2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

FUTURE DIRECTIONS IN GBM THERAPY
Challenges for the Evaluation and Efficacy of
Targeted Therapies in GBM
As in other solid tumors, there are currently a large
number of ongoing trials in GBM testing various targeted
therapies and other approaches to overcoming resistance
including those targeting DNA repair, receptor tyrosine
kinases and other signaling pathways, and pathways involved
in tumor stem-cell maintenance and regulation.
Unfortunately, the use of targeted therapies in brain tumors
and their evaluation in clinical trials face some additional
challenges that are different than with solid tumors
elsewhere in the body. First, many small molecule inhibitors
have relatively poor penetration into the brain and
cerebrospinal fluid, resulting in lower effective dose. Second,
evaluating the biologic effects of a drug on its target in
brain tumors is challenging because of its anatomic location
and increased difficulty in doing repeat biopsies during or
Author’s Disclosure of Potential Conflicts of Interest
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Howard Colman Castle
Biosciences
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Nonetheless, if experience from other solid tumors is any
indication, future successful clinical trials in recurrent
GBM will likely need to have a larger emphasis on pharmacodynamics
and biologic tissue effects as important endpoints.
In summary, the dramatic increase in our understanding
of the molecular underpinnings and subtypes of glioblastoma,
along with increases in the number and type of
available small molecule inhibitors, indicates that improvement
in patient outcome in GBM with appropriate targeted
therapy is indeed feasible. However, the success and rapidity
of these developments will hinge on successful integration
of molecular and preclinical data with the more efficient
and innovative clinical trial designs in order to identify
those key pathways and drugs that will have the highest
benefit for particular GBM subtypes.
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