|
By: Dr. Ron Blasberg
Head - NeuroOncology
Laboratory
Memorial Sloan-Kettering Institute
We thank Dr. Ron Blasberg for contributing the following
narrative and helping us understand the Molecular Imaging space
During the
past two decades we have witnessed a revolution in our basic understanding
of human disease, including cancer. This has been made possible through
the rapid development of basic molecular and new biological assay techniques.
These advances have provided the tools to better understand and treat
disease processes at a molecular and cellular level. They have also lead
to the development of transgenic animal models of human disease, where
the molecular basis of that disease can be studied in a living organism.
Associated with these developments in basic molecular and cell biology,
the imaging sciences have also made remarkable advances in technology
for visualizing tissue structure and function.
The recent development of 'cellular and molecular imaging'is a hybrid
of the developments cited above. This effort has been strongly supported
and has been designated as one of six "Extraordinary Scientific Opportunities
for Investment" by Richard Klausner, Director of NCI. Novel imaging paradigms
are being developed to provide non-invasive assessments of tissue (tumor)
at a cellular or molecular level. For example, using appropriate reporter
constructs and imagable probes, it is now possible to measure and monitor
the transcriptional activity (both activation and suppression) of endogenous
genes in host tissue. Similarly, it is likely that post-transcriptional
modulation/stabilization of mRNA and protein-protein interactions of specific
steps in selected signal transduction pathways that determine phenotype
at a molecular level, will be imaged in the very near future.
These developments will provide new and exciting opportunities, where
it will be possible to assess specific signal transduction pathways targeted
by specific anti-tumor drugs. For example, patients may be selected for
a particular drug therapy on the basis of imaging prior to drug administration,
and drug effect could be monitored by measuring the drug's effect on specific
protein-protein interactions, signal transduction or metabolic pathways.
Thus, new 'end points' for monitoring drug response could be developed.
In all probability we could create nomograms of response for populations
receiving therapies. Clinicians would benefit from quantitative methods
for the identification of 'partial response' and 'complete response'.
These would serve as endpoints to replace survival in clinical trials.
Another aspect of the molecular imaging effort, which has been validated
in animals and is soon to be implemented in the clinic, is the ability
to use reporter constructs to monitor gene therapy. For example, it is
now possible to monitor the distribution, concentration and persistence
viral vectors and the level of therapeutic transgene expression using
reporter constructs and noninvasive imaging techniques.
Further development of imaging probes (including radiolabeled substrates,
targeted contrast agents and ligands), will allow for non-invasive elucidation
of specific cell cycle systems and specific signal transduction pathways
that become altered in cancer. This development and evolution of chemistry
and imaging techniques, coupled with continued progress in genetics, molecular
and cell biology, will have a profound impact on the practice of medicine
in the future. For example, it is very likely that we will be able to
visualize and quantitate critical changes that occur in the transformation
of cells from normal to pre-cancerous to cancerous. It is also likely
that it will be possible to evaluate 'at-risk' patients earlier in
cancer pathogenesis, perhaps before a tumor has even had the chance to
become malignant. With further development of molecular imaging techniques,
it is anticipated that we will be able to visualize the actual molecular
signatures of cancer in patients. For example, the molecular imaging specialist
within the next decade may be able to visualize and determine which genes
are being expressed in a specific cancer, and be able to translate this
information directly into better clinical management of that individual
patient. In other words, the ability to detect the fundamental changes
associated with tumor cells in individual patients through non-invasive
molecular imaging, will vastly improve our ability to detect and stage
tumors, select appropriate treatments, monitor the effectiveness of a
specific treatment, and determine prognosis.
In imaging, as elsewhere in cancer research, animal models of cancer are
making it possible to perform certain kinds of studies that are difficult,
if not impossible, to perform in humans. In addition to learning more
about cancer, research with animal models will facilitate imaging technology
improvements and developments that then can be eventually applied to the
clinical care of patients with cancer. A distinct advantage of non-invasive
imaging in animal models of cancer is the ability to perform repetitive,
non-invasive observations of the biological processes underlying cancer
growth and development without sacrificing the animal. Furthermore, the
level of resolution with some small animal imaging modalities is now approaching
the size of individual cells. Imaging in animals can also help assess
the effectiveness of new instruments and therapeutic technologies such
as radiation therapy and directed drug therapies. Animal models are critical
in providing insights that are difficult or impossible to perform in humans
because of practical or ethical considerations. Imaging provides a parallel
modality (in conjunction with biopsy and tissue assays) for obtaining
information from human subjects as well as animal models, and this dual
approach can be applied in a rigorous fashion. The development of small
animal imaging devices that can serially image experimental tumors in
small animals and incorporate all of the functional strategies listed
above should provide a powerful new tool for experimental studies of tumor
behavior and response to treatments.
Layman's Summary
The concept of 'cellular and molecular-based
imaging' is a new and hybrid development that evolved from a merger of
the extraordinary technological advances in the biological and imaging
sciences over the past two decades. This evolution has been fostered by
Richard Klausner, Director of NCI, and is strongly supported through the
"Extraordinary Scientific Opportunities for Investment" program at NCI.
The investment in 'Cancer Imaging' by NCI will provide many new opportunities
to assess tumors at a molecular level in patients and in animal models
of cancer. It is anticipated that within this decade it will be possible
to visualize and quantitate critical cellular changes that occur as cells
transform from normal to pre-cancerous to cancerous. Within the next decade,
it may be possible to evaluate 'at-risk'patients earlier in cancer pathogenesis,
perhaps before a tumor has even had the chance to become malignant, and
that it may be possible to visualize the actual molecular signatures of
cancer in individual patients.
The ability to detect and image fundamental changes associated with tumor
cells will vastly improve our ability to detect and stage tumors, select
appropriate treatments, monitor the effectiveness of a treatment, and
determine prognosis. For example, patients may be selected for a particular
drug therapy on the basis of molecular imaging results before drug
administration. In addition, molecular imaging could provide new end points
for monitoring treatment response; namely, imaging endpoints based on
the molecular action of the drug. These molecular endpoints are likely
to seen 'early' in the course of treatment, before there is a change
in physical size of the tumor. This will provide clinicians with the opportunity
for earlier assessment of treatment response (or lack of response)
in comparison to our current MR and CT imaging assessments. In all probability,
we could create nomograms of response for populations receiving different
therapies, and they would serve as end points to replace survival in clinical
trials.
|
