Treatment Can Make Cancer Stronger
But New Cancer Treatment 'Revolution' Under Way
HIF: Key to Cancer Treatment Success?
"It's been shown that in a variety of different cancer types, those with
most HIF-1 have the worst outcome," Semenza tells WebMD. "The basis for
this is the fact that HIF-1 controls the expression of hundreds of genes that
play critical roles in cancer biology."
One of the first researchers to start looking for drugs that target HIF-1 is
oncologist Giovanni Melillo, MD, of the U.S. National Cancer Institute (NCI).
After screening hundreds of compounds for anti-HIF activity, Melillo and
colleagues made a surprising discovery: A number of existing cancer
chemotherapies turn out to inhibit HIF.
The most potent, Melillo says, is a drug called topotecan, marketed under
the brand name Hycamtin. It's already approved by the FDA as a second-line
treatment for ovarian and small-cell lung cancers. So why isn't this drug
already revolutionizing cancer treatment?
"The key to this treatment is the dose," Melillo tells WebMD.
"For chemotherapy, one usually gives the maximum tolerated dose. And the
timing is important, because when topotecan is used as chemotherapy one needs
to let the patient recover from toxicity. We propose to give lower doses of
topotecan daily to achieve this effect on HIF-1 in a nontoxic fashion."
Indeed, in an NCI clinical trial, Melillo and colleagues found that
topotecan given this way does not have the toxic effects seen when the drug is
used in massive doses as a chemotherapy.
But if cancer researchers have learned one thing, it is that no single type
of treatment is going to cure cancer.
"Successful treatment of tuberculosis requires the
administration of three antibiotics; successful treatment of AIDS requires the administration
of three antiviral agents," Semenza recently wrote. "It is not
reasonable to expect that the successful treatment of cancer can be
accomplished reliably with any fewer than three anticancer agents."
Semenza, Dewhirst, and Melillo agree that HIF-1 inhibitors will have major
effects only when combined with other agents.
Dewhirst proposes using such inhibitors along with radiation and
chemotherapy. Melillo and Semenza are excited about using the drugs with
angiogenesis inhibitors, such as Avastin, which prevent tumors from growing new
Melillo's team is planning a clinical trial testing Avastin in combination
with topotecan. And Dewhirst and colleagues have just completed an early safety
study of another HIF-1 inhibitor, ENMD-1198 from EntreMed Inc. (Dewhirst has no
financial interest in the company).
"HIF-1 inhibition is a very exciting opportunity for cancer
treatment," Dewhirst says.