National Cancer Institute - NCI Division of Cancer Treatment and ...

With this approach, patients are not cured,
but tumors are controlled by starving
them and inhibiting growth.
Metronomic therapy remains a controversial
area; however, these pioneering
experiments have improved treatment
outcomes. The goal is to identify biomarkers
to monitor the status of tumor progression
in patients and to try successive
combinations of anticancer agents that
will keep tumors dormant until a cure
can be achieved.
This approach has many benefits: treatments
are not expensive because they
usually involve existing anticancer agents,
existing agents can be quickly translated
to the clinic, and treatments are often
given at doses that are well tolerated.
In animal studies, researchers have shown
that the circulating bone marrow–derived
endothelial progenitor cells (circulating
endothelial progenitors, or CEPs) are the
source of tumor blood vessels and the
target of certain drugs. By combining
a 5-fluorouracil (5-FU) prodrug called
tegafur-uracil (UFT), which targets CEPs,
and antitumor agents such as cyclophosphamide,
a standard alkylating agent,
there was an enhanced survival of tumorbearing
mice. CEP levels can also be used
as a biomarker to establish optimal doses
of the drugs. A number of combinations
are now in clinical testing.
Shaked Y, Emmengger U, Man S, Cervi D,
Bertolini F, Ben-David Y, Kerbel RS. The optimal
biological dose of metronomic chemotherapy
regimens is associated with maximum antiangiogenic
activity. Blood 2005;106:3058–61.
Munoz R, Man S, Shaked Y, Lee C, Wong J,
Francia G, Kerbel RS. Highly efficacious non-
toxic treatment for advanced metastatic breast
116 ■ P R O G R A M A C C O M P L I S H M E N T S 2 0 0 6
cancer using combination UFT-cyclophosphamide
metronomic chemotherapy. Cancer Res
(In press).
Mancuso P, Colleoni M, Calleri A, Orlando L,
Maisonneuve P, Pruneri G, Agliano A, Goldhirsch
A, Shaked Y, Kerbel RS, Bertolini F. Circulating
endothelial cell kinetics and viability predict survival
in breast cancer patients receiving metronomic
chemotherapy. Blood [Epub Mar 16 2006].
Ferrara N, Kerbel RS. Angiogenesis as a therapeutic
target. Nature 2005;438:967–74.
Kerbel RS. Antiangiogenic therapy: a universal
chemosensitization strategy for cancer? Science
(In press).
Targeting Hypoxic Cell Signaling
for Drug Discovery
DTP researchers collaborated with investigators
in CCR to establish the activity of
DNA topoisomerase I inhibitors as selective
inhibitors of HIF-1α, a key regulator
of hypoxic cell signaling. Because of this
research, a clinical trial of topotecan as
an HIF-1α inhibitor was designed and
approved in 2005. This trial opened in
early 2006 and is currently recruiting
patients. Additional information on
the clinical trial can be found at:
http://bethesdatrials.cancer.gov/
clinical-research/search_detail.
asp?ProtocolID=NCI-05-C-0186.
Recent efforts have defined additional
mechanistic categories of HIF-1α
inhibitory compounds identified in
high-throughput drug screening as
exemplified by the sequence-specific
DNA binder echinomycin. The primary
drug candidate (NSC 644221) was identified
as a screening lead with yet a different
mechanism of action. Preliminary
xenograft studies support the potential of
this compound for in vivo modulation of