Beating bone marrow cancer

Saturday 26 October 2013

Islamabad, Oct 27 (Newswire): To lessen the impact of chemotherapy on bone marrow cancer patients, hematologists are recruiting the patients' own immune systems to help.

White blood cells are extracted before a bone marrow transplant, treated to up their activity, and injected back after chemotherapy. Doctors hope to test technique on other patients with immune deficiencies, including HIV.

A heavy dose of chemo takes a huge toll on cancer patients' bodies, making them weak and prone to infection. Now, a new, life-saving therapy is helping some cancer patients win the war against a deadly disease.

Having bone marrow cancer hasn't slowed down Todd Ewell, but the chemotherapy to fight the disease stopped him in his tracks. "It's kind of like if you had the worst flu in your life for about six weeks straight," he says.

The body's immune system takes a beating from chemotherapy. Patients can't fight off infection or disease, but Todd's body fought back, thanks to a new immune-boosting therapy.

Aaron Rapoport, a hematologist and oncologist at the University of Maryland Greenebaum Cancer Center in Baltimore, says, "What we're seeking to do is to harness the power of the patient's own immune system."

Before a bone marrow transplant, hematologists collect a patient's own immune cells, then activate, or turn on, the cells in a lab. The enhanced cells are injected back into the patient, along with a pneumonia vaccine, jump-starting the immune system. "It will be better able to respond to infections and also be better able to attack and eliminate cancer cells that may remain," Dr. Rapoport tells DBIS.

The new therapy worked wonders for Todd. "It's going fantastic. It's almost like it never happened." His cancer is in complete remission, and now he's focused on rebuilding his life cancer free.

Doctors are hopeful the new therapy could be tested and used to treat other people with compromised immune systems liked HIV patients and the elderly.

A new form of immunotherapy combines a vaccine with an infusion of a person's own T-cells that have been given a "jump start" and then are grown in the laboratory. The new approach helps to restore cancer patients' ability to fight off infection after high-dose chemotherapy. It could also one day be used to treat others with compromised immune systems, such as those with HIV and the elderly.

Patients with advanced myeloma, a cancer of the plasma cells in the bone marrow, received high-dose chemotherapy and a bone marrow transplant.

They received a series of vaccinations against a common bacterial form of pneumonia as well as an injection of their own lab-enhanced immune cells.

Researchers found the therapy was most effective when patients received vaccinations before the bone marrow transplant to jump-start their immune system, and then collected the "vaccine-primed" T cells, activated them in the lab, and gave them back to the patients 12 days after the transplant.

Within one month, those patients showed significant improvement in their immune response. The researchers will next combine this T-cell therapy with a cancer vaccine that would target tumor cells, hopefully to one day enhance the body's immune response to cancer.

A slow or non-functioning immune system is a serious problem for cancer patients, especially those who receive intensive chemotherapy prior to bone marrow transplants.

Patients are at high risk of developing infections and recurrence of their cancer. Immunotherapy stimulates a patient's own immune system to work harder. It's often used in conjunction with other forms of therapy -- in the case of cancer, it is combined with surgery, radiation therapy, or chemotherapy.

In general, immunotherapy is most likely to be effective when treating small cancers and is less effective for advanced stages of the disease.

T-cells are a type of white blood cell called lymphocytes, and help the immune system fight off diseases. There are two kinds of T-cells. T4 cells are "helper" cells that lead the attack against infections.

T8 cells are "suppressor cells" that end the immune response, although they can also kill cancer cells and cells infected with a virus. Scientists tell T4 and T8 cells apart by the different proteins attached to the outside of each cell. The number of T4 cells in your blood tells you how healthy your immune system is. A person with a healthy immune system has an average T-cell percentage of more than 30 percent.

Chemotherapy is a treatment for cancer, in which certain drugs (poisonous to cancer cells) are injected into the blood to kill cancer cells or to stop them from spreading. They can travel around the body and attack cancer cells wherever they find them, so chemotherapy is used when cancers have spread beyond one region of the body.

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Synthetic molecule makes cancer cells commit suicide

Islamabad, Oct 27 (Newswire): Howard Hughes Medical Institute researchers have developed a small molecule that can turn the survival signal for a variety of cancer cells into a death signal. The molecule mimics the activity of Smac, a protein that triggers the suicide of some types of cancer cells.

The researchers say their findings suggest that Smac-mimetic compounds could be useful as targeted cancer treatments for lung and other cancers. Such therapy may be less toxic to healthy cells than current compounds used in cancer chemotherapy.

The researchers, led by Howard Hughes Medical Institute investigator Xiaodong Wang, published their findings in the journal Cancer Cell. Wang is at the University of Texas Southwestern Medical Center.

Cells that are defective or that become unnecessary during growth and development are induced to commit suicide through a finely balanced process known as apoptosis, or programmed cell death. A protein called Smac, which is a shortened version of "second mitochondria-derived activator of apoptosis," is a part of the cell's programmed cell death machinery. When that machinery is switched on, Smac is released from the mitochondria and triggers the pathway that kills damaged or abnormal cells. Cancer cells, however, can survive Smac's death signal by switching off the apoptotic machinery.

To see if they could get around this problem, Wang and other researchers have developed small-molecule mimetics of Smac that can enter the cell and trigger apoptosis. These mimetic molecules do their damage without the need for the Smac signal from the mitochondria. In earlier studies, Wang and his colleagues found that a Smac mimetic that they developed in the lab could kill cancer cells in culture. But they found that the cancer cells are only killed when the mimetic molecule is introduced in conjunction with another component of the apoptotic machinery known as TNFá.

In the new studies published in Cancer Cell, Wang and his colleagues found that a significant percentage of human non-small-cell lung cancer cell lines were sensitive to treatment by the Smac mimetic alone. When the researchers introduced those sensitive cells into mice and allowed them to produce tumors, they found that the Smac mimetic caused the tumors to regress and, in some cases, even disappear.

"These findings made us wonder what it was about these cell lines that made them sensitive to the Smac mimetic alone," said Wang. "Cancer cells are hard to kill, but these cell lines seemed to have already become sensitized to apoptosis."

The researchers' studies revealed that the sensitive cell lines produced their own TNFá, so they were already "primed" for apoptosis. The paradox, said Wang, is that TNFá signaling is also part of a complex pathway that gives cancer cells a "survival" signal, offering them a growth advantage. The researchers also found that some breast cancer and melanoma cell lines were sensitive to the Smac mimetic alone.

"Thus, in these cancer cell lines, the TNFá survival advantage turns out to be a fatal flaw, because the same pathway can be switched to apoptosis by Smac mimetics," said Wang. "So, for some cancers, we might be able to use Smac mimetics as a single treatment agent. And we can use the presence of TNFá as a marker to tell us which tumors will respond to the Smac mimetic alone."

"People have been suspecting for a long time that some cancer cells may somehow turn on their apoptotic pathway already," said Wang. "And now we know what pathway they turn on and why. We can take advantage of this phenomenon for potential cancer therapy by switching a signal into a deadly one with Smac mimetics."

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'Reaper' protein strikes at mitochondria to kill cells

Islamabad, Oct 27 (Newswire): Our cells live ever on the verge of suicide, requiring the close attention of a team of molecules to prevent the cells from pulling the trigger.

This self-destructive tendency can be a very good thing, as when dangerous precancerous cells are permitted to kill themselves, but it can also go horribly wrong, destroying brain cells that store memories, for instance.

Rockefeller University scientists are parsing this perilous arrangement in ever finer detail in hopes that understanding the basic mechanisms of programmed cell death, or apoptosis, will enable them eventually to manipulate the process to kill the cells we want to kill and protect the ones we don't.

In experiments published in the Journal of Cell Biology, researchers led by postdoctoral associate Cristinel Sandu in Hermann Steller's Strang Laboratory of Apoptosis and Cancer Biology drilled down on a protein aptly named Reaper, which was first described in a 1994 paper by Steller in Science.

Under the right conditions, Reaper interferes with molecules called inhibitor of apoptosis proteins (IAPs), which prevent the cell from irrevocably initiating its autodestruct sequence. By inhibiting these inhibitors, Reaper essentially takes the brakes off the process of apoptosis, pronouncing a cell's death sentence. Other molecules called caspases then carry that sentence out.

"Like the grim reaper, Reaper is an announcer of death, but not the executioner," says Steller, who is also a Howard Hughes Medical Institute investigator. "It's like the key that starts the engine."

Reaper and the other Drosophila IAP antagonists Hid and Grim are known to trigger apoptosis in flies, and related proteins serve a similar function in humans and other mammals.

But exactly how and where Reaper initiates apoptosis has not been well understood. Sandu and colleagues bred genetically modified strains of flies that expressed variations on the Reaper protein specifically in flies' eyes.

This allowed them to assess the contribution of individual protein motifs to Reaper's apoptosis inducing powers, and what they found was that a particular helical domain was crucial for the formation of Reaper complexes, and could be modified to be even more powerful than the regular protein. The more deadly Reaper variants were obvious by the damage caused to the flies' eyes.

In a series of biochemical experiments, the researchers also found that Reaper must travel to the mitochondria, the cell's energy factories, to effectively deliver its death sentence, and that to get there, it must hitch a ride on the Hid protein, with which it interacts.

By tagging Hid and Reaper fluorescently, Sandu could visualize Hid and Reaper acting in a complex and gathering at the membrane of the mitochondria. When Reaper was engineered to go directly to the mitochondrial membrane, it resulted in a molecule that is far superior at triggering cell death than regular Reaper.

Further experiments suggested that in a complex with Hid, Reaper is protected from degradation as the cells began to die.

"So now we have Hid and Reaper working very closely together," Sandu says. "And the localization to the mitochondria is crucial to the initiation of apoptosis."

Drugs that mimic a small part of the function of Reaper are already in clinical trials. The discovery of a way to make Reaper a much better killer, namely by targeting it directly to the mitochondria, provides new avenues to explore for improving cancer therapies.

"Adding this element that takes Reaper directly to the mitochondria is not something people would have thought of before this," Steller says.

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Proteins regulating water retention in salt-sensitive hypertension identified

Friday 25 October 2013

Islamabad, Oct 26 (Newswire): Research conducted by scientists at LSU Health Sciences Center New Orleans has found that two proteins in the brain act as valves to turn the hormone that regulates water retention in the body on and off.

Their findings may lead to advances in treatment for diseases like high blood pressure, congestive heart failure, and cirrhosis of the liver.

Daniel Kapusta, PhD, Professor of Pharmacology at LSU Health Sciences Center New Orleans, and Richard Wainford, PhD, LSUHSC Instructor of Pharmacology, report the role of these brain proteins, called Gaq and Gaz, in producing elevated secretion of the hormone, vasopressin, and water retention in salt-sensitive hypertension, a condition in which blood pressure becomes elevated when salt is consumed. It is estimated that salt-sensitive hypertension occurs in about 26% of Americans with normal blood pressure and in 58% of those whose blood pressure is already high.

"Throughout the day, vasopressin, a peptide hormone produced by the hypothalamus, is released into the circulation from the pituitary gland and plays a vital role as the flood-gate keeper to prevent excessive loss of water from the kidneys," notes Dr. Kapusta.

"Under most conditions, the water-retaining action of vasopressin is vital for survival. However, it has remained essentially a black box as to why, in susceptible individuals, the regulatory mechanisms that control vasopressin secretion cannot turn off when the body already has elevated water content."

For 21-days, the research team fed groups of male salt-resistant and salt-sensitive rats a diet containing either normal or high salt. Then they measured how the treatments influenced the animal's ability to excrete water and how the salt stress altered levels of vasopressin, Gaq and Gaz.

The consumption of high salt triggered a decrease in Gaq proteins in the brain of salt-resistant, but not salt-sensitive, rats. In salt-sensitive rats, the team demonstrated that reducing brain Gaq proteins returned plasma vasopressin to normal levels, decreased salt-induced water retention, and restored the animal's ability to excrete water.

"Our findings are novel and provide evidence that the Gaq sub-unit proteins in the hypothalamus act as a molecular/cellular switch to control the level of vasopressin secretion," says Dr. Wainford.

The researchers concluded that reducing brain Gaq proteins plays a critical counter-regulatory role in preventing the secretion of too much vasopressin in those with salt-resistance and may represent a new therapeutic target in diseases associated with fluid retention.

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