June 10, 2008 — What doesn’t slaughter cancer cells makes them more grounded, Duke analysts have observed.
Specialists use radiation and chemotherapy to annihilate cancer cells. Approximately half of patients are cured — that’s, all of their tumor cells die.
The other half of the time, a few tumor cells survive treatment. These cancer cells are more forceful than they were some time recently treatment, says Mark W. Dewhirst, DVM, PhD, teacher of radiation oncology at Duke University.
“When you give a tumor treatment, anything cells survive are going to be more resistant to that treatment,” Dewhirst tells WebMD. “Those not slaughtered are more advantageous cancer cells.”
This does not mean radiation and chemotherapy don’t work. It does mean that additional new treatments will be required. And to know what medicines will work best, Dewhirst says doctors have to be compelled to know how cancer cells survive radiation and chemotherapy.
The key may be a protein called HIF — hypoxia-inducing figure. Government, college, and drug-company analysts are racing to develop new drugs that inhibit HIF. But patients may not have to be compelled to wait that long: Existing drugs, as of now affirmed by the FDA for cancer treatment, turn out to be potent anti-HIF specialists.
Why is HIF all of a sudden a huge deal? It’s the key to a different way of looking at cancers.
A ‘New’ Theory of Cancer
It’s been known for almost 50 a long time that solid tumors have regions that don’t get much blood — and that cells in these regions survive without much oxygen.
For a long time, this was thought to be an interesting curiosity. But presently the ability of cancer cells to outlive without oxygen — to become hypoxic — is being seen as a driver of cancer progression.
“A cancer cell that doesn’t get much oxygen is like a rodent leaving a sinking ship,” Dewhirst says. “It will do things to try to help itself.”
So the cell does four things:
It sends out a signal for help, asking the body to develop more blood vessels within the tumor. It changes the way it eats, switching from oxygen digestion system to anaerobicmetabolism. It prepares itself for the day it gets offer assistance, building guards against a burst of oxygen atoms that is poisonous to anaerobic cells. And the cell is progressing to attempt to induce out of there — to attack a blood vessel and go somewhere else in the body to develop.
Each of these things makes cancer more awful:
Modern blood vessels let the tumor develop larger. Cells that do not utilize oxygen are much less touchy to chemotherapy and radiation. Cells resistant to bursts of oxygen (oxidative stress)also are resistant to a few of the ways the body gets rid of cancer cells. Cells that wander spread cancer to far off parts of the body.
Johns Hopkins researcher Gregg Semenza, MD, PhD, calls this discovery one of the four “major conceptual advances over the final century which have the potential to revolutionize cancer treatment.”
Part of that revolution has been Semenza’s disclosure of HIF-1. HIF-1 is the flag that changes a cell from an oxygen-using cell to an anaerobic cell.
HIF: Key to Cancer Treatment Victory?
“It’s been appeared that in a variety of distinctive cancer sorts, those with most HIF-1 have the worst outcome,” Semenza tells WebMD. “The basis for this is often the reality that HIF-1 controls the expression of hundreds of qualities that play basic parts in cancer science.”
One of the primary analysts to start seeking out for drugs that target HIF-1 is oncologist Giovanni Melillo, MD, of the U.S. National Cancer Organized (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, could be a sedate called topotecan, showcased beneath the brand name Hycamtin. It’s already affirmed by the FDA as a second-line treatment for ovarian and small-cell lung cancers. So why isn’t this sedate already revolutionizing cancer treatment?
“The key to this treatment is the dosage,” Melillo tells WebMD. “For chemotherapy, one ordinarily gives the greatest tolerated measurements. And the timing is vital, because when topotecan is utilized as chemotherapy one needs to let the quiet recover from harmfulness. We propose to provide lower doses of topotecan daily to realize this effect on HIF-1 in a nontoxic design.”
In fact, in an NCI clinical trial, Melillo and colleagues found that topotecan given this way does not have the poisonous effects seen when the drug is used in massive dosages as a chemotherapy.
But in case cancer analysts have learned one thing, it is that no single type of treatment is reaching to cure cancer.
“Successful treatment of tuberculosis requires the organization of three anti-microbials; effective treatment of Helps requires the organization of three antiviral operators,” Semenza recently wrote. “It isn’t reasonable to anticipate that the effective treatment of cancer can be accomplished dependably with any fewer than three anticancer agents.”
Semenza, Dewhirst, and Melillo concur that HIF-1 inhibitors will have major impacts only when combined with other agents.
Dewhirst proposes using such inhibitors in conjunction with radiation and chemotherapy. Melillo and Semenza are excited approximately using the drugs with angiogenesis inhibitors, such as Avastin, which avoid tumors from developing unused blood vessels.
Melillo’s team is arranging a clinical trial testing Avastin in combination with topotecan. And Dewhirst and colleagues have fair completed an early safety consider of another HIF-1 inhibitor, ENMD-1198 from EntreMed Inc. (Dewhirst has no budgetary intrigued within the company).
“HIF-1 restraint is a very energizing opportunity for cancer treatment,” Dewhirst says.