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Even as the targeted therapy ibrutinib makes its way through clinical trials as a single treatment for chronic lymphocytic leukemia (CLL), researchers are studying the new drug in combinations and identifying genomic changes that allow malignant cells to resist treatment.

Jan Burger, M.D., Ph.D., associate professor of Leukemia at The University of Texas MD Anderson Cancer Center, presented two such studies at the 55th Annual Meeting of the American Society of Hematology this month.

  • Combining ibrutinib with the targeted antibody rituximab resulted in complete or partial responses in 37 of 39 (95 percent)  high-risk CLL patients. At a median follow-up of 18 months, 31 patients (78 percent) remained on the drug with no sign of progression, with overall survival at 84 percent.
  •  Genomic analysis of CLL before treatment and after resistance so far point to mutations inside and outside the B cell receptor pathway targeted by ibrutinib as promoting resistance.

"This combination improves on the already excellent response rate from ibrutinib alone, which is usually around 70-80 percent.  It's also well-tolerated with manageable side effects and significantly improves patients' quality of life," Burger said.

 

When it comes to equipping T cells, the immune system's attack dogs, to find and kill cancer cells, Sleeping Beauty just might be a heroine in the story.

Genetically altering T cells to recognize a surface protein called CD19 and destroy cells that wear it has shown great promise for treating blood cancers, most recently in clinical trials presented during this week at the 55th American Society of Hematology (ASH) Annual Meeting in Exposition, now under way in New Orleans.

 

Encouraging early results from the first clinical trials of T cells modified by gene transfer using the Sleeping Beauty transposon to deliver a genetic package that creates an anti-CD19 receptor on T cells were reported Sunday night at ASH.

"Five months into these clinical trials, no acute or late toxicities have been noted from treatment with genetically modified chimeric antigen receptor (CAR) T cells in nine patients after they received blood stem cell transplantation," says Partow Kebriaei, M.D., associate professor of Stem Cell Transplantation and Cellular Therapy.

"Delivering CAR T cells after transplant targets minimal residual disease in hopes of maintaining remission for people with high-risk B cell malignancies," Kebriaei says.

Of the first five patients with acute lymphoblastic leukemia, three treated with the initial, minimal T cell dose had their disease progress while the first patient treated at the next highest dose remains in remission. It was too early to evaluate the fifth, who received an umbilical cord blood transplant.

Four non-Hodgkin lymphoma patients treated with the higherT cell dose all remained in remission after three months. Eventually, 25 patients will be treated in the clinical trial.

Glioblastoma multiforme, the most common and lethal form of brain cancer, "is one of the science and medical world's hardest nuts to crack," writes W.K. Alfred Yung, M.D., chair of Neuro-Oncology at MD Anderson, in a guest blog at Cure

102199_Yung_A.jpgYung explains how an alliance formed this year called Defeat GBM Research Collaborative reaches across institutions to improve collaboration and data sharing through an innovative scientific plan to speed progress against the disease.

Formed under the auspices of the National Brain Tumor Society, Defeat GBM aims to double 5-year survival of glioblastoma patients within five years. Five-year survival ranges from 4% to 14% of patients depending on age range.

New information from research by The Cancer Genome Atlas, as well as interesting developments in immunotherapy provide new avenues to explore to treat GBM.

Yung's blog post: Defeating glioblastoma multiforme will take full-force effort

TCGA research update in Oct. 10 edition of Cell and MD Anderson news release.

Eating and swallowing exercises during treatment benefit cancer patients later

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New MD Anderson research published in JAMA Otolaryngology Head and Neck Surgery indicates that oral exercises help patients maintain their swallowing and eating ability after undergoing radiation and chemotherapy for head and neck cancers.

Therapy can cause fibrosis, or hardening, of tissues and muscles, which affects critical functions such as swallowing and eating.  Side effects can lead to a range of negative consequences including malnutrition, mouth sores and the need for a feeding tube, that cause many patients to stop eating  foods during cancer treatment.

The retrospective study enrolled 497 patients with throat cancer who were receiving radiation therapy and chemotherapy between 2002 to 2008.

Researchers examined per oral (PO) status which was defined as: NPO (nothing by mouth, feeding tube dependent), partially PO (tube feeding supplemented by daily oral intake) and fully PO (100% oral intake).  They also measured self-reported swallowing exercise adherence.

Returning to regular diet

By adherence to swallowing goals during cancer treatment, the proportion of patients returning to a regular diet after treatment was:

  • 65% for those who did neither (no eating nor exercise), 
  • 77% to 84% for those who maintained some swallowing goals (eat or exercise), 
  • 92% for patients who met both goals (eating and exercise).
"The primary finding is that both swallowing therapies, eating and exercise, were significantly and independently associated with favorable swallowing outcomes," said Kate Hutcheson, Ph.D., assistant professor in the Department of Head and Neck Surgery.  "When we looked at subgroups of patients we found those who both ate and exercised during radiation and chemotherapy had the best outcomes."

The results also highlight the important role speech pathologists play in understanding and preventing negative side effects associated with treatment of the head and neck.

"This study adds guidance to patients and clinicians to help them understand that the best outcomes will be achieved when we motivate our patients not only to continue doing their swallowing exercises, but also to continue eating throughout radiation treatment," Hutcheson said, who's the primary author of the study.

Hutcheson said new data from a clinical trial should become available soon, allowing the researchers to prospectively validate their findings.

A full copy of the study can be viewed here.

A protein called Skp2, overexpressed in many types of cancer, for years has gotten away with promoting tumor growth and progression unhindered by effective treatments.

Hui-Kuan Lin, Ph.D., of Molecular and Cellular Oncology, has spent the last decade characterizing Skp2 and how it fuels cancer growth, and the past five years looking for a way to shut it down..

Lin teamed with Shuxing Zhang, M.D., Ph.D., in Experimental Therapeutics, to find an inhibitor that shuts down Skp2 among a galaxy of drug candidates. Their discovery, opening a completely new avenue for potential cancer treatment, was published today at the leading journal Cell,

The compound selectively attacked prostate, lung, liver and bone cancer cells in lab experiments while largely sparing normal cells. It also suppressed prostate cancer stem cells, which are thought to drive cancer progression and metastasis. In mouse models, the drug shrank tumors and overcame resistance to chemotherapy.

"The beauty of this study is we identified an inhibitor and showed how it functions to block Skp2. Inhibitors often are discovered without an initial understanding of how they work," Lin said.

Steps are under way to define the drug's potential off-target effects before it can advance to human clinical trials.

Triple-negative breast cancer cells produce inflammatory cytokines Interleukin-6 (IL-6) and Interleukin-8 (IL-8), which in turn stimulate the growth of cancer cells, according to a study published in the June issue of Cancer Research, a publication of the American Association for Cancer Research.

The study identified new targeted therapies for patients with triple-negative breast cancer focused on signaling molecules called cytokines, which are essentially hormones produced by the cells to tell breast cancer cells to grow.

"Currently, there are no effective targeted therapies for triple-negative breast cancer, and this type of breast cancer is most associated with lack of response to therapy and poor prognosis," says Powel Brown, M.D., Ph.D., professor and chair of Clinical Cancer Prevention at The University of Texas MD Anderson Cancer Center and senior author on the study conducted with colleagues at MD Anderson and Baylor College of Medicine.

"There are no prevention strategies for this form of breast cancer," Brown said. "We use non-specific chemotherapy on all stage II or higher triple-negative breast cancer patients."

Triple-negative breast cancer lacks hormonal and growth factor drug targets present in most breast cancers, making it the deadliest form of the disease, typically diagnosed in women under the age of 50 and accounting for 15 to 20 percent of breast cancer deaths annually.  Although there is a high incidence in both Hispanic and African-American women, African-American and women from Africa are more likely to die from this disease.

Protein biomarker may signify aggressive colon cancer

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By Laura Sussman

MET protein levels correlate strongly with a cellular transition that occurs in a treatment-resistant type of colorectal cancer, according to new research from The University of Texas MD Anderson Cancer Center.

The study results, which compared MET protein expression with protein/gene expression of epithelial to mesenchymal transition (EMT) markers and evaluated impact on survival, were released today at the annual meeting of the American Society of Clinical Oncology in Chicago.

"When the epithelial cells that line the colon become cancerous, some of them develop special features to allow migration, causing the cancer to be more aggressive," says Kanwal Pratap Singh Raghav, M.D., fellow in MD Anderson's Division of Cancer Medicine. This transition from immobile epithelial cells to mobile mesenchymal cells is associated with cell migration and invasion, treatment resistance and metastasis.

"Although EMT is a dominant molecular subtype, a biomarker suitable for clinical use has not been found. This research gives us an important step toward learning more about treating this colorectal cancer subtype," Raghav says.

The study takes another step toward personalized cancer diagnosis and treatment.

"While we know there are many of types of colorectal cancer, we're not as advanced as we'd like to be in our understanding of them," says Scott Kopetz, M.D., Ph.D., associate professor in MD Anderson's Department of Gastrointestinal Medical Oncology and senior author of the study. "One of the larger goals of our research is to classify simple biomarkers that can be used by doctors in the community to identify subtypes. We want to condense sophisticated gene signatures down to single markers and simple tests that can be used to guide therapy."

heffernan cropped.jpg"Cancer is a complex and heterogeneous disease driven by gene mutations. As we enter the era of personalized medicine, the characterization of the cancer genome has begun and will continue to influence diagnostic and therapeutic decisions in the clinic."

 

So begins Timothy Heffernan, Ph.D., associate director of target discovery at the Institute for Applied Cancer Science (IACS), in an article discussing how cancer genome discoveries have led to recent successes in oncology drug development through the identification of genetic alterations known as driver mutations.

 

"The translation of genomic data into drug development endpoints requires coordinated integration across multiple scientific disciplines. Genomic technologies provide comprehensive lists of genes that are altered in human cancer. Sophisticated computational models and powerful data analytics prioritize genes with the strongest weight of genomic evidence," he notes.

 

"Subsequent functional studies in relevant disease models provide biological significance by identifying genes that confer a proliferative and/or survival advantage to cancer cells. Lastly, deep biological exploration is required to provide a mechanistic understanding of the gene's cancer-relevant activity," Heffernan writes.

 

Systematic approaches to apply genomic data

 

Heffernan's article in the current issue of the Insights and Developments newsletter discusses the systematic approaches implemented at IACS to functionalize genomic data and identify novel therapeutic targets.

 

For years, scientists have crafted vaccines designed to treat cancer, rather than to prevent it, by priming the immune system to track down and kill tumors.

They identify antigens - distinctive targets - on tumors, combine them with substances (adjuvants) to enhance immune response, and then inject the vaccine to treat a given cancer.

A frustrating pattern emerged, says Willem Overwijk, Ph.D. associate professor in MD Anderson's Department of Melanoma Medical Oncology.  In both mouse experiments and human clinical trials, the vaccines created abundant T cells specialized to find the antigen and destroy cells that have it.

These T cells were easily observed in the bloodstream, yet there was little or no effect on tumors in the vast majority of cases.

Overwijk and colleagues decided to focus their attention on potential problems in the vaccine itself.  What they found, reported this week in Nature Medicine, could profoundly alter vaccine design and effectiveness.

"We discovered that only a few T cells actually get to the tumor, while many more are stuck or double back to the vaccination site," Overwijk says.

 

New initiatives drive personalized cancer care via genetic analysis of tumors

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102621_Mills_G.jpg 124068_Meric_F.jpgBy William Fitzgerald

Gordon Mills, M.D., Ph.D., recalls a proposal he wrote 18 years ago detailing the concept of personalized cancer therapy and its potential impact. Today, that idea is no longer a proposal, but a reality, and it's about to get a boost.

Under a new and innovative institutional protocol called Clearing House, which started in March 2012, scientists are delving deeper into the biology of patients' tumors, with hopes of identifying specific genetic markers and prescribing therapies to attack those markers directly.

Funda Meric-Bernstam, M.D., professor in MD Anderson's Department of Surgical Oncology, and Mills, professor and chair of the institution's Department of Systems Biology, are leading the effort that will test up to 200 genes known to influence cancer in patients with aggressive or recurring disease.

"In the first year, we'll have sequenced the genes of far more than 1,000 MD Anderson patients and are targeting to have more than 3,000 by the second year," Meric-Bernstam says. "This will accelerate our discovery approaches, and we can develop new clinical trials, in which we already have patients pre-identified to enroll."

While the research began with solid tumors, the Clearing House protocol has expanded to all diseases that have ongoing genomically selected trials, Meric-Bernstam says.

Mills is co-director of MD Anderson's Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy and Meric-Bernstam is medical director of the institute.

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