly
undergoing mutations, and some of these mutations give the cell new proliferation
or survival advantages. As these mutated cells proliferate, an ever increasing
pool of target cells is available for new mutations. Some new mutations
provide new selective advantages. Over a lifetime, repetition of this selection
process can lead to full tumor development and the manifestation of cancer.
A common adult tumor may undergo 10 or more key mutations to reach its full
devastating character. In the laboratory we have been able to identify a
number of these mutations and now have a growing understanding of how these
mutations fuel the initial steps in tumor development. The study of these
mutations and how they change the properties of a normal cell has been limited
by the types of experimental settings in which we could examine these changes.
Most importantly, studying how these mutations participate in the development
of tumors in mammals has not been possible. Obviously, it is not possible
to study these events in humans. The inability to establish a model system
to study the great variety of human cancers, their development and their
progression has been a major roadblock to the discoveries needed to reduce
the cancer burden in people.
This roadblock has now been overcome by recent advances in mouse genetics.
These new techniques provide the remarkable ability to introduce mutations
into the genetic material of mice that can be passed to their offspring.
Using techniques developed through NIH support, investigators can now place
any mutations they choose into a mouse. This strategy will ultimately allow
us to study, in laboratory animals, the mutations that are likely to drive
the development of human cancer. These mice will provide a natural setting
to study all stages of tumor development. They will allow us to test in
animals early detection, prevention, and treatment strategies.
Many new avenues of investigation will be opened following these developments.
They include the following.
* Studying cancer mutations in a living animal.
* Investigating the action of multiple cancer mutations. Since
cancers arise from multiple events, we have needed a method to examine the
contributions of the different mutations in a physiological setting. This
is now possible using modern mouse genetics approaches.
* Identifying new cancer genes and
examining tumor development. Our knowledge of the number and type
of genes that contribute to cancer is still growing. Using animal models,
we can induce the first steps of cancer development, and then let the next
steps of tumor development proceed naturally. After isolating the resulting
tumors, we will be able to identify the new mutations that have occurred
during the next steps of tumor development. This is particularly important
for angiogenesis (blood vessel development without which tumors cannot grow)
and metastasis, which are still poorly understood stages of tumor development
but pose the most threatening problems in human cancers. In particular,
this approach may be the best way to be able to identify and understand
other genes and environmental factors that affect cancer development and
progression.
* Testing new interventions. Cancer therapeutics research
would benefit significantly from being able to model faithfully in an animal
the great variety of diseases we call cancer. These systems will allow us
to answer the critical questions of why therapy works in some cancers and
why, in other cancers, it doesn't work. In addition, animal models for human
cancer predisposition and development will allow us to rigorously test prevention
strategies. These models will facilitate the development and evaluation
of agents that could intervene and arrest the disease process. As we approach
an era when cancer therapy will be tailored to the particular mutations
that have driven tumor development, we will need accurate models to test
new therapies. Having animal models that reflect the sometimes mysterious
processes of tumorigenesis in humans will speed and improve the development
and testing of these therapies. New ideas and new approaches to therapy
abound, from manipulation of the immune system to gene therapy. Such new
approaches require experimental settings such as these animal models to
address the real problems and potentials of 21st century therapeutics.
The Plan
Although the need for this technology and the promise for real advancement
are great, at present we cannot fully exploit these new technologies. Creating
animal models of human cancer is now possible, but we lack the ability to
use this resource fully. The expense of creating and maintaining these animal
models is generally beyond the budgets available to individual researchers.
We now need the added investment and the infrastructure to support, to help
manage, and to coordinate the use of this powerful new technology.
We need to support:
* Development of animal models;
* Procedures to make the animals available to all researchers; and
* Development of the knowledge, expertise, and technology to use these
animals to their fullest potential in cancer research.
To fully utilize this new resource will require support for animal repositories
and distribution mechanisms. This new technology requires a work force expert
in the genetic manipulation of mice, complex genetic analysis, and mouse
pathology.
Consequences: Investing vs. Waiting
We are witnessing an explosion of innovative ideas and approaches to
early detection, prevention and treatment of disease. In all areas of medicine,
the new ability to create valid animal models of specific diseases is revolutionizing
testing of the safety and efficacy of these desperately needed interventions.
Failure to fully use this breakthrough technology in cancer will slow down
and greatly limit the number and types of novel therapies that we can test
and thereby use to prioritize the establishment of human clinical trials.
The backlog of new ideas and new approaches is growing but we can neither
afford nor justify trying them all in humans. The most rapid, efficient,
and cost-effective way to sort through these innovations is through animal
models.
If we fail to enact this plan, we will have no reliable and practical
way to test interventions that prevent the development and progress of cancer.
Before this new technology, we could transfer fully developed cancer into
animals but we could not make animals predictably susceptible to specific
cancers via the same genetic predispositions now known in humans. Without
the tools this plan will provide, our ability to rapidly understand what
environmental or dietary factors alter cancer risk and what preventions
actually work to prevent the development of cancer will be greatly hampered.
Animal models quicken the pace of discovery. We are all committed to
more rapid, more accurate and more economical means to translate basic research
to the benefit of patients. The NCI also is committed to the humane care
and use of animals in research. Without this plan, we will be tied to a
slower pace of progress; too many worthy ideas will have to get in the long
queue of human clinical trials without the guidance compelling results in
animals could provide. Not enacting this plan will shackle us to yesterday's
research tools just as we should be capitalizing on the approaches of the
future.