One of the
key obstacles in identifying effective anti-cancer therapies is the lack of translation ability of experimental treatment results to actual tumors in
humans. Replicating promising anti-tumor effects observed in animal models of
various cancer therapies in humans has proven extremely difficult. This goal is
even more challenging when attempting to do so from outcomes and results
documented in cell culture experiments. Only approximately 7% of therapies
identified in pre-clinical studies are actually approved by the Food and Drug
Administration (FDA) to proceed beyond clinical trials for use in human cancer
treatment. Costs to develop drugs for human use currently approach nearly 3
billion dollars, which compounds the overwhelming failure of oncotherapies to
show effects in humans and further limits progression of cancer-targeting
treatments.
Why do so
many drugs fail to show benefits in humans while demonstrating promise in
pre-clinical experimental studies? A primary contributor to this discrepancy
lies in the differences in biology of humans compared to that in experimental
conditions. The tumor microenvironment in humans may vary in pH, oxygenation,
and other chemical features, and the human immune and inflammatory response can
alter the drug's chemical potency or specificity toward tumor cells, or
alter the cells’ ability to respond to the treatment. Also, human cancers are
often treated, respond, and return, exhibiting some level of chemotherapeutic
resistance, which makes recurring cancers harder to treat. It is difficult to
model this in an experimental setting. The bottom line is that experimental
models do not accurately reflect the human condition. Therefore, improving a
therapy’s ability to target human cancers with the desired efficacy and potency
while minimizing off-target and unexpected influences of the drug on the body,
and vice versa, are critical to advancing cancer therapies for human use. A multi-drug approach is likely going to be
a viable answer to overcoming so many issues to get the job done correctly.
A recent
study by Klinghoffer et al. in Science Translational Medicine tested a
device known as CIVO that is designed to deliver multiple potential
therapeutic agents into carefully planned spatial locations within a biological
tumor, and utilized paired software to analyze each compound’s effects within
the tumor microenvironment. The premise behind such a bioengineering approach
is to enhance prediction of the value and efficacy of therapies in pre-clinical
animal models, and improve the target specificity, limit unintended side
effects, and characterize compound-specific anti-tumorigenic effects in
experimental and human cancers. This can help researchers and clinicians
predict the potential of one or many compounds for use, as well as serve as a
delivery and monitoring device for application in human cancer patients.
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Figure 1. CIVO chemotherapy microinjection system diagram. The CIVO system can microinject up to 8 (7 depicted here) therapeutic agents into localized area of a tumor. This allows for analysis of local agent-specific treatment effects as well combined chemotherapeutic agent delivery directly into the tumor, reducing off-target side effects. |
The researchers
tested
the CIVO system, which has the capability to deliver microinjections of up to 8
different drugs into the tumor, in xenograft lymphoma models. Such models
involve transfer of human cancers into animals for testing drug efficacy. Using the CIVO microinjection system, a
variety of extensively studied and well-characterized anticancer drugs
(vincristine, doxorubicin, mafosfamide, and prednisolone) caused clearly
defined localized changes to the biology and structure of cancer cells around
sites of drug exposure that were reflective of the previously identified and
defined mechanisms of each drug’s effects. Interestingly, these local responses
were predictive of responses to systemic administration of the agents in animal
models. Perhaps one of the most exciting results of the study identified a new
mammalian target of rapamycin (mTOR)-specific inhibitor that exhibited efficacy
in killing tumor cells in drug-resistant tumors versus its effects in
tumors that had previously not been exposed to any chemical therapy. mTOR is a
widely-studied protein in cancer due to its role in enhancing cell growth,
protein synthesis, and cell survival - all characteristics of cancer cells that
contribute to cancer pathobiology and treatment difficulty. In addition,
studies designed to determine the feasibility of the CIVO system for its
effects of use in humans and canines showed that the microinjection approach of
CIVO highly limited the toxicity of chemotherapeutics while improving the
anti-cancer targeting effects. This study is exciting as it combines an
engineering approaching with chemotherapeutic delivery and demonstrates the
potential to enhance the benefits of chemotherapy in killing tumors while
reducing the often-serious toxic side effects inflicted by systemic delivery of
such agents. Also, CIVO appears to be a useful experimental system to utilize
in pre-clinical studies to better predict the effects of certain drugs, or
combinations of drugs, in treating various types of cancer before bringing the
therapy to humans. This approach will hopefully bridge the major gap between
the results observed in experimental models and the effects documented in human
application and advance the treatment of cancer in the very near future.
#cancer #chemotherapy #doxorubicin #chemoresistant #CIVO #mTOR
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