Recently in Discovery Category

Phase I clinical trials of patients with advanced cancers indicate that testing their tumors for a cancer-promoting genetic mutation is feasible in clinical practice and could be used to guide treatment.

Early results also show promising signs of an improved response rate among patients treated with drugs that inhibit the molecular pathway that is switched on by a mutation in the PI3CA gene.

Filip Janku, M.D., a fellow in M. D. Anderson's Department of Investigational Cancer Therapeutics, presented new findings on the PI3CA gene this week at the a major conference in Boston - the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

Mutations in the gene turn on the PI3K-AKT-mTOR pathway, which is often abnormally activated in cancer cells.  

Of 117 tumors tested from people with various late-stage cancers, 14 had the mutation and 10 of those were treated with PI3K-AKT-mTOR inhibitors based on that genetic analysis. Four of those 10 had partial responses, a high rate for a Phase I clinical, yet Janku notes the trial numbers are too small to draw conclusions now.

"These results need to be confirmed in a larger number of patients," Janku says. "We will have that opportunity as we continue to offer PI3K screening to patients considering a phase I clinic trial."  So far, responses were observed in patients with endometrial cancer, ovarian cancer, and breast cancer.

The American Association for Cancer Research highlighted Janku's presentation in its news media program. The meeting is a combined effort of the AACR, the National Cancer Institute, and the European Organisation for Research and Treatment of Cancer.


Reprogramming Genes as Cancer Therapy

Jean-Pierre Issa, M.D., professor in the Department of Leukemia, and a leader in the field of epigenetics, discusses this very different approach to cancer therapy in a podcast from the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics.

"Cancer is as much an epigenetic disease as it is a genetic disease," Issa notes. Epigenetic factors cause changes of gene expression and cellular behavior in cancer that are quite apart from those caused by genetic mutations or damage. 

Issa studies these chemical influences on genes at the basic science level and has successfully translated his findings into the clinic. The podcast addresses the challenge of translational research as well as the case for epigenetic therapy.

Resources:

Read the News Release from AACR

November 18 Teleconferences and Podcast Recordings

Cancer eludes, suppresses or subverts the body's immune system to survive and grow. Scientists at M. D. Anderson have found that the helper T cell Th17 awakens the immune system to attack and destroy tumors with custom-made killer T cells. Professor of Immunology Chen Dong, Ph.D., and colleagues report their findings online today in the journal Immunity.  

Working with a mouse model of metastatic human melanoma tumors, the researchers show that the absence of Th17 led to virulent growth of melanoma in the lungs, while injecting Th17 cells prevented melanoma development and destroyed existing tumors. Th17 secretes the inflammatory protein interleukin-17 (Il-17), which launches the immune system response. 



"While there is much work to be done, these preclinical findings imply the possibility of taking a patient's Th17 cells, expanding them in the lab, and then re-infusing them as treatment," Dong says. Development of a vaccine to stimulate Th17 cells would be another possible application.

Dong is co-discoverer of Th17, one of only four known types of T helper cells that guide adaptive immune system response. His team also established that Th17 produces interleukin-17 and further showed that overexpression of IL-17 causes both autoimmune and inflammatory diseases.  

Th17's involvement in autoimmune disease is probably why it's able to recognize and attack cancer, which is also self tissue. "So a key to developing therapy will be to use Th17 cells that only recognize tumor antigens but do not react to normal tissue," Dong says.

Read the full news release
AAI Honors Chen Dong for Breakthrough T Lymphocyte Research

It takes some imagination to grasp the raw computational challenge researchers face trying to understand the molecular causes of cancer. John Weinstein, M.D., Ph.D., professor and chair of M. D. Anderson's Department of Bioinformatics and Computational Biology, likes to start with this imagery.

"If you unpacked the DNA in every cell of a single person and stretched it end to end, it would circle the equator 917,000 times -- the equivalent of 120 round trips to the sun. One error in replicating the genome in one unlucky place -- over a length of 120 trips to the sun and back -- can lead to cancer. Our challenges are to understand how that happens, and to know what to do about it if we can't prevent it in the first place."  

Now, consider that there are usually many more errors spread across that expanse and that they tend to interact with each other in a maze of complexity. Add current techniques to profile genetic expression and variation that capture a galaxy of data, and you have enough information to choke traditional methods of analysis.

The Cancer Genome Atlas, a federally funded project to make sense of the genetics that drive 20 different cancers, has enlisted Weinstein and colleagues at M. D. Anderson to help with this problem. A five-year, $8.3 million grant will allow the team to apply cutting-edge approaches to find the right buckets of information in an ocean of data.

They will blend agile software development, Bayesian statistics, and a flexible and efficient database infrastructure called semantic web with M. D. Anderson's expertise in clinical and translational research to compile the most meaningful data in a tumor's tangled molecular profile.

Success will mean better treatment choices, improved risk assessment, diagnosis and prognosis. "The bottom line is personalizing cancer medicine," Weinstein says.

By Susan Kelly M. D., Assistant Professor, Department of Pediatrics

What is cord blood?
When a baby is born, there are a high number of stem cells circulating in the blood that are generally discarded with the placenta. The primary responsibility of these stem cells (what we refer to as umbilical cord blood or cord blood) is to make components of blood -- red blood cells, white blood cells and platelets.

Cord blood can be collected and stored in liquid nitrogen for years and later used for transplants. There are public banks, where mothers can donate the cord blood for use by anyone who needs a transplant (at no charge). There also are private cord blood banks that allow a family to store their baby's cord blood for use by someone in the family (the family pays for its collection and storage). The cord blood units stored in public banks are searchable through a computer registry that's accessible throughout the world.

Cord blood transplants
The first transplant using umbilical cord blood was done in 1988. Since then, thousands of transplants have been performed using cord blood as the source of stem cells.

Why is this important? The first choice for a stem cell donor is usually a perfectly matched sibling (or other matched family member). We look at markers on the cells called HLA types (different than blood type) to see how closely a patient and potential donor match. Matched cells from a family member have a higher chance of taking (engrafting) and cause fewer side effects, such as graft-versus-host disease (GVHD), where the transplanted cells attack their new "host." 

However, as families are changing and getting much smaller, the chance of having a fully matched sibling is quite low. Only one in four full siblings will be a match, and half- and step-siblings are almost never a match. The other options for stem cell transplants include finding an unrelated stem cell donor or receiving stem cells from cord blood.

While the bone marrow registry is expanding, the chance of finding a match is less than 50% and much lower for minority patients or patients with mixed ethnicity. Cord blood doesn't need to be matched as closely as other stem cells because they're more naïve immunologically, causing less GVHD. Therefore, a match can be found for a much higher percentage of people.

Recent research at M. D. Anderson shows that obesity is a risk factor for pancreatic cancer, and being overweight may play a role in the outcomes of people who develop the disease.

Donghui Li, Ph.D., professor in M. D. Anderson's Department of Gastrointestinal Medical Oncology and the study's senior author, answers questions about this landmark investigation.

What inspired you to do this study?
We know obesity is a risk factor for pancreatic cancer, but few studies have looked at body mass index (BMI) throughout a patient's lifetime rather than just when they are adults or the year they are diagnosed. We wanted to show the relationship between BMI and the risk of developing pancreatic cancer across a patient's life span and determine if being overweight in a specific time period raised that risk.

Also, we were curious about the links among BMI, cancer occurrence and overall survival.
Why is this study important?

Pancreatic cancer is one of the most dangerous types of cancer. It's the fourth leading cause of cancer death in men and women in this country. Median survival is less than 10 months, and the five-year survival rate is less than 5%.

Obesity and smoking are known risk factors for the disease, and while smoking is on the decline, obesity is increasing.

This study helps us understand the cause-and-effect relationship between obesity and pancreatic cancer, and we hope it will help identify high-risk people and specific ways to prevent them from getting the disease.

What were the research methods?
First, we enrolled 1,595 people:
•    841 pancreatic cancer patients treated at M. D. Anderson from 2004 to 2008
•    754 cancer-free people

We interviewed each person about his or her:
•    Smoking history
•    Family cancer history
•    Alcohol use
•    Medical history

Participants were asked to recall their height and body weights at 14 and 19 years old; in their 20s, 30s, 40s, 50s, 60s and 70s; and the year prior to their pancreatic cancer diagnoses or enrollment in the study.

We then calculated each person's BMI during each decade and compared the healthy patients with the pancreatic cancer patients.

Among the cancer patients, we also looked at the average age of diagnosis and the overall survival time, then compared those to their BMIs.



What were the results?
As we suspected, the research confirmed an association between obesity and pancreatic cancer.

People who were obese when they were young had a higher risk of developing pancreatic cancer than those who became overweight later in life.
For example, people who became overweight:
•    Between 14 and 19 years old had 100% increased risk
•    In their 20s had 65% increased risk
•    In their 30 had 27% increased risk

The risk of developing the disease diminished for those who gained excess weight in their 40s and later in life.

Also, we found an association between excess weight and earlier onset of pancreatic cancer. Median age at diagnosis was 64 for those at normal weight, compared to 61 and 59 for overweight and obese patients respectively.

Obesity later in life, especially within a year before a patient's cancer diagnosis, reduced overall survival time.

Did these results surprise you?
It was surprising that overweight and obese pancreatic cancer patients were diagnosed at a younger age. This underscores the impact of obesity on loss of life, especially in productive years.

What do these results mean for pancreatic cancer?
Obesity is a risk factor that can be controlled. This study shows that we should try hard to help people control their weight at an early age to reduce the risk of pancreatic cancer.

What's next?
We need to further investigate the links among obesity, pancreatic cancer and poor outcome, looking at insulin resistance as a possible mechanism.

We also will research factors, such as heredity, diet and others, that might affect the relationship between excess body weight and the disease. One day, we hope to develop ways to prevent this dangerous cancer and detect it earlier.

Related article:
After Pancreatic Cancer, 'Southern Style' Gets A Healthy Makeover

M. D. Anderson resources:

Pancreatic Cancer (M. D. Anderson)

M. D. Anderson Study Finds Even Stronger Relationship Between High Body Mass Index,
Pancreatic Cancer (M. D. Anderson News Release)

How Common Is Use of Off-Label Drugs in Breast Cancer?
Many Patients Receive Legal But Non-Approved Drugs

 More than one-third of breast cancer patients receive chemotherapy drugs that, while approved by the U.S. Food and Drug Administration (FDA), have not been vetted specifically to treat the disease.

The use of drugs for conditions other than those for which they were approved is legal, and, according to a study by M. D. Anderson researchers, prevalent in breast cancer treatment. The study was presented at the American Society of Clinical Oncology's (ASCO) annual meeting in May.

Vaccine Gives Hope Against Advanced Melanoma
First-of-Its-Kind Study Shows Benefit

Patients with advanced melanoma, one of the most dangerous cancers, showed improved response to treatment and length of progression-free survival when a vaccine was added to their treatment with the immunotherapy drug interleukin-2 (IL-2).

Results from the Phase III clinical trial - the first of its kind in melanoma and one of the first in any type of cancer - were presented by M. D. Anderson researchers at the American Society of Clinical Oncology (ASCO) annual meeting in May.

Two-drug Combo Shows Benefit in Lung Cancer
Targeted Agent, Chemotherapy Slow Cancer Growth

When combined with the standard chemotherapy drug Taxotere® (docetaxel), the oral targeted therapy Zactima® (vandetanib) improves progression-free survival for patients with advanced non-small cell lung cancer.

Researchers from M. D. Anderson presented the findings of the first-of-its-kind, international Phase III trial at the American Society of Clinical Oncology's (ASCO) annual meeting in May.

Cancer Newsline Audio Podcast Series

Hodgkin's Lymphoma Treatment Anas Younes, M.D., Professor of the Department of Lymphoma/Myeloma discusses frontline, pre-transplant, and post-transplant treatment options for Hodgkin's lymphoma.

Ways You Can Help Without Giving Money: Donate Blood
Andrea Johnson, Community Representative for the University of Texas M. D. Anderson Blood Bank, discusses the challenges blood banks face when getting blood and platelets for their patients and explains how you can help.

Common genetic variations spread across five genes raise a person's risk of developing the most frequent type of brain tumor, an international research team reports online in Nature Genetics.

"This is a ground-breaking study because it's the first time we've had a large enough sample to understand the genetic risk factors related to glioma, which opens the door to understanding a possible cause of these brain tumors," says co-senior author Melissa Bondy, Ph.D., professor in M. D. Anderson's Department of Epidemiology. 

The genetic variations identified are the first glioma risk factors of any type identified in a large study.



Read the News Release


Bondy and colleagues expect their findings eventually to help identify people most at risk for the disease and to provide potential targets for treatment or prevention.

For Bondy, the findings are particularly gratifying. "I've been collecting families and case studies since the early 90s," she says. "We have only just begun to understand the causes of brain tumors. Our findings give reasons for hope for those who might be affected and an incentive for a more comprehensive investigation of what has been a mysterious disorder."

Gliomas, deadly tumors that form in the supportive tissue of the brain and spine, account for about 80% of all primary malignant brain tumors, with about 22,000 new cases and 13,000 deaths annually in the United States.

Investigators at the Institute of Cancer Research in the United Kingdom were co-leaders on the study, which also included teams from France, Germany and Sweden.

By Jennifer Litton, M.D., from ASCO 2009

A lymphoma vaccine uniquely made for each patient extended time in remission during a Phase III clinical trial, scientists reported today at the 2009 annual meeting of the American Society of Clinical Oncology in Orlando.

"This is the first vaccine in lymphoma that's shown a positive result, improving time to relapse," said Sattva Neelapu, M.D., assistant professor in M. D. Anderson's Department of Lymphoma and Myeloma.He is also principal investigator for M. D. Anderson's portion of the multicenter clinical trial. The vaccine, derived from a patient's cancer cells, sparks an immune system response against the disease.

Cancer Newsline Podcast: Drs. Patrick Hwu and Sattva Neelapu discuss Vaccines in Cancer Therapy  

 A likely key to success, Neelapu noted, is that only patients in complete remission or with minimal residual disease after chemotherapy were vaccinated.  Two other recent Phase III vaccine trials that vaccinated patients who were in partial remission or with stable disease were negative.
 
"With lymphoma, you can get patients to a minimal disease state with chemotherapy and then bring in the vaccine to mop up remaining cancer cells.  That's the strategy, and it should work for other cancers," said Larry Kwak, M.D., Ph.D., who invented the vaccine while at the National Cancer Institute and now chairs M. D. Anderson's Department of Lymphoma and Myeloma.

The 234 patients enrolled in the trial were first treated with a chemotherapy combination known as PACE.   The 117 patients who were in complete remission or had a complete response (unconfirmed) for at least six months then received either the vaccine or a placebo.  Median time to relapse for the 76 vaccinated patients was 44.2 months, compared with 30.6 months for the 41 who received placebo.  Follicular lymphoma is a slow-growing type of non-Hodgkin lymphoma.

"Immunology shows us that there's a weak immune response at the onset of cancer but it's somehow shut down very early," Kwak said. "The next generation of vaccines probably will be combined with therapy that interferes with mechanisms that shut off immune response."

The crucial component of Kwak's vaccine is a receptor protein extracted from the patient's malignant B cell lymphocytes and purified in large amounts.  The protein is combined with a delivery agent and an adjuvant growth factor and the whole cocktail is injected back into the patient.  "It's the ultimate in personalized therapy," Kwak said.  "Even if two patients have the same type of lymphoma, their tumors will still have different proteins."

The NCI advanced the vaccine by sponsoring its first randomized phase III clinical trial, Kwak said, with the intention of handing the trial off to a corporate partner. BioVest International subsequently prevailed in a competitive process to collaborate with the NCI and took over the trial as planned in 2004. BioVest is developing the vaccine under the brand name BioVaxID™. 

By Jennifer Litton M.D., from ASCO 2009

The 2009 ASCO annual meeting continues to highlight personalizing care for breast cancer patients.  By improving our knowledge of the different pathways within a tumor cell that are either enhanced or silenced, oncologists can tailor discussions regarding risk of recurrence and death.  Additionally, this knowledge is being used to guide oncologists in determining the best surgical and chemotherapy treatments for our patients.


For several decades in breast cancer care, treatments have been determined based on tumor hormone sensitivity for recommending the use of anti-estrogen treatments such as tamoxifen and the aromatase inhibitors.  With the identification of the HER-2/neu receptor, targeted agents such as trastuzumab, substantial strides in cure rates and survival were made.
 
At this year's annual meeting multiple new, targeted therapies are emerging in clinical trials.  Several new trials evaluating innovative anti-HER-2 therapies show promising results.  The new trastuzumab DM-1 compound combines the power of targeting HER2 receptors on the outside of tumor cells and then making the cell take that compound directly into the tumor cell where it releases a powerful tumor-killer directly into the tumor cell.  As the particular molecular changes in an individual's tumors are analyzed, this new generation of engineered drugs is being devised to maximize killing tumor cells and leaving healthy, unaffected cells alone.  This would hopefully translate into minimal side effects and maximum efficacy.  Other agents targeting HER2 or other HER family members are currently in large clinical trials with some preliminary results scheduled for release during this meeting.

 Tomorrow, during the plenary session, Dr. Joyce O'Shaugnessy will be presenting results from a study in metastatic breast cancer with a PARP inhibitor combined with gemcitabine and carboplatin.  This particular new class of anti-cancer drugs may specifically be effective in patients with known BRCA deleterious mutations and may play a part in multiple solid tumors.  We are also awaiting results, later in this meeting, of new molecular profiling studies that may help clinicians also tailor specific chemotherapy choices.

by Scott Kopetz, M.D. from ASCO 2009

Research presented at ASCO this year improves our understanding of how cancer cells make use of factors that regulate normal cell growth.  Our normal cells grow, divide, and use energy in the form of glucose under very tight control.  The result is a coordinated system of cells that only multiply when the conditions are right in the body, meaning that we have enough energy to support the increased numbers of cells.  This system normally regulates our body size and circulating energy levels, and is related to obesity and diabetes.

We increasingly understand how one part of this system (called the insulin-like growth factor receptor or IGFR) is co-opted by cancer cells in order to maintain their growth.  Work presented this morning by Dr. Shroff, a medical oncology fellow working with Dr. Dongyu Li in the Department of Gastrointestinal Medical Oncology, demonstrated that variations in the IGFR gene resulted in differences in outcomes for patients with advanced pancreas cancer.  This effect was fairly strong, as survival time was twice as long in patients with the "good" gene variation.  In the discussion that followed the presentation, it was noted that this IGFR system may play a significant role in the growth and spread of pancreas cancer.

The next goal is to take advantage of this finding to improve outcomes for cancer patients.  Fortunately, there are a number of chemotherapies in development that may block the IGFR system.   One such agent in development in lung cancer, as reported by Dr. Daniel Karp in the Department of Thoracic/Head and Neck Medical Oncology, is showing an impressive benefit in patients with a certain type of non-small cell lung cancer.  In updated results he presented at ASCO (#8072), he reported a response rate of above 60% in patients treated with an IGFR inhibitor plus chemotherapy, with several patients with dramatic responses.  We hope these are only the first of several good reports for agents targeting IGFR, as this approach has the potential to benefit not just patients with pancreas and lung cancer, but a host of broader tumor types.