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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.

A unique approach to understanding how cancer cells or microbes become capable of warding off drugs has earned a New Innovator Award from the National Institutes of Health for an M. D. Anderson scientist.

Gábor Balázsi, Ph.D., assistant professor in the Department of Systems Biology, will receive $1.5 million over five years under the highly competitive program. The NIH announced awards Thursday in three prestigious programs that fund bold ideas, with the potential to speedily translate research into improved human health. 



"Therapy fails when cancer cells or disease-causing microbes become resistant to drugs. We will apply new, non-conventional methods to control expression of a drug-resistance gene in cells that are then treated with chemotherapy," Balázsi says. "We expect to discover new mechanisms underlying the emergence of drug resistance, which could improve treatment of cancer and of microbial infections as well."

Balázsi and colleagues are synthetic biologists who have created gene circuits that allow them to tightly control expression of a gene, dialing it from completely off through varying levels of expression to completely on.

A newly developed circuit also will permit them to control fluctuations in gene expression. This unique degree of control will allow more detailed investigation of the effects of genes involved in drug resistance.

"These are highly competitive awards for the most innovative science. Being chosen as a recipient is a significant accomplishment," says M. D. Anderson Provost and Executive Vice President Raymond DuBois, M.D., Ph.D.  "His research concept is exciting and holds promise for improving our ability to adjust very specific cellular levels of a variety of genes and then test drug resistance, among other things."


Read the News Release
M. D. Anderson Scientist Wins NIH New Innovator Award

A carefully controlled program of progressive weight training benefited women with lymphedema, a study out today in the New England Journal of Medicine reports.

Clinical trial results out of the University of Pennsylvania offer hope for women with the debilitating condition that arises after surgery or radiation therapy for breast cancer. When lymph nodes are removed or blocked during treatment, lymph fluid can build up in the upper arm, causing pain and swelling.

The study is a substantial contribution to the accumulating evidence for weightlifting, a reversal in conventional wisdom that women with lymphedema should avoid such activity, notes Wendy Demark-Wahnefried, Ph.D., professor in M. D. Anderson's Department of Behavioral Science in the Division of Cancer Prevention and Population Science.  

Demark-Wahnefried's accompanying editorial in the New England Journal of Medicine notes that women have been advised to avoid any vigorous, repetitive arm movements (scrubbing, pushing, pulling or hammering) or lifting more than 15 pounds. "But what should a woman do if, after her treatment, she returns home to a houseful of toddlers or has to push a mop for a living?"

The Penn study, distinguished from previous research by its larger size and longer duration, compared patients receiving usual care with women who followed a specific workout twice a week while wearing a custom-fitted compression bandage over the affected arm. All patients had a history of breast cancer treatment and clinically confirmed lymphedema.

Those in the weightlifting program reported improvement in their lymphedema symptoms and demonstrated increased lower and upper body strength, without a significant increase in arm swelling.

Cost analysis was not part of the study, Demark-Wahnefried writes, but weightlifting has the potential for cost savings by reducing direct health care costs, potentially reducing the risk of disability and  allowing women to return to work full time, whether in or outside of the home.

Lymphedema results when the lymph nodes are removed or blocked due to treatment and lymph fluid accumulates causing chronic swelling in the upper arm.
    
 

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.

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™. 

Top scientists at M. D. Anderson, Harvard Medical School and Memorial Sloan-Kettering are joining together to find a way to block a twisted molecular pathway that propels endometrial, breast and ovarian cancers.

The three institutions share a three-year, $15 million Dream Team grant from Stand Up To Cancer, an entertainment industry initiative to fund cancer research that moves new treatments to patients more quickly.  

"The pathway involved here is the most common abnormally activated pathway in all of cancer," says Gordon Mills, M.D., Ph.D., professor and chair of M. D. Anderson's Department of Systems Biology and a co-leader on the project with two other scientists. "What we learn in women's cancers will apply to many other types."



"Stand Up To Cancer's novel approach, bringing top investigators together in Dream Teams across institutions, has never been tried on this scale before," says Raymond DuBois, M.D., Ph.D., M. D. Anderson provost and executive vice president and a member of the Stand Up To Cancer Scientific Advisory Committee.
 
"Most funding sources award research grants to groups housed within the walls of a single institution. These five powerful collaborations generated proposals that could have a major impact on the care of cancer patients, and do so more quickly than would have occurred if the institutions had acted separately."

DuBois, who helped organize the project during his term as president of the American Association for Cancer Research, was interviewed on the CBS Early Show by the network's news anchor, Katie Couric.

M. D. Anderson researchers have significant roles on two other Dream Teams.

A Dream Team designed to advance epigenetic cancer therapy will draw on the expertise of Jean-Pierre Issa, M.D., professor in the Department of Leukemia. Epigenetics involves the biochemical regulation of genes rather than actual damage to or mutation of DNA. Issa and colleagues were instrumental in the development of decitabine, one of the first epigenetic drugs, which turns on genes that have been chemically shut down.

"Our plans are to find markers that can guide individualized epigenetic therapy by identifying patients most likely to respond and we will start in leukemia, primarily at M. D. Anderson," Issa says. 

Research to translate results in leukemia to solid tumors such as breast, colon and lung will be done at other Dream Team institutions. Scientists at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University and the University of Southern California lead the team. 

Clinical trials of new epigenetic drugs will be conducted jointly at USC and M. D. Anderson.

Roy Herbst, M.D., Ph.D., professor in the Department of Thoracic/Head and Neck Medical Oncology, brings the department's innovative BATTLE clinical trial to a Dream Team applying a technology that detects circulating tumor cells in the bloodstream to detect specific mutations in a variety of cancers and predict patients' responses to treatment.  

The BATTLE program uses biomarkers to guide treatment for late-stage lung cancer patients, relying on tumor biopsies to detect relevant mutations. "We hope circulating tumor cells will allow us to do the same thing without having to do a biopsy," Herbst says. "We would be able to conduct continuous sampling with this technology. We're excited to be collaborating on this project."

Researchers at Massachusetts General Hospital Cancer Center and Harvard Medical School lead the team.

Jer-Yen Yang's publications include a lead-authorship in Nature Cell Biology

Jer-Yen Yang graduated Saturday from The University of Texas Graduate School of Biomedical Sciences at Houston (GSBS), departing with hard-earned expertise about a crucial cancer-suppressing protein, an impressive publication record and a blueprint for success as a scientist. And his doctorate, of course.

"I've learned a lot here from Dr. Hung about how to do science, how to stay focused and to not waste time," Yang says. "I want to cure cancer patients. This is my goal, and I'm trying to achieve it step by step."

"Dr. Hung" is Mien-Chie Hung, Ph.D., professor and chair of M. D. Anderson's Department of Molecular and Cellular Oncology, and one of the world's leading experts on the molecular disruptions that fuel cancer.  Hung also is a multi-year winner of the graduate school's annual teaching award.  The GSBS is a joint graduate program of M. D. Anderson and The University of Texas Health Science Center at Houston. 

Hung hired Yang as a staff research scientist and quickly noted one of the many things that he has come to admire about the young researcher. "This guy is highly committed," Hung says. "He didn't view it as just an 8-to-5 job."  In 2004, Yang's work earned him co-authorship on a paper published in the journal Cell. Hung's group demonstrated that the oncoprotein IKKbeta promotes cancer growth by inhibiting the tumor-suppressing transcription factor FOXO3a.

The scientists suspected other proteins might block FOXO3a from its regulatory role in the cell nucleus. Yang, by now a GSBS student, set up a project to examine that proposition. In early 2008, Yang was first author of a paper in Nature Cell Biology showing how two known cancer-causing proteins gang up to destroy FOXO3a.  

First, the protein kinase ERK attaches phosphate groups to FOXO3a, which forces the tumor-suppressor out of the cell nucleus. Out in the cytoplasm, the phosphorylated FOXO3a is marked for death by the oncoprotein MDM2. By attaching a string of targeting proteins called ubiquitins, MDM2 subjects FOXO3a to destruction by the ubiquitin-proteasome degradation pathway.

"So this important tumor-suppressor is targeted by three oncoproteins. If we can knock out those three, we can fully restore FOXO3a to inhibit tumor growth," Yang says.

In Hung's lab, Yang is the FOXO man. "He probably knows the literature better than I," Hung says. The two co-authored a review of the tumor suppressor that was published in February 2009 by Clinical Cancer Research.

Yang moved to the United States from Taiwan, where he earned a master's degree from the prestigious Academica Sinica. Hung efficiently sums up his student's strong points: "He works hard. He's smart, reads a lot, thinks and comes up with an idea. Then he sits down and gets it done. When you teach him something, he listens, digests and he improves."

Yang says lessons learned go well beyond the lab. Hung is great at sharing information, he says, whether it's the latest from a scientific meeting or important internal updates about M. D. Anderson that keep his team in the loop. Yang has had opportunities to explore grant applications and the review process, getting a feel for the lifeblood of scientific funding, and to hone both his presentation and writing skills.  

Hung taps an extensive collaborative network to help his researchers. "If you need a reagent or tumor samples, he'll know someone who can help and we can get it, sometimes within days," Yang says.

Such collaborations lead to a critically important lesson: Share. "Teamwork is so important," Yang says, "you can't do anything by yourself. Opening your mind to share information with others helps you gain their respect, and it helps everyone do better research." Yang's sharing earned him 11 co-authorships, along with the six papers on which he was lead author.

"Learning how to be part of a team is a critical factor in becoming a scientist and a leader," Hung says. "I expect Jer-Yen to do even better as a postdoctoral fellow, and to make significant contributions to science in the future."

If Yang has one bit of advice for new students, it's to focus. "Some students are smart, they work hard, but they try to do too many things," Yang says. "Initiate one project at a time and you'll be successful."

Professor of Experimental Therapeutics Kapil Mehta earned one of four pilot grants awarded this year by the Pancreatic Cancer Action Network (PANCAN) and the American Association for Cancer Research.

The $195,870 two-year grant supports Mehta's ongoing inquiry into how overexpression of tissue transglutaminase (TG2) promotes pancreatic cancer drug resistance and metastasis.

He and other awardees were honored Tuesday night at the AACR Research Grants Dinner at its annual meeting in Denver.

Mehta has connected overexpression of the gene to treatment resistance and metastasis in pancreatic and breast cancer and melanoma.  Mehta and colleagues have shown that expression of TG2 can be shut down with a targeted small-interfering RNA (siRNA).

Young scientists from M. D. Anderson earned eleven Scholar-in-Training Awards at the American Association for Cancer Research 100th Annual Meeting 2009, the most of any institution at the session in Denver.

 About 17,000 scientists from 90 countries are attending. The highly competitive travel grants go to postdoctoral fellows and graduate students judged to have submitted meritorious abstracts for the AACR meeting.  Overall, 200 were awarded.

Three of M. D. Anderson's winners came from the lab of XifengWu in the Department of Epidemiology - two postdocs and one graduate student.

M. D. Anderson honorees are:

Ahmed A. Ahmed of Experimental Therapeutics
Ugur Akar, Breast Medical Oncology
Chandra Bartholomeusz, Breast Medical Oncology
Tina Cascone, Thoracic Head and Neck Medical Oncology
Meng Chen, Epidemiology, and a graduate student in The University of Texas Graduate School of Biomedical Sciences.
Puja Gaur, Surgical Oncology.
Longfei Huo, Molecular and Cellular Oncology
Xia Pu, Epidemiology
Manish Shanker, Thoracic and Cardiovascular Surgery
Jingmin Shu, Leukemia
Hushan Yang, Epidemiology. 

National Cancer Institute Director John Niederhuber, M.D., described the institute's plans and priorities for the $1.3 billion it will receive over two years from President Obama's stimulus plan and  for a 3 percent increase in its baseline budget. He addressed the American Association for Cancer Research 100th Annual Meeting 2009. A text copy is available.

Higher RO1 Grant Payline

Using the budget increase for FY 2009, the payline for RO1 grants will rise from last year's 12th percentile (grant must score in top 12 percent to be funded) to the 16th percentile. Coordinated but separate use of stimulus and budget funds will raise it to the 25th percentile.

The payline for young investigators will rise concurrently.

Start-Up Grants

NCI is planning to fund early stage start-up packages to help young faculty members establish their labs.  Physician-scientists and Ph.D.s who are committed to translational research will receive the grants.

Three Signature Initiatives

Niederhuber discussed three central projects:  expansion of The Cancer Genome Atlas, establishment of a personalized cancer care platform to better move "from data, to function, to target, to therapy," and start up of a network of Physical Sciences-Oncology Centers to explore new approaches by better connecting physical sciences to cancer biology.

A webcast of speech will be posted around 2 p.m. CDT (after the speech).