For Mike Harris, life is good.
"I'm alive today because of a clinical trial," he says of a Phase I study he entered at MD Anderson four years ago for his myelofibrosis, a rare blood cancer that had no standard treatment at the time.
Last year, he and wife Sandy celebrated their 45th wedding anniversary. They live in Kingwood, north of Houston, near their son's family, and enjoy strong connections to their two grandchildren.
First sign of hope
The drug Harris received on that earliest-stage study -- and has taken ever since -- went on to become in November 2011 the first drug ever approved by the U.S. Food and Drug Administration to treat myelofibrosis.
Srdan Verstovsek, M.D., Ph.D., associate professor in MD Anderson's Department of Leukemia, led that Phase I study and was principal investigator on every U.S. clinical trial for ruxolitinib, developed by Incyte Corporation. It is known commercially as Jakafi™.
Recently by Scott Merville
For Mike Harris, life is good.
Identifying, removing and analyzing a few select lymph nodes often tells the tale
A 38-year-old woman comes to her dermatologist with a mole on her right upper back that has begun to itch and bleed. Examination shows that the mole has irregular borders and varied coloration. A biopsy reveals that it's a melanoma, 2.8 mm deep and with ulceration. There were no clinical signs or symptoms indicating that the melanoma had metastasized. A surgical oncologist recommends wide excision of the primary tumor site and a sentinel lymph node biopsy.
This case, paraphrased, opens an invited article in the May 5 issue of the New England Journal of Medicine by two MD Anderson surgeons. It provides a clinical update on a surgical lymph node biopsy technique that facilitates evaluation of possible microscopic spread of melanoma and indicates who needs further treatment.
MD Anderson was one of the first institutions to use sentinel lymph node biopsy, 20 years ago for melanoma and expanding into other cancer types.
"Sentinel lymph node biopsy allows us to obtain more information in the setting of less invasive surgery than our historical approach," says Jeffrey Gershenwald, M.D., co-author with Merrick Ross, M.D., both professors in the Department of Surgical Oncology. "And this allows a more personalized approach to surgery for our patients."
After years of failure in the treatment of advanced melanoma, two new drugs have emerged that help patients with one of the most deadly and difficult-to-treat cancers.
The experimental drug PLX4032 targets a specific genetic mutation found in the tumors of about half of all patients. Ipilimumab, an antibody that stimulates an immune system attack on melanoma, recently was approved by the U.S. Food and Drug Administration for treatment of the disease.
Like the plastic tips on shoelaces, telomeres sit at the end of chromosomes, protecting them from unraveling telomeres are protective, preventing harmful damage to DNA on the chromosome and inappropriate fusion with other chromosomes.
These caps grow shorter over time and as that occurs, they become associated with diseases of aging, such as Alzheimer's disease, stroke and some cancers.
Evidence has indicated that there's an inherited factor that helps determine telomere length and that short telomere length is a risk factor for cancer. No one had ever connected the two, until now.
MD Anderson researchers followed a surprising clue to discover that a known cancer-fighting protein also limits the growth of cells damaged by reactive oxygen species, one type of the highly reactive molecules known as free radicals.
Their groundbreaking paper in the Proceedings of the National Academy of the Sciences won the Cozzarelli Prize Tuesday as the best paper in the Biological Sciences category published in the Proceedings during 2010. The prizes are given to the top paper in six categories out of more than 3,700 studies published by the journal each year.
Cheryl Walker's research team was studying one tumor-suppressing protein when they found another protective protein known to work inside the cell nucleus moonlighting in another part of the cell.
Following up on this surprise, they found the cancer-blocking nuclear protein ATM has a second job controlling and killing damaged cells out in the area between the nucleus and the cell membrane called the cytoplasm. ATM recognizes damage caused by reactive oxygen species and tells the injured cells to stop growing or orders them to devour themselves, a process called autophagy.
Elevated ROS has been linked to more than 150 diseases, including diabetes, cancer, neurodegenerative diseases and atherosclerosis. ATM is commonly mutated in cancer.
Previously, ATM was known to monitor DNA damage in the nucleus, halt cell division and order the cell to repair the damage. If repair fails, ATM sets off apoptosis -- programmed cell death.
"The Cozzarelli Prize is wonderful recognition of research that brought to light a brand new aspect of cell biology and marked a new direction for our lab," says Walker, a Ph.D. and professor in the Department of Molecular Carcinogenesis, located at MD Anderson's Virginia Harris Cockrell Cancer Research Center, Science Park, near Smithville, Texas.
"Discovery of ATM's additional anti-tumor role is the type of basic science research that heightens our understanding of cancer and paves the way for improved prevention and treatment," says Raymond DuBois, M.D., Ph.D., MD Anderson provost and executive vice president. "The Cozzarelli Prize is a great honor for Cheryl, her lab and MD Anderson.
"The award also highlights the opportunities available for graduate students at MD Anderson," DuBois says. Co-first author Angela Alexander is a doctoral student in The University of Texas Graduate School of Biomedical Sciences, which is operated jointly by MD Anderson and The University of Texas Health Science Center at Houston (UTHealth).
The PNAS paper can be read here.
MD Anderson news release about the paper: Researchers Discover Second Protective Role for Tumor-Suppressor
People with higher levels of folate in their red blood cells were more likely to have two cancer-preventing genes shut down by methylation -- a chemical off switch for genes, researchers report this week in the December issue of Cancer Prevention Research.
DNA hypermethylation, notes co-author Jean-Pierre Issa, M.D., professor in MD Anderson's Department of Leukemia, is found in a variety of cancers and diseases of aging. Methyl groups attach to genes, protruding like tags, preventing gene expression.
"Our new finding is that having high levels of folate in the blood as observed in a sensitive measure of red blood cell (RBC) folate is related to higher levels of DNA methylation," Issa says.
Folate is a natural B vitamin that plays a role in DNA creation, repair and function, as well as red blood cell production. Pregnant women who have a folate deficiency are at elevated risk of having a child with neural tube defects, which occur when the spinal cord or brain fail to fully close.
Folate's found in leafy vegetables, fruits, dried beans and peas. Since 1998 its synthetic version, folic acid, has been added to breads, cereals, flours, pastas, rice and other grain products under order from the U.S. Food and Drug Administration, reducing the rate of neural tube defects in the United States.
The recommended daily requirement is 400 micrograms for adult men and women from a balanced diet and an additional 400 for women capable of becoming pregnant. Folate also is taken as a dietary supplement.
Folate's effect on cancer, once thought to be mainly preventive, has become less clear in recent years, with scientists finding cancer-promoting aspects of folate intake in colorectal and other cancers.
The research team analyzed the association between folate blood levels and dietary and lifestyle factors on DNA methylation in normal colorectal tissue. They enrolled 781 patients from a parent clinical trial that compared folate to aspirin in the prevention of precancerous colorectal polyps.
The genes, ERα and SFRP1, are expressed in normal colorectal tissue but silenced by methylation in colon cancer. They also have been found to be methylated in breast, prostate and lung tumors.
Age was strongly associated with increased methylation -- a finding that confirmed longstanding research. Neither folate nor aspirin treatment had a significant effect. However, RBC folate was associated with methylation of both genes with significant differences emerging between the top quarter of patients with the highest RBC folate count and the bottom quarter with the lowest. RBC folate levels closely reflect long-term folate intake.
"These differences were not trivial. They were the equivalent of 10 years of extra aging for those with high RBC folate counts," Issa says.
"Today, it's worrisome that taking extra folate over the long term might lead to more DNA methylation, which then might lead to extra diseases including potentially an increased chance of developing cancer and other diseases of aging," Issa says.
As cozy as it looks, the scene pictured here is one that oncologists prefer to break up. The purple cells are chronic lymphocytic leukemia cells and they are being nourished by the green cell, appropriately called a nurse-like cell.
Jan Burger, M.D., assistant professor in Leukemia at MD Anderson, discovered nurse-like cells as a post-doctoral fellow. Now he, graduate student Julia Hoellenriegel and colleagues have shown that an experimental drug called CAL-101 interferes with this connection and also directly attacks the abnormal B cells that cause CLL.
(B cells are white blood cells that fight infection. CLL is the most common form of leukemia.)
The drug works by jamming chemical signals -- chemokines and cytokines -- produced by B cells, including those that communicate with nurse-like cells. The nurse-like cells are part of CLL's microenvironment -- external factors that support cancer and need to be suppressed. In this case, external signaling is transmitted by PI3Kδ, part of a signaling pathway often involved in cancer development, and the drug's target.
CAL-101, developed by Calistoga Pharmaceuticals, also kills malignant cells by forcing them to commit suicide -- a process called apoptosis.
"We've identified a central mechanism of action of this drug," Burger says. "It blocks B cell antigen receptor signaling and BCR-derived survival signals."
Hoellenriegel presented their findings at the 52nd American Society of Hematology Meeting in Orlando Sunday evening. Only involved in this field for a year, Hoellenriegel held her own in a room full of CLL experts.
In a series of lab experiments, the researchers found that the drug reduced CLL cell viability and steeply cut the production of a number of important chemokines. They then treated CLL cell cultures with either CAL-101, the chemotherapy drug bendamustine, or a combination of both. By itself, CA-101 produced a 20% reduction in cells compared to untreated controls. Bendamustine alone cut the cells by 30%. Together, they pushed the cell count down by more than 40%.
Separately, plasma samples from 14 patients treated with the drug also showed sharp reductions in cytokine levels. For example, one of these, CCL3, fell from 186 picograms per milliliter to 29 pg/mL 28 days after treatment.
Burger is co-principal investigator on a soon-to-open Phase II study at MD Anderson of CAL-101 and rituximab in elderly patients with no previous treatment. "We will further explore the drug's activity in CLL patients," Burger says.
Hodgkin's lymphoma is one of the more curable cancers. About 75% of patients are cured by initial therapy.
However, for those failed by chemotherapy, there is no standard therapy. New drugs moving through clinical trials at MD Anderson appear to provide an answer for resistant or relapsed Hodgkin's lymphoma.
Two MD Anderson patients and two oncologists from the Department of Lymphoma/Myeloma talk about the latest developments at Patient Power
Breakthroughs in Lymphoma from Patient Power® on Vimeo.
Follow Dr. Younes on Twitter
Targeted therapy for chronic myeloid leukemia is one of the great success stories of cancer treatment.
CML is driven by an abnormal chromosome that creates a hybrid gene called bcr-abl that produces a protein which causes and fuels the disease. This abnormality is called the Philadelphia chromosome because it was discovered by scientists in that city.
Only half of CML patients survived to the five-year mark. Imatinib, known as Gleevec, changed all of that. Scientists at the Oregon Health Sciences University discovered the drug's effect on CML and worked with Novartis, the drug's owner, to develop Gleevec. Clinical trials were conducted largely at MD Anderson.
The result: 90% of patients survive to five years. However, some patients have their disease grow resistant to the drug. And for those with a mutation called T315I, the drug does not work. This held true for second-generation drugs -- nilotinib (Tasigna) from Novartis and dasatinib (Sprycel) from Bristol-Myers Squibb.
A new, experimental drug called ponatinib appears to hit all versions of CML. Jorge Cortes, M.D., professor in the Department of Leukemia at MD Anderson, presented Phase I results Monday morning at the American Society of Hematology Annual Meeting in Orlando.
Developed by ARIAD Pharmaceuticals, ponatinib cleared CML cells from the blood in 30 of 32 patients in the chronic, early stage of the disease. All 11 chronic phase patients with T315I had that hematological response. Eight had complete cytogenetic response, which means absence of malignant cells in the bone marrow.
"Ponatinib seems to be filling the gap we had for patients who right now have no good treatments left," Cortes says. "We are very encouraged by such strong results in the Phase I setting and have begun a pivotal Phase II clinical trial."
For more detail on results please see the abstract
American Society of Hematology 2010 Meeting and Expo
MD Anderson experts covered multiple aspects of cancer prevention at the American Association for Cancer Research Frontiers in Cancer Prevention meeting.
Powel Brown, M.D., Ph.D., professor and chair of MD Anderson's Department of Clinical Cancer Prevention, chaired a session on novel targets and strategies for breast cancer prevention.
In an AACR video interview, he also discusses early detection, the role of growth factors and hormones in the growth and metastasis of breast cancer and external risk factors for the disease that women can modify to help prevent it.
Provost and Executive Vice President Ray DuBois, M.D., Ph.D., presented a wide-ranging report on a joint think tank between AACR and the National Cancer Institute about the future of cancer prevention.
In a subsequent video interview with AACR, DuBois highlighted three areas among many addressed by the project:
- Ensuring adequate federal funding for prevention clinical trials, which by their nature take longer than clinical trials that test new treatments.
- Engaging pharmaceutical companies in chemoprevention development, which is expensive, time-consuming and has a higher bar for side effects than therapeutic trials.
- Building public awareness of how cancer begins and develops and how to prevent it.
He also addresses possible scientific priorities for Stand Up to Cancer.
Follow Ray DuBois, M.D., Ph.D. on Twitter
Just as cancer treatment is becoming more tailored to better strike a patient's tumor with minimal side effects, so cancer prevention is on the path to a more personalized approach.
Scott Lippman, M.D., professor and head of MD Anderson's Department of Thoracic/Head and Neck Medical Oncology, led a plenary session on the topic at the annual meeting this week of the American Association for Cancer Research Frontiers in Prevention in Philadelphia.
"We focused on various biomarkers that predict a person's cancer risk or response to a preventive intervention that are in clinical trials or are very close to clinical trial," Lippman says.
Lippman cited a model of head and neck cancer risk prediction that combines behavioral and medical history factors with genetic variations associated with susceptibility to recurrence or development of a secondary cancer. He reviewed research by Xifeng Wu, M.D., Ph.D., professor in MD Anderson's Department of Epidemiology, and colleagues that has honed the model's predictive ability by steadily adding single-point genetic variations that are linked to a patient's vulnerability to recurrence or a new cancer.
"We are moving toward having the ability to put individuals in specific risk groups that reflect their likelihood to benefit from an intervention, not only in chemoprevention but also with other interventions, such as smoking cessation options," Lippman says.
He covers these topics, including challenges to personalized prevention and other issues in a video podcast filmed at AACR. Lippman also is editor in chief of the AACR's journal Cancer Prevention Research.
Lippman also moderated a news briefing on the emerging science of chemoprevention Monday. That podcast also is available from AACR.
The Emerging Science of Chemoprevention
Moderated by Scott Lippman, M.D., editor-in-chief of Cancer Prevention Research and professor and chair in the Department of Thoracic/Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center.
Links to releases about work presented at the AACR briefing:
Krystal Sexton, Ph.D., talked to Time Magazine about her research last Friday morning, then reviewed it again for a room full of colleagues, friends and family that afternoon to complete the final step for her doctorate.
Monday, her results were displayed on a poster at the annual American Association for Cancer Research Frontiers in Prevention meeting in Philadelphia.
"Obviously, we aren't recommending that women go out and gain weight," Sexton said. "These results are preliminary and need to be validated in a larger study. Obesity remains a risk factor for cardiovascular disease."
Sexton studied 148 Mexican-American women who had breast cancer and 330 in a control group who did not have it. "We found that risk fell by 8 percent for every 5 kilograms (11 pounds) gained," Sexton said. Weight was analyzed at ages 15, 30 and at diagnosis or an equivalent age in controls.
One hypothesis for the risk reduction: Women who are overweight or obese enter menopause earlier, which reduces their lifetime exposure to estrogen, thus decreasing their cancer risk. Women who did not have breast cancer in Sexton's study entered menopause two years earlier.
Her study highlights an important point, that you can't study one population group and assume that the findings apply to others. Most previous research showed that obesity reduces breast cancer risk for premenopausal women and increases risk for post-menopausal women, but focused on non-Hispanic white women almost exclusively.A massive literature search by Sexton turned up hundreds of studies of white women, but only a handful that looked at Mexican-American or African-American women.
Sexton said her career will be devoted to understanding such health disparities. She will continue the breast cancer study as a postdoctoral fellow working with Melissa Bondy, Ph.D., professor in MD Anderson's Department of Epidemiology in the Division of Cancer Prevention and Population Science.
She conducted her research with Bondy as a Susan G. Komen fellow in breast cancer disparities research at The University of Texas Health Science Center at Houston (UTHealth) School of Public Health.
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- Patient enjoys life, thanks to right drug for his rare cancer
- Interrogation of Sentinel Lymph Nodes Finds Hidden Metastatic Melanoma
- New Melanoma Drugs Raise Hopes, But More Choices Needed
- Gene Variation Links Lower Bladder Cancer Risk, Long Chromosome Tips
- Discovery of Protein's Doubly Protective Role Wins Research Prize
- High Red Blood Folate Levels Linked to Silenced Tumor-Suppressors
- Scientists Find Drug Scrambles Signals of CLL and Its Food Source
- Doctors, Patients Discuss New Hope for Relapsed Hodgkin's Lymphoma
- New Drug Aims at Chronic Myeloid Leukemia That Resists Treatment
- DuBois and Brown Talk Cancer Prevention With AACR
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