Cancer treatment typically involves surgery, radiation therapy, chemotherapy, hormone therapy or biological therapy. An oncologist may use one therapy or a combination of methods, depending on the type and location of the cancer, whether the disease has spread, the patient’s age and general health, and other factors.

At Georgia Tech, researchers are pursuing many different directions toward improving existing cancer treatment methods and developing new therapeutic techniques, including:
- Attacking cancer stem cells;
- Improving radiation therapy;
- Including motion and biological information in planning treatment;
- Assessing a tumor’s ability to create new blood vessels;
- Developing a new approach to targeted cancer therapy;
- Increasing responses to chemotherapy;
- Enabling personalized drug delivery; and
- Analyzing gene expression data to predict response to drugs.

This is the third in a series of three reports focusing on cancer research at Georgia Tech. The first highlighted efforts to understand how cancer arises, and the second featured cancer detection and diagnostic techniques.

ATTACKING CANCER STEM CELLS
Recent evidence suggests that certain cancers may persist or recur after treatment because a few cells – called cancer stem cells – survive existing therapy and then seed new tumors. These stem cells can be particularly resistant to chemotherapy and radiation.

“In the future, effective cancer therapy may require the detection and elimination of cancer stem cells in tumors,” said Gang Bao, the Robert A. Milton Chair in Biomedical Engineering in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. “Developing a method to detect cancer stem cells is challenging because evidence suggests there is only one cancer stem cell for every 100,000 to 1 million cancer cells in tumor tissue, so the method must be very sensitive.”

Bao and postdoctoral fellow Won Jong Rhee recently developed a new method that effectively discriminates cancer stem cells from other cancer cells by locating protein markers on the surface of stem cells and stem cell-specific genes inside cancer stem cells. The work was published on April 2, 2009, in the journal BMC Biotechnology.

Gang Bao, the Robert A. Milton Chair in Biomedical Engineering, displays fluorescence images that show levels of Oct-4 mRNA (red) and total mRNA (green) in the cytoplasm of cancer stem cells The researchers located live stem cells by simultaneously detecting the presence of the stem cell surface protein marker SSEA-1 with dye-labeled antibodies and stem cell-specific mRNA – called Oct-4 – inside the stem cells using molecular beacons.

“By fluorescently imaging the level of Oct-4 mRNA in the cytoplasm of live stem cells with molecular beacons, we were able to increase the detection sensitivity and specificity,” explained Bao, who is also a Georgia Tech College of Engineering Distinguished Professor.

Since initially developing this method for detecting and isolating stem cells, the research team has been improving the method’s efficiency and specificity by targeting multiple mRNAs and cell surface markers using molecular beacons and antibodies.

According to Bao, the next stage for this research is to isolate cancer stem cells from human tumor tissue samples.

“After we isolate the cancer stem cells, we still need to learn more about them, including the pathways or genes responsible for their development and whether they behave the same when isolated from different patients. Then we need to identify drug molecules that can kill them,” he added.

Funding for this research is provided by the Emory-Georgia Tech National Cancer Institute Center for Cancer Nanotechnology Excellence (CCNE). This work was funded by grant number U54CA119338 from the National Institutes of Health (NIH). The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NIH.

IMPROVING RADIATION THERAPY
One critical challenge in radiation therapy has always been how best to minimize damage to normal tissue while delivering therapeutic doses to cancer cells. Intensity-modulated radiation therapy (IMRT) is an advanced type of radiation treatment that utilizes computer-controlled linear accelerators to deliver precise radiation doses to tumors while avoiding critical organs. Clinicians can use IMRT to treat difficult-to-reach tumors – such as tumors in the brain, head, neck, prostate, lung and liver – with new levels of accuracy.

“Constructing an IMRT treatment plan that radiates the cancerous tumor without impacting adjacent normal structures is challenging,” explained Shabbir Ahmed, an associate professor in the Stewart School of Industrial and Systems Engineering at Georgia Tech. “Because of the many possible beam geometries and the range of intensities, there are an infinite number of treatment plans and many metrics to assess their quality.”

To develop better treatment plans faster, Ahmed began working with School of Industrial and Systems Engineering professor Martin Savelsbergh and graduate student Halil Ozan Gozbasi, as well as collaborators Ian Crocker, Timothy Fox and Eduard Schreibmann from the Emory University School of Medicine’s Department of Radiation Oncology. Funding for this research
was provided by Emory University.

The Georgia Tech researchers built on an existing model and developed a fully automated program that simultaneously generates several high-quality treatment plans satisfying the clinician-provided requirements. The optimization program uses three-dimensional computed tomography images of the patient and information about (1) the type, location and size of the tumor; (2) maximum allowable doses to non-cancerous organs; and (3) the patient’s health.

“Previous models would produce one treatment plan in an hour and then if it was not exactly what the clinician wanted, someone would have to change the requirements and rerun the program to create a new treatment plan,” explained Ahmed. “Our program produces several optimized solutions in a fraction of the time.”

The technology, which has been tested successfully on real brain, head/neck and prostate cancer cases, produces clinically acceptable treatment plans in less than 15 minutes.

INCLUDING MOTION AND BIOLOGICAL INFORMATION IN TREATMENT PLANNING
Intensity-modulated radiation therapy (IMRT) treatment planning is challenging because some organs, such as the prostate, move due to normal daily volume changes in the bladder and rectum. In addition, a tumor can change shape during radiation treatment, which typically lasts five days a week for five to 10 weeks.

By collecting computed tomography images over time, the researchers can track every spatial point of interest in the tumor and surrounding area during each phase of the breathing cycle. This allows them to develop treatment plans that account for breathing, motion and shape changes throughout the treatment regimen.

“Accounting for motion in the image-guided treatment planning dramatically improves under-dosing the tumor tissue and even reduces the dose to normal tissue and critical organs,” noted Lee, who is also director of the Center for Operations Research in Medicine and HealthCare at Georgia Tech.

In lung cancer cases, that means reducing the average dose of radiation to the normal lung tissue, heart and esophagus. For liver cancer, the researchers have reduced the radiation delivered to normal liver and non-liver tissues.

In another project, Lee and Marco Zaider, an attending physicist and head of brachytherapy physics in medical physics at Memorial Sloan-Kettering Cancer Center in New York, are incorporating biological information into treatment planning for prostate cancer IMRT and brachytherapy – the placement of radioactive “seeds” inside a tumor.

Using magnetic resonance spectroscopy, the researchers identified regions of the prostate that had denser populations of tumor cells. These areas could then be targeted with an escalated radiation dose, while maintaining a minimal dose to critical and normal tissues.

“One of our main concerns is avoiding normal tissue toxicity, so by targeting only the ‘bad’ pockets of tumor cells, we hope to improve the outcome,” said Zaider. “Biological optimization attempts to target tissue that is potentially responsible for metastatic spread.”

Lee’s research has been supported by the National Science Foundation (NSF), the National Institutes of Health (NIH) and the Whitaker Foundation.

This project was partially supported by Award No. 0800057 from the NSF and Award No. 5UL1RR025008-02 from the NIH. The content is solely the responsibility of the principal investigator and does not necessarily represent the official views of the NSF or NIH.

ASSESSING A TUMOR’S ABILITY TO CREATE NEW BLOOD VESSELS
Cancer manifests itself in different ways – some cancers proceed slowly, while others spread aggressively. These differences have led clinicians to believe that personalized cancer therapies might be the best solution for treating the disease.

Now, new research, published in the June 2009 issue of the journal PLoS ONE, is providing insight into the aggressiveness of tumors. This information could facilitate development of a personalized treatment regimen.

Because aggressive tumors create more new blood vessels to sustain their growth, researchers designed long-circulating nanoprobes that were 100 nanometers in diameter and contained a contrast agent that could only seep into tumors from blood vessels that were growing and therefore leaky.

“We exploited the fact that the nanoprobes are too big to leak out of normal blood vessels, but they can leak out of newly forming tumor vessels because these immature vessels have bigger holes in them,” explained lead author Ravi Bellamkonda, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University.

The study showed that the degree of “leakiness” of tumor blood vessels to the nanoprobe correlates to its expression of vascular endothelial growth factor (VEGF), a protein that stimulates the growth of new blood vessels in tumors.

“Clinical studies have shown that VEGF expression varies among tumors, with higher levels of VEGF expression correlating with unfavorable prognosis, but scientists haven’t been able to non-invasively determine VEGF expression levels in individual tumors until now,” said Bellamkonda, who is also a Georgia Cancer Coalition Distinguished Scholar.

After injecting the contrast-containing nanoprobes into rats with six-day-old breast cancer tumors, the research team visualized the levels of nanoprobe accumulation in the tumor using digital mammography. The results showed increased “leakiness,” nanoprobe accumulation and tumor growth rates in tumors with higher levels of VEGF. Similar-size tumors showed various degrees of angiogenesis and blood vessel permeability, which caused them to behave differently, emphasizing the inherent variability in tumors and the need for a personalized approach to each tumor.

“In the future, instead of just measuring the size of a tumor, clinicians can quantify the leakiness of tumor blood vessels to determine the extent of angiogenesis in each tumor and decide which patients should undergo anti-angiogenic therapy or other aggressive treatment regimens,” added Bellamkonda.

Collaborators on this research include Efstathios Karathanasis, formerly a Coulter Department postdoctoral fellow and currently an assistant professor in the Department of Biomedical Engineering at Case Western Reserve University; Carl D’Orsi and Ioannis Sechopoulos of the Department of Radiology and Winship Cancer Institute at the Emory University School of Medicine; and Ananth Annapragada, an associate professor of health information sciences at the University of Texas, Houston.

This project is supported by the National Science Foundation (NSF) (Award Nos. 0401627 and ERC-EEC-9731643), the Nora Reed Foundation, the Wallace H. Coulter Foundation and the Georgia Cancer Coalition. The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NSF.

DEVELOPING A NEW APPROACH TO TARGETED CANCER THERAPY
A new therapeutic strategy for cancer treatment is to inhibit enzymes called histone deacetylases, which play an important role in the regulation of gene expression. Vorinostat (SAHA) – a histone deacetylase inhibitor – was approved by the U.S. Food and Drug Administration in 2006 to treat an immune system cancer called cutaneous T-cell lymphoma.

While these inhibitors are clinically valuable, they typically inhibit many of the 18 different histone deacetylase subtypes, a process that can be harmful to essential cell functions throughout the body.

“Our goal is to create inhibitors for these enzymes that target specific cancerous organs so that we can exploit their anti-cancer activity in the cancerous tissue areas only and not negatively affect other areas of the body,” said Adegboyega “Yomi” K. Oyelere, who holds the Blanchard Assistant Professorship in the Georgia Tech School of Chemistry and Biochemistry.

In the January 22, 2009, issue of the Journal of Medicinal Chemistry, Oyelere and Georgia Tech biology assistant professor Yuhong Fan described a new class of potent non-peptide histone deacetylase inhibitors that can be selectively accumulated in the lungs.

To create them, the researchers modified the amine sugar portion of common antibiotics such as azithromycin and clarithromycin with a histone deacetylase inhibiting structure. Experiments have shown that the new compounds are more potent than SAHA and are lung-specific. As a result of these preliminary findings, Oyelere was recently awarded a five-year, $1.5 million grant from the National Institutes of Health to continue this lung cancer research.

Oyelere is also designing histone deacetylase inhibitors that can be taken up by the hormones expressed on the surface of hormone-positive breast cancer cells to stop the cells from dividing. For this project, he is working with Donald Doyle, an associate professor in the Georgia Tech School of Chemistry and Biochemistry.

“A majority of hormone-positive breast cancers develop resistance to anti-cancer hormone drugs, so if we can exploit the ability of our compounds to be accepted by hormone-positive breast cancers, whether they’re resistant or not, this could lead to the identification of new, broad anti-cancer agents for targeted cancer therapy,” explained Oyelere.

Next up on Oyelere’s list of cancers to tackle with this approach is prostate cancer.

This work is funded by grant number R01CA131217 from the National Institutes of Health (NIH). The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NIH.

INCREASING RESPONSES TO CHEMOTHERAPY
Lakeshia Taite is investigating ways to smuggle powerful chemotherapeutic drugs and chemical compounds into tumor cells, thus increasing the drugs’ cancer-killing activities and reducing their toxic side effects on healthy cells.

As an assistant professor in the Georgia Tech School of Chemical and Biomolecular Engineering, Taite is developing cancer drug delivery vehicles composed of a gold nanoshell core with dendrimers attached to the surface. Dendrimers are polymers that exhibit a tree-like structure with many branches and cavities where chemotherapy drugs can be encapsulated.

The dendrimers are synthesized with targeting molecules on their surfaces that can seek out and bind to cancer cells. Introduced into the body, they bind to cancer cells, and when near-infrared light shines on the body, the gold nanoshell heats up. That heat leads the dendrimers to shrink, the drug to be released, and the tumor cells are exposed to both the heat and drug therapies.

“In some cases, ablation takes place at temperatures that can be uncomfortable to the patient, so we are trying to develop dendrimers that require lower transition temperatures to release the drug,” said Taite. “We believe that even if the lower temperature does not kill all of the cancer cells, it will still damage them enough that they will become extremely vulnerable to the drug, ultimately still leading to cell death.”

Amanda Lowery, a research fellow in radiation oncology at Vanderbilt University, is collaborating with Taite on this research.

Taite is also designing another delivery vehicle to carry and release nitric oxide for the treatment of aggressive brain tumors. She is focusing on nitric oxide because it has the ability to cross the blood-brain barrier and help other molecules cross both the blood-brain barrier and the blood-tumor barrier.

“Nitric oxide has been shown to increase the sensitivity of certain tumors to chemotherapeutics and radiation, so we are working to form materials that can be attached to imaging particles and a chemotherapeutic that can be targeted to specific tumors. That would significantly enhance current tumor treatment approaches,” explained Taite.

The targeted nitric oxide delivery system will be used to study the efficacy of using nitric oxide to sensitize brain tumors to treatment and improve patient prognosis.

“My ultimate goal in designing all of these drug delivery systems is to improve patient quality of life and reduce cancer recurrence,” added Taite.

ENABLING PERSONALIZED DRUG DELIVERY
The search is on for drug delivery systems that allow treatment to be tailored to an individual patient and a particular tumor. Researchers at Georgia Tech are contributing to the pursuit by developing ways to program the assembly and disassembly of multi-particle drug delivery vehicles.

“Cancer is a complicated disease, and we wanted to find a way that we could simultaneously deliver many different particles to the tumor site as a package and, upon arrival, break open the packages so that the individual particles could then carry out their particular functions,” said Valeria Milam, an assistant professor in the Georgia Tech School of Materials Science and Engineering.

Individuals benefit from this type of personalized treatment through the increase in the drug’s cancer-killing power and the reduction of its toxic side effects. Milam and her students are using short nucleic acid polymers called oligonucleotides to connect the particle surfaces for simultaneous delivery of different therapeutic and diagnostic agents to the tumor site.

“To assemble the pieces, we are using short oligonucleotides as the glue because they have a weak, yet sufficient affinity for their partner strand,” explained Milam, who is also a Georgia Cancer Coalition Distinguished Cancer Scholar. “This allows us to direct particles A and B to attach to particle C through oligonucleotide linkages, while keeping particles A and B unconnected to one another.”

Then, to disassemble the particle package, a competitive oligonucleotide – one with a stronger affinity as a partner strand – is introduced into the system. These competitive strands displace the original partner strands, allowing the package to break open. Milam and her team are further improving the drug delivery vehicle so that it can be initially camouflaged to avoid any host response that would clear it out of the body before arriving at the tumor site.

“Our ongoing work involves initially masking the presence of the therapeutic carriers by applying a stealth coating to the vehicle surface,” noted Milam. “Then, after the desired circulation time, the coating will be shed to reveal cancer-targeting ligands.”

While Milam’s experiments are still at the laboratory stage, her ultimate goal is to develop materials that can be used in the clinical setting to treat cancer. Former Georgia Tech students Christopher Tison and Sonya Parpart, and current graduate students James Hardin and Bryan Baker, also worked on this research. This work is currently supported by the Georgia Cancer Coalition, a National Science Foundation CAREER award, and the U.S. Army. It was previously supported by the Emory-Georgia Tech National Cancer Institute Center for Cancer Nanotechnology Excellence (CCNE).

This material is based upon work supported by the U.S. Army (Award No. W911NF-09-1-0479), National Institutes of Health (NIH) (Award No. U54CA119338) and National Science Foundation (NSF) (Award No. DMR-0847436). Any opinions, finding, conclusions or recommendations expressed are those of the principal investigator and do not necessarily reflect the views of the U.S. Army, NIH or NSF.

ANALYZING GENE EXPRESSION DATA TO PREDICT DRUG RESPONSE
The major clinical goals in applying gene expression profiling to cancer are to develop predictors of drug response that will guide more individualized therapies.

Ming Yuan, an associate professor in the Stewart School of Industrial and Systems Engineering at Georgia Tech, is using computational and mathematical approaches to analyze how gene expression evolves over time in individuals with breast cancer and whether these patterns can predict treatment outcome. Specifically, Yuan is studying how gene expression evolves during the menstrual cycle and whether there is any association between these patterns and cancer relapse.

“Our goal is to weed out the genes that just change expression level due to a woman’s menstrual cycle and not because of tumor progression or treatment,” explained Yuan, who is also a Georgia Cancer Coalition Distinguished Cancer Scholar. “We want to know which genes are abnormally expressed over time and behave differently than the majority of genes because that would make them likely drug targets.”

Better predictors of relapse risk could help cancer patients make better treatment decisions in consultation with their physicians. Yuan is working with William Hrushesky of the University of South Carolina and the Dorn Veterans Affairs Medical Center on this research.

In another project, Yuan is collaborating with two University of Wisconsin professors, Alan Attie and Christina Kendziorski, to conduct expression quantitative trait loci (eQTL) studies. This analysis allows the researchers to identify genomic hot spots that regulate gene transcription and expression on a genome-wide scale.

“We want to determine which regions of the genome are most predictive of expression variations, but it’s challenging because there are a vast range of possible regulatory loci and many of them are correlated, making it hard to differentiate which is actually responsible for a given effect,” said Yuan.

Yuan’s analysis will determine the hot spots as well as how those genes are connected to each other, but ultimately, the proposed genes will need to be studied further by biologists.

Yuan’s research is supported by the National Science Foundation and the Georgia Cancer Coalition.

This work was partly funded by grant number DMS-0846234 from the National Science Foundation (NSF). The content is solely the responsibility of the principal investigator and does not necessarily represent the official view of the NSF.

Source:  Georgia Institute of Technology, Research Communications