Multitasking meds: Scientists discover how drug for leukemia, psoriasis, may tackle vascular disease

ScienceDaily (May 26, 2011) — A drug that has been on the market for decades to treat leukemia and skin disorders such as acne and psoriasis may be a possible therapy for vascular diseases, including atherosclerosis and hypertension, which can lead to heart attack or stroke.

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Previously, researchers discovered that retinoids -- commonly used natural or human-made drugs related to vitamin A -- blunted experimental vascular disease by spurring into action a very particular segment of a gene known for its ability to curb cancer cell growth.

The gene, usually shut off or silenced in cancer cells, enabling tumors to form, could be an attractive treatment target not only for vascular diseases, which involve the detrimental growth, spread and accumulation of cells in blood vessels, but for a wide range of cancers, which involve unchecked cell growth, as well.

In the journal PLoS One, a team of researchers led by Joseph M. Miano, Ph.D., associate director of the Aab Cardiovascular Research Institute at the University of Rochester Medical Center, found that a specific section of the complex AKAP12 gene, called AKAP12 beta, is extremely responsive to treatment with retinoids, and that ramping up its activity reduces vascular cell growth.

"Several studies have shown that when this gene is turned on, it decreases the growth of cancer cells, but this is the first time anyone's shown its ability to inhibit growth in non-cancer cells," said Miano, the study's lead author. "In addition to the vascular angle, we hope this work inspires researchers in different disciplines to see if our findings apply in other disease contexts."

A vascular biologist, Miano became interested in retinoids after people close to him battled cancer. When he learned that retinoids, which have several actions, including regulating cell growth, were a treatment option for some cancer patients, he wondered if they might have any use in treating diseases of blood vessels. Like cancer, vascular diseases such as atherosclerosis -- the narrowing of the arteries -- involve excessive cell growth and invasion. Such activities can lead to blocked arteries that obstruct blood flow.

Miano decided to give the idea a try, and in the late 1990's he showed in tissue and in an animal model of vascular disease that retinoids inhibited the growth of smooth muscle cells, which are found within the walls of vessels and contribute to atherosclerosis, which can lead to heart attack or stroke.

In the early 2000's, his team identified a number of genes that were activated or turned on by retinoids, one of which was AKAP12. Because research in the cancer field suggested it was a tumor suppressor gene, named for its ability to hinder cancer cell growth, Miano honed in on AKAP12 to see if it might be a target of retinoids in the context of vascular disease.

The team discovered that AKAP12 is a very complex gene, with three distinct DNA segments, named AKAP12 alpha, beta and gamma. Miano noted, "It is essentially like having three genes in one." Gene expression analyses revealed that the treatment of damaged vessels with retinoids immediately stimulated AKAP12 beta into action, while the alpha and gamma segments showed no response to the therapy.

"There are lots of tumor suppressor genes out there, and a few are mildly responsive to retinoids, but this is the first time we've seen a gene -- AKAP12 beta -- respond so early and so profoundly to retinoid stimulation," said Miano. "Without AKAP12 beta up and running, it is as if there are no brakes and the smooth muscle cells are free to grow. But when AKAP12 beta is amplified, the opposite is true, and we see major decreases in smooth muscle cell growth."

Once AKAP12 beta is switched into "go" mode by retinoids, the team believes it helps deter cell growth by reigning in and directing the action of specific signaling proteins that influence cell growth and migration. More research is needed to pin down the exact processes involved, and Miano hopes to pursue this work in the future by exploring animal models in which AKAP12 is eliminated or turned on with drugs.

According to Irwin H. Gelman, Ph.D., who was the first to identify the AKAP12 gene and has been studying its role in cancer for many years, "This study makes sense and is very consistent with what we've found in cancer cells, which is that AKAP12 is a prime driver to stop the proliferation of cells." Gelman, a study author who has worked with Miano for more than ten years, is the Palisano Chair of Cancer Genetics at Roswell Park Cancer Institute in Buffalo, New York.

"It may be possible that other diseases marked by inappropriate cell proliferation due to AKAP12 turn-off could also be reversed by retinoid treatment," added Gelman.

In addition to Miano, Jeffrey W. Streb, Xiaochun Long, Ting-Hein Lee, Qiang Sun, Chad M. Kitchen, Mary A. Georger, and Orazio J. Slivano from the Aab Cardiovascular Research Institute contributed to the research. Gelman, William S. Blaner, Columbia University, and Daniel W. Carr, Portland Veterans Affairs Medical Center participated in the research as well. The study was funded by the National Heart, Lung and Blood Institute at the National Institutes of Health and the Department of Veterans Affairs at the Veterans Health Administration.

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Stem cell treatment to prevent leukemia returning is a step closer, say scientists

ScienceDaily (June 3, 2011) — Researchers at King's College London have identified a way of eliminating leukemic stem cells, which could lead to new treatments that may enable complete remission for leukemia patients. An early study in mice has shown that leukemic stem cells can be abolished by suppressing two proteins found in the body.

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Leukemic stem cells sustain the disease and are likely to be responsible for relapse, so elimination of these cells is believed to be key for achieving complete remission. These encouraging findings highlight the two proteins as potential therapeutic targets to prevent the most aggressive forms of leukemia returning. The study, funded by Cancer Research UK and leukemia Lymphoma Research, is to be published in the journal Cell Stem Cell.

King's scientists looked at leukemic stem cells found in a type of leukemia that involves mutations of the MLL gene. This accounts for around 70 per cent of infant leukemias and 10 per cent of adult acute leukemias. The prognosis for MLL in children is not good -- only 50 per cent survive past two years after receiving standard treatment.

The protein Bmi1 was already known to play a key role in the survival and proliferation of various cancer stem cells. But this study has for the first time shown that, although the protein is needed for survival of various Acute Myeloid leukemia (AML) cells, in MLL leukemia the cancer stem cells actually survive independently of Bmi1. This shows that for these MLL patients, targeting Bmi1 alone would not have a major impact on eradicating leukemic stem cells, as was previously thought.

However, the team also found high levels of another protein called Hoxa9 in the MLL mice and human patients. Similar to Bmi1, a major role of this protein is to ensure leukemia cells divide and grow by allowing their escape from the inherent surveillance system, which will otherwise cause cell death. They found that in mice with MLL leukemic stem cells (that can proliferate without Bmi1), suppression of both Bmi1 and Hoxa9 completely abolishes the ability of MLL mutation to induce leukemia.

These findings provide evidence for the different pathways involved in the development of different types of leukemic stem cells, and highlight the importance of targeting Bmi1 and Hoxa9 together to abolish MLL leukemic stem cells in particular.

Professor Eric So, Head of the leukemia and Stem Cell Biology group at King's, said: 'These findings take us a step forward in our understanding of how this devastating disease can return in patients after they have received the standard treatment.

'Now we know that leukemic stem cells in certain types of leukemia, such as MLL, can survive and proliferate independently of the Bmi1 protein, we need to consider more carefully the future of stem cell therapy to treat the disease. It's not as easy as people originally thought it might be.

'But these findings provide us with vital information that will help us look at alternative ways of combating different forms of the disease, which will ultimately allow patients to achieve long-term complete remission.

'What we need to do now is to find out exactly how Bmi1 and Hoxa9 proteins sustains the growth of cancer cells in order to develop an effective treatment to stop the disease returning.'

Professor Peter Johnson, Cancer Research UK's chief clinician, said: 'This study builds on previous Cancer Research UK-funded work trying to pinpoint the molecules responsible for driving the development of MLL-related leukemia stem cells.

'Cancer stem cells appear to be more resistant to radiotherapy and chemotherapy than the other leukemia cells, so understanding how they originate -- and how we can kill them -- will be a major step in being able to help even more people survive leukemia in future.'

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Antibody-guided drug works against acute lymphoblastic leukemia

ScienceDaily (May 24, 2011) — An antibody packaged with a potent chemotherapy drug to selectively destroy acute lymphoblastic leukemia (ALL) cells eradicated or greatly reduced the disease for 61 percent of 46 patients in a phase II study. It will be presented at the 47th annual meeting of the American Society of Clinical Oncology in Chicago June 3-7.

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Patients enrolled in the trial led by investigators at The University of Texas MD Anderson Cancer Center had ALL that resisted other therapies or recurred after treatment.

"A response rate of more than 50 percent in this patient population probably makes inotuzumab ozogamicin the most active single-agent therapy ever for ALL," said Hagop Kantarjian, M.D., professor and chair of MD Anderson's Department of Leukemia and study senior investigator.

ALL is an aggressive form of leukemia in which immature white blood cells, called lymphoblasts, grow rapidly, crowding out normal blood cells.

The drug, also known as CMC-544, links an antibody that targets CD22, a protein found on the surface of more than 90 percent of ALL cells, and the cytotoxic agent calicheamicin. Once the drug connects to CD22, the ALL cell draws it inside and dies.

Response rate for other second options is 20-30 percent

Kantarjian said second-line chemotherapy combinations used for ALL typically have a complete response rate of 20-30 percent. The monoclonal antibody-based drug developed by Pfizer, Inc., also is the first of its type for ALL.

The drug is safe, said Elias Jabbour, M.D., assistant professor in MD Anderson's Department of Leukemia, who will present the study results at ASCO on Monday, June 6. Almost all side-effects were of low grade (1-2) and manageable. Drug-induced fever was the most common side effect, reaching higher grades in nine of 48 patients.

Out of 46 patients evaluable for response, nine had a complete response, 14 had complete response without full recovery of platelets, and 5 had less than 5 percent blasts in their bone marrow without blood count recovery.

Sixteen responders subsequently received a donor blood stem cell transplant, Jabbour noted.

Drug combinations

Combining inotuzumab with other chemotherapy might further improve ALL treatment, Jabbour said. MD Anderson has a phase II clinical trial under way following inotuzumab treatment with another monoclonal antibody drug, rituximab, currently used in some types of non-Hodgkin's lymphoma.

Rituximab targets the CD20 surface protein, which occurs in 50 percent of ALL cells.

In addition to combinations, the authors suggest that a shift from dosing every three weeks to weekly should be explored.

Frontline therapy for ALL is a combination chemotherapy regimen known as HyperCVAD.

The National Cancer Institute estimates that 5,330 people received an ALL diagnosis in 2010 and 1,420 died of the disease.

ALL is the most common type of childhood cancer. Combined chemotherapy regimens have raised long-term survival from 5 percent of pediatric patients in the 1960s to 85 percent today.

The clinical trial was funded by a grant from Pfizer.

Co-investigators with Jabbour and Kantarjian are Susan O'Brien, M.D., Deborah Thomas, M.D., Farhad Ravandi, M.D., Sergernne York, Monica Kwari, Stefan Faderl, M.D., Tapan Kadia, M.D., Guillermo Garcia-Manero, M.D., and Jorge Cortes, M.D., of MD Anderson's Department of Leukemia; Christopher Wilson and Robert Tarnai, of PPD, Inc.; and Anjali S. Advani, M.D., of the Cleveland Clinic Taussig Cancer Institute.

Kantarjian and co-author Cortes receive research funding from Pfizer, and Cortes has been a consultant to the company.

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Study reveals need for personalized approach in treatment of acute myeloid leukemia

ScienceDaily (May 16, 2011) — A new discovery in mice by researchers at Wake Forest Baptist Medical Center may one day allow doctors to spare some patients with acute myeloid leukemia (AML) from toxic treatments, while also opening the door for new therapeutic research.

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AML, the most common form of acute leukemia seen in adults, is an aggressive form of cancer that primarily affects the elderly. Despite years of research, outcomes for most patients remain poor, particularly for one subset of patients with a specific mutation of the FLT3 receptor.

At a microscopic level, each cell's surface is covered in proteins that allow for signals on the outside of a cell to "turn on" various activities inside that cell. FLT3 is one of those receptor proteins. Mutations of the FLT3 receptor are among the most common mutations seen in the disease -- affecting about 20 to 30 percent of AML patients -- and have been associated with worse prognosis.

A new study, published recently in the journal Experimental Hematology, reveals that one particular mutation of the FLT3 receptor, called internal tandem duplication (ITD), alters the patient's responsiveness to standard therapy.

"This research uses a mouse model to define the changes in chemotherapy response that the presence of the FLT3-ITD causes," said Timothy S. Pardee, M.D., Ph.D., an assistant professor of hematology and oncology and lead author of the study. "While its affect on prognosis has been well documented, its affect on therapy response has been poorly understood."

Pardee and colleagues used mice that had leukemia, either with or without the FLT3-ITD, to examine the effects of the mutation on responsiveness to two drugs used in combination as standard chemotherapy treatment for AML patients: cytarabine and doxorubicin. Both drugs work by altering the DNA of cells in different ways, causing them to essentially commit suicide.

The researchers found that the presence of the FLT3-ITD mutation makes cells resistant to doxorubicin, but makes them extra sensitive to cytarabine, when the drugs are administered separately. More importantly, the mutation causes the cells to be resistant overall to the combination of the two drugs, the most common clinical application.

When the mutation occurs, it is a cancer-initiating event. The receptor is no longer able to turn itself off, so it continuously signals the cells to grow and repair damage, such as the damage intentionally caused by doxorubicin.

"The mice who had this mutation seemed to be able to repair certain kinds of DNA damage, specifically, the double strand DNA breaks that the doxorubicin creates," Pardee said. "The FLT3-ITD mutation is telling the cell to repair itself at a pace that keeps up with the amount of damage the drug is designed to cause. If you have a cancer cell that you're trying to kill by doing a certain type of damage and that cell is better at repairing that kind of damage, you have to do more damage to get the cell to die. The mice that were treated with just doxorubicin died at the same rate as those that received no treatment at all."

And, while the FLT3-ITD mutation seems to make cells more sensitive to the impact of cytarabine when exposed to just the one drug, the mutation lessens the impact of the combination of the two drugs together.

"It's almost like the doxorubicin is protecting the cancer cells somewhat from the impact of the cytarabine, which is trying to kill the cell," Pardee said. "When this mutation is present, there is no benefit to adding the doxorubicin. The amount of leukemia does not lessen with the use of it."

Doxorubicin falls into a class of extremely toxic drugs known as anthracyclines. As with other chemotherapy agents, they are known to cause hair loss. However, they are also known to suppress normal cells in the bone marrow and to cause cardiac toxicity. Treatment with drugs of this class can directly injure the heart muscle and sometimes even cause heart failure, Pardee explained.

"Virtually every AML patient in America and Europe who can handle this combination of drugs will receive this standard treatment under current practice guidelines," Pardee said. "More studies are needed to determine the applicability of these findings in humans, but this study shows, in an animal model, that those with the FLT3-ITD mutation are deriving no benefit from the addition of doxorubicin.

"We're hopeful that in the future, these findings will lead to more personalized patient care," he said. "The 'one-size-fits-all' approach to treating AML needs to be re-examined."

In addition to investigating ways to personalize approaches in treatment, Pardee said that future research may focus on developing drugs that can be combined with cytarabine in patients with this mutation and be effective, perhaps by inhibiting the FLT3 receptor or working in ways other than creating double strand DNA breaks.

This research was funded by several sources including the Leukemia and Lymphoma Society, National Cancer Institute, and Wake Forest University Comprehensive Cancer Center. Johannes Zuber, M.D., and Scott W. Lowe, Ph.D., of the Cold Spring Harbor Laboratory, in New York, appear as co-authors on the paper. Lowe is also affiliated with Howard Hughes Medical Institute, in New York.

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Key to fighting drug-resistant leukemia discovered

ScienceDaily (May 18, 2011) — Doctors who treat children with the most common form of childhood cancer -- acute lymphoblastic leukemia -- are often baffled at how sometimes the cancer cells survive their best efforts and the most powerful modern cancer drugs.

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Now a team of scientists led by researchers at the University of California, San Francisco has uncovered the basis for this drug resistance: BCL6, a protein that leukemia cells use to stay alive. Targeting this protein may be the key to fighting drug-resistant leukemia, a discovery that may make cancer drugs more powerful and help doctors formulate powerful drug cocktails to cure more children of leukemia.

"We believe this discovery is of immediate relevance to patient care," said Markus Müschen, MD, PhD, a professor of laboratory medicine at UCSF and the senior author on the study.

As described in the journal Nature this week, Müschen and his colleagues showed that mice with drug-resistant leukemia can be cured of the disease when given conventional cancer drugs in combination with a compound that disables the BCL6 protein. This compound was initially developed by Ari Melnick, a professor of pharmacology at the Weill Cornell College of Medicine in New York and a co-author of the study.

A Common Form Of Cancer In Children

Acute lymphoblastic leukemia is the most common form of cancer in children and accounts for about 23 percent of all cases of cancer in children under the age of 15, according to the National Cancer Institute.

In this form of cancer, leukemia cells in the bloodstream and bone marrow continuously multiply, crowding out other, healthy cells. The disease progresses rapidly, and the leukemia cells begin to infiltrate tissues in other parts of the body. Treatment is neither cheap nor easy -- but it can be miraculous. It usually involves a long course of drugs that can be physically and emotionally taxing for the children and their parents. Once finished, many enjoy complete remission and are able to live cancer-free, cured of the leukemia.

Still a large number of children are not cured and ultimately succumb to the disease. In those cases, some of the cancer cells resist the therapy and survive quietly in the body. When the cancer reemerges, it is no longer sensitive to the drugs.

In their new report, Müschen and his colleagues show that the key to this resistance is the protein BCL6, offering the first evidence of how the cancer cells managed to survive.

"It is something like an emergency mechanism whereby tumor cells try to evade drug-treatment," Müschen said.

One Among 22,000 Genes

The work started four years ago when Müschen wanted to figure out what happens to cancer cells during cancer treatments. He and his colleagues exposed leukemia cells in the petri dish to drugs and then looked at how they responded to the treatment. They analyzed how the expression of 22,000 different genes changed when different cancer cells were given different drugs, and they found that BCL6 levels always rocketed up following treatment.

The BCL6 protein was already known to cancer researchers because it is active in other forms of cancer. In lymphoma, for instance, BCL6 protects cancer cells from dying, and the protein has long been the target for research and drug design. But it had never been connected to leukemia.

Reasoning that blocking BCL6 would make leukemia cells more sensitive to chemotherapy, the scientists showed exactly that. Working with Melnick and colleagues at Weill-Cornell Medical College in New York City who had developed a biotech drug-like peptide that blocks BCL6, they showed that giving the peptide to mice along with anti-leukemia drugs increased the potency of conventional drugs and helped the mice survive the disease.

Now Müschen is looking for ways to do the same thing with small molecules, which are generally easier to formulate into an oral drug and cheaper to mass produce than biotech drugs like peptides.

Last year, he was awarded a $3.6 million grant from the California Institute for Regenerative Medicine (CIRM) to develop such a molecule.

The article was authored by Cihangir Duy, Christian Hurtz, Seyedmehdi Shojaee, Leandro Cerchietti, Huimin Geng, Srividya Swaminathan, Lars Klemm, Soo-mi Kweon, Rahul Nahar, Melanie Braig, Eugene Park, Yong-mi Kim, Wolf-Karsten Hofmann, Sebastian Herzog, Hassan Jumaa, H. Phillip Koeffler, J. Jessica Yu, Nora Heisterkamp, Thomas G. Graeber, Hong Wu, B. Hilda Ye, Ari Melnick and Markus Müschen.

In addition to scientists at UCSF and Weill Cornell Medical College in New York City, the team included researcher at the Children's Hospital Los Angeles and University of Southern California, Universitatsklinikum Hamburg-Eppendorf in Hamburg, Germany, Cedars Sinai Medical Center in Los Angeles, the Albert-Ludwigs-Universitat Freiburg and Max-Planck-Institute for Immunobiology in Freiburg, Germany, Universitat Heidelberg, Klinikum Mannheim, Mannheim, Germany, Albert Einstein College of Medicine in New York City, and the University of California, Los Angeles.

This work was supported by grants from the National Institutes of Health and the National Cancer Institute, grants from the Leukemia and Lymphoma Society, the California Institute for Regenerative Medicine, the William Laurence and BlancheHughes Foundation and a StandUp To Cancer-American Association for Cancer Research Innovative Research Grant. Markus Müschen and Ari Melnick are Scholars of the Leukemia and Lymphoma Society.

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Ex-Dallas Maverick survives rare form of leukemia thanks to experimental drug treatment

ScienceDaily (May 19, 2011) — Ray Johnston's goal in three years is for his band to sell out at the 1,600-seat House of Blues in Dallas. In eight years, he wants to pack the 6,400-seat Verizon Theatre in Grand Prairie, and by 2030, to play to tens of thousands of fans at Cowboys Stadium in Arlington.

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Mr. Johnston's unmentioned goal, though, is to live another year after battling leukemia for the past seven. Despite four relapses, the former Dallas Mavericks basketball player is enjoying life as a rising musician in The Ray Johnston Band.

Although he credits God for his recovery, Mr. Johnston also gives thanks to Dr. Robert Collins, director of the Bone Marrow Transplantation/Hematologic Malignancies Program at UT Southwestern Medical Center, and the experimental drug that has killed his rare, stubborn form of cancer called acute promyelocytic leukemia.

"It's got to be inspiring to Dr. Collins to see that I'm alive because I'm supposed to be done by now," Mr. Johnston said of his painful yet rewarding journey, which was chronicled last year in an HDNet series called "Ray Johnston Band: Road Diaries."

Today, Mr. Johnston's self-described "happy rock" Dallas band is working on its second CD and booking about 100 shows a year. "My primary goal is to keep playing," Mr. Johnston said.

Tamibarotene, the drug that's kept the 32-year-old musician alive, is a retinoid drug that induces cancer cells to differentiate into mature cells and eventually die. Available only in clinical trials in the U.S., tamibarotene was sought for Mr. Johnston under a compassionate use protocol since he did not qualify for those studies and other treatments had been exhausted. The drug, approved only in Japan for cancer treatment, is being developed domestically by CytRx.

"It's amazing that he's still doing so well," said Dr. Collins, professor of internal medicine and senior author of a report on this case published online April 11 in the Journal of Clinical Oncology. "This drug happens to be just right for him."

Mr. Johnston's treatment with tamibarotene, which is considered 10 times more potent than all-trans retinoic acid, another retinoid commonly used to treat this type of leukemia, began in December 2009. He took the drug twice daily for 56 days, followed by a two-week break. Since then, Mr. Johnston has been taking the drug 28 days on, 28 off.

On April 18, he returned to UT Southwestern for a positron emission tomography (PET) scan, which showed his cancer had not relapsed for the fifth time.

"The type of acute leukemia he has is very rare. It's usually curable with current therapies, but as it relapses it becomes more resistant and harder to treat," said Dr. Collins.

Gambling on life, and success as a musician, doesn't scare the Alabama native who once dreamed of a professional basketball career. But cancer ended his NBA stint, which began when he won a spot on the Dallas Mavericks summer league roster during a Hoop It Up tournament in 2004.

Mr. Johnston didn't even know he had leukemia until that August, when he injured his leg in a pick-up game. He was diagnosed with compartment syndrome, a condition in which pressure in the muscle builds to dangerous levels. Following surgery, doctors were unable to control bleeding. They soon discovered that Mr. Johnston's body was riddled with advanced leukemia.

His treatment included chemotherapy, surgery and a bone marrow transplant. Mr. Johnston's type of leukemia, which affects soft tissues rather than blood and bone marrow, represents just 5 percent to 8 percent of acute myelogenous leukemia, the most common form of the disease.

Discouraged by failing treatments and the thought of his first bone marrow transplant, he nearly gave up hope. In 2006, a recommendation from a friend led him to Dr. Collins and UT Southwestern.

"When you achieve a life milestone that you're not supposed to, when you hug it out, you can see and feel Dr. Collins drop a tear on your shoulder. That's life. That's real," said Mr. Johnston.

Reality for this cancer survivor also means getting serious about music. Mr. Johnston has a lot of work ahead after launching the six-member band in September 2009. Some of the band's performances raise money for The Ryan Gibson Foundation, a Dallas-based nonprofit dedicated to leukemia research.

One of the songs on the band's first CD, "Sweet Tooth," is Rise & Go, based on a verse in the Bible, Luke 17:19. Mr. Johnston said it sums up "my last seven years."

"Wake up and I go outside, I see my blue sky, I'm happy to be alive … I got a tough upper lip, but a bottom little broken heart. When I look into the sky, I see my Maker's eyes. That's when I know my Plan B for eternity is strong as gold, so I rise and go.

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