Recently in Translational Cancer Research Category

"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.

By 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.

A key to the perils of endless injury repair, the molecular path from stress through a cancer-promoting gene to ovarian cancer progression, and signals by endothelial cells that strengthen  colorectal cancer are among recent discoveries by MD Anderson researchers.

By uncovering these new connections, scientists expose new potential targets for fibrosis, the lethal scarring of organs, and cancer.

Endothelial cells make cancer cells tougher, more dangerous 

"Cancer stem cells initiate and sustain tumor growth, promote metastasis and resistance to chemotherapy and have a variety of other attributes," says Lee Ellis, M.D., of MD Anderson's Department of Surgical Oncology. The blood vessels cells activate Notch signaling.  Drugs in  clinical trials attack Notch. 

News release and Cancer Cell paper

Stress hormone breaks dam, cancer-promoting flood follows

The hormone noradrenaline turns on the oncogene Src, which promotes ovarian cancer growth and spread through beta-adrenergic (ADRB) receptors expressed on tumor cells.

"When Src is triggered by stress, it works like a dam letting out water that causes a flood downstream. Src, like the dam, is a master regulator switch that causes a chain reaction in the cells," says Anil Sood, M.D., of the departments of gynecological medical oncology and cancer biology. One implication: beta blockers might work against ovarian cancer.

News release and Nature Communications paper

Protein plays pivotal role in scarring that destroys organs

When the body's wound-healing process gets endlessly turned on, the tissues that provide a scaffold for injury repair can destroy the kidneys, liver and lungs. This process, known as fibrosis, also is tightly tied to cancer.

"Fibrosis is wound-healing that never stops. The body thinks an injury exists when it doesn't, so it just keeps going, producing scars that clog an organ's system and destroy its functional tissue until it fails," says Raghu Kalluri, Ph.D., M.D., chair of the Department of Cancer Biology. Kalluri and colleagues identified the role of HE4 in promoting fibrosis. A test already approved for ovarian cancer detects HE4 levels in the blood.

News release and Nature Medicine paper

Cancer begins when a single cell goes haywire.  Now the keys to understanding that cell's transition to lethal tumor may be found in the unprecedented analysis of single tumor cells.

By isolating, capturing and then analyzing the genome of individual cells, Nicholas Navin, Ph.D., assistant professor in MD Anderson's Department of Genetics, proposes to identify the mutations that allow a primary tumor cell to escape into the bloodstream and then to establish a deadly colony in another organ.

Successfully analyzing differences in active mutations among single cells would help researchers understand, map and eventually block the lethal path to metastasis - the spread of the primary cancer to other organs.  Primary tumors are rarely lethal, Navin notes, but their genetic diversity from cell to cell hinders scientists' ability to understand metastasis.

The Damon Runyon Cancer Research Foundation will give Navin the opportunity to try his unique approach.  He is the Nadia's Gift Foundation Innovator, one of only seven 2013 Damon Runyon-Rachleff Innovation Awards announced earlier this month.

The foundation announcement notes the innovation awards are for "cancer research by exceptionally creative thinkers with "high-risk/high-reward" ideas who lack sufficient preliminary data to obtain traditional funding." Navin's approach "will have myriad clinical applications, which have prognostic value in predicting invasion, metastasis, survival and response to chemotherapy."

A new technique for expanding blood stem cells from umbilical cords in the lab before transplanting them into a patient reduces the perilous time it takes for the new blood supply to take hold.

Cord blood transplants provide a source of blood stem cells to cancer patients who need a transplant after high-dose chemotherapy for leukemia, lymphoma and other malignancies but cannot find a matched donor. 

This is particularly true for people of Latino, African or Asian heritage, who are underrepresented in the bone marrow donor pool, which makes it hard to find a matched blood stem cell donor.

"Pre-transplant cord blood expansion on mesenchymal precursor cells could become the new standard of care if our findings are confirmed in a randomized clinical trial," said Elizabeth Shpall, M.D., professor in the Department of Stem Cell Transplantation and Cellular Therapy.  She is principal investigator of an early stage clinical trial and senior author of a paper published this week in the New England Journal of Medicine.

Umbilical cords provide a much lower dose of cells than those given by a matched donor whose stem cells are taken from the bone marrow or circulating blood. The result: slower establishment of the new blood supply, particularly white cells (neutrophils) and platelets, exposing patients to greater risk of infection and bleeding.

Shpall and colleagues show how expanding one of the two cords on a bed of supportive  in the lab increases the number of cells transplanted and the speed of establishment (engraftment) of white cells and platelets for the patient over those who get the usual unexpanded double cord transplant. 

Two papers published by MD Anderson clinical researchers are included in the American Society of Clinical Oncology's report, Clinical Cancer Advances 2012: ASCO's Annual Report on Progress Against Cancer.

The world's largest oncology organization annually conducts an independent review of advances in clinical cancer research in the past year that have the greatest potential to improve patients' survival and quality of life.  The report is compiled under the guidance of 21 experts in specific areas of cancer research.

MD Anderson's publications addressed serous ovarian carcinoma, the most difficult-to-treat version of that cancer, and chronic myeloid leukemia.

Study titles and principal investigators are
:
Jorge Cortes, M.D., professor in MD Anderson's Department of Leukemia, "A pivotal phase II trial of ponatinib in patients with CML and Ph+ALL resistant or intolerant to dasatinib or nilotinib, or with the T315I mutation."  Presented at the ASCO 2012 annual meeting, data show ponatinib, a third-generation tyrosine kinase inhibitor, acts against disease with specific resistance mutations that other drugs are usually unable to reach.

Yuexin Liu, Ph.D., instructor in MD Anderson's Department of Pathology, "Integrated Analysis of Gene Expression and Tumor Nuclear Image Profiles Associated with Chemotherapy Response in Serous Ovarian Carcinoma."  Published in  PLOS One in May 2012, this study found a genetic signature that accurately predicts chemotherapy response in serous ovarian cancer.

The report is available online and an interactive version with illustrations, sources and additional information is available at http://www.cancerprogress.net/latest_advances.html

An effective drug that kills cancer by damaging DNA also attacks heart muscle, which for some patients leads to heart failure. In new research, scientists have discovered how the drug attacks the heart, opening potential new options to prevent or minimize the life-threatening side effect. 

Doxorubicin is a 50-year-old chemotherapy drug still in widespread use in combinations to treat a variety of cancers, including breast, ovarian, lung and bladder cancers as well as leukemia and lymphoma.

"However, its use is limited by its cardiotoxicity. We're excited because we've identified the molecular basis for doxorubicin's damage to the heart," said Edward T.H. Yeh, M.D., professor and chair of MD Anderson's Department of Cardiology and senior author of the study reported online today at Nature Medicine.

This knowledge can mobilize researchers to find a way to identify those who are sensitive to heart damage by doxorubicin and either use other drugs, or include cardio-protective drugs and more closely monitor patients. 

Another exciting alternative is to develop drugs that only target Top2a, Yeh said. "We want to make sure that cancer patients will have healthy hearts to enjoy their life after successful cancer treatment."