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Bringing Tumors Into Sharper View

Conquest - Spring 2007

By Eileen A. Ellig

By combining PET images with computed tomography scans
(right), radiologists are better able to characterize
tumors and monitor therapies.

Picture this: A day when physicians can detect the subtlest molecular changes within your DNA that may predispose to cancer not with a tissue biopsy or blood test, but with something much less invasive — imaging.

“That’s the pie in the sky,” says Reginald Munden, M.D., D.M.D., chair ad interim of M. D. Anderson’s Department of Diagnostic Radiology. “Someday, we may be able to screen populations truly at risk for certain cancers and let them know if we see any early genetic transformations well before a tumor becomes visible or causes problems.”

With new and improved imaging technology, the ability to do this may not be too far off.

Advances in medical imaging, which initially was based solely on detection of anatomically different or abnormal structures, have made it possible to now visualize not only the body’s physiological function, but also various intracellular processes that promote cancer.

When asked what is making so-called molecular imaging possible, M. D. Anderson radiologists point to “fusion imaging,” or the pairing of positron emission tomography with computed tomography.

In diagnostic imaging, “I haven’t seen anything make that kind of an impact on the cancer patient since CT was introduced back in the 1970s,” says Donald Podoloff, M.D., head of the Division of Diagnostic Imaging and professor of nuclear medicine.

When CT came on the scene, radiologists were able to understand each individual’s anatomy in greater detail than they were able to do with plain X-rays, bringing into three-dimensional view the body’s organs, bones and other tissues, as well as tumors. They now had a tool that could determine more precisely the location of a tumor in relation to critical structures and determine the stage of disease.

PET emerged some 20 years later, providing a way to measure the metabolic, or chemical, activity of cells within the body — primarily the regional distribution of glucose, or sugar, in cancer cells.

Tumors entrap and more readily absorb glucose than normal cells and show up as active bright spots on the PET scan, indicating their location and concentration throughout the affected organ, according to Podoloff. The latter is of particular benefit when it comes to identifying volumes of tissue within a mass that may be more or less sensitive to certain therapies.

One drawback to using PET alone, however, is it doesn’t provide an anatomic landmark like CT. But add the two images together and “you now have a very powerful machine that can complete the picture,” Podoloff says. “It combines both form and function, and for addressing the cancer problem, this produces some unique opportunities because we know that the function of an organ is disturbed before its form.”

Partners in discovery

“Frankly,” Munden says, “I don’t think any of us were truly aware of the benefit of merging PET with CT until we started looking at the images and saw the added sensitivity and specificity they provided in detecting and localizing tumors.”

Reginald Munden, M.D., D.M.D., fore-sees a day when imaging, instead of a biopsy or blood test, could be used to screen people at high risk for cancer and detect early genetic changes before a tumor becomes visible or causes problems.

This technology, he adds, is contributing greatly to “our ability to characterize tumors and image the very biomarkers our clinical colleagues are trying to target.”

There is a large body of research being conducted to develop molecular imaging agents that could trace whether a drug is actually reaching the tumor, being taken up in the cells and whether it’s working.

“And we can do this not at a bench with a microscope — as is the traditional approach — but non-invasively in the context of the whole body and over time, which means repetitive imaging of these processes and close monitoring of therapies,” says Juri Gelovani, M.D., Ph.D., chair of the Department of Experimental Diagnostic Imaging.

Use of the radiotracer fluorodeoxyglucose has proven beneficial in evaluating the early effects of Gleevec® in treating gastrointestinal stromal tumors, for example. Since these tumors take up a lot of sugar, they can easily be seen on a PET image, says Homer Macapinlac, M.D., chair of the Department of Nuclear Medicine and head of the PET imaging program at M. D. Anderson.

Within 24-48 hours, he says, “we can determine if there has been a response even though the mass is still there. If it’s no longer absorbing glucose, for instance, then we know the drug is working and that generally correlates with a good outcome. That’s the paradigm we hope to emulate for other novel therapies in the early assessment of treatment response.”

A limiting factor, Macapinlac notes, is that while a good surrogate marker for active cancer, fluorodeoxyglucose doesn’t show proliferating cells or cell turnover, which might be a better index of tumor activity than glucose. To date, this is the only federally approved tracer for use in PET imaging.

With Gelovani’s support, Macapinlac says, “we’ll soon have available to us tracers that are more specific in measuring these kinds of metabolic parameters.”

On assignment

Gelovani wants nothing less than to expose tumors, from the largest to the tiniest of metastatic cells that often go undetected until they have spread throughout the body.

One way he and his team are doing this is by developing agents for molecular imaging with PET, MRI, single photon emission computed tomography and optical (near-infrared) imaging of tumor-specific receptor molecules and substrates to proteins that are critical in tumor cell signaling, metabolism and regulation of oncogene expression.

They are investigating the potential use of several novel molecular imaging agents that can be used to predict or monitor the effectiveness of novel anti-cancer drugs that target specific proteins once they get inside the tumor and induce cell death or cut off the tumor’s blood vessel supply.

While viewing CT and PET scans separately offers benefit, combining the two technologies to produce one image gives Homer Macapinlac, M.D., a more complete picture of where a tumor is located, what structures are affected and whether
a drug is reaching its target.

With these imaging agents, they can bring tumors into view and then follow the drug and observe its activity in real time.

This is highly important for clinicians “because previously the only method of validation was a biopsy-based assessment of gene expression from a single point in a tumor, which doesn’t describe heterogeneity either within the tumor or metastatic sites. It also doesn’t tell you what critical tumor genes had been activated, sustaining tumor survival and progression,” says Gelovani, who directs the Center for Advanced Biomedical Imaging Research. The center is one of six facilities that will comprise M. D. Anderson’s Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer.

The team’s efforts to assist clinicians in finding better ways of targeting therapies doesn’t stop there.

They also are employing cellular tracers that can be labeled with different imaging-sensitive reporter genes, such as herpes simplex viral thymidine kinase, or HSVTK, to track and assess the effectiveness of therapeutic cells in killing tumors. HSVTK, Gelovani says, is widely used as a pro-drug sensitization gene in combination with standard chemotherapies.

Juri Gelovani, M.D., Ph.D., and his colleagues are developing new molecular imaging agents and meth-ods that will increase the sensitivity and accuracy of cancer diagnosis and treatment monitoring.

Gelovani, who originally developed a technique to image this particular gene, says it also can be incorporated or co-expressed with other therapeutic genes, such as p53, in a variety of gene-delivery vectors. And if properly designed and expressed, he notes, HSVTK would provide a means of imaging and monitoring not only genetic therapies, but cellular ones as well.

In collaboration with Steven Kornblau, M.D., associate professor in the Department of Stem Cell Transplantation and Cellular Therapy, for example, Gelovani and his team have developed a tracer for monitoring transplantation of T cells genetically modified with HSVTK for treatment of leukemia. While these T cells are thought to elicit a graft-versus-leukemic response, they also can later cause graft-versus-host disease, a serious immune reaction of the donor’s cells to the recipient’s.

“We’ll be able to image the location, migration and site-specific proliferation of the T cells because all of the donor cells will have the reporter gene and we can inject our tracer multiple times to monitor the patient’s status and, hopefully, diagnose graft-versus-host disease before severe clinical symptoms develop. Until now, this could only be proven by a biopsy,” Gelovani explains.

Armed with this early information, clinicians can then be proactive and administer drugs that can eliminate any diseased cells that may be present.

Gelovani and his team also have joined forces with investigators from M. D. Anderson’s Departments of Cardiology and Stem Cell Transplantation and Cellular Therapy, and colleagues at Texas Heart Institute to develop a reporter gene system for monitoring the location, fusion and survival of stem cells injected into the myocardium, the thickest layer of the heart wall.

“In a way, we’ll be able to visualize how many of those stem cells have developed into viable heart muscle,” Gelovani explains. “Using more conventional imaging approaches like magnetic resonance imaging, we’ll also be able to determine how much of that newly formed myocardium has contributed to the function of the heart.”

Similarly, the team is developing applications to image stem cells for cancer therapies. They have demonstrated, for instance, that genetically modified stem cells carrying the HSVTK reporter gene engraft into the supportive tissue (stroma) surrounding the tumor, even in microscopic cancer cells, and contribute to its growth.

John Hazle, Ph.D. (back), chair of the Department of Imaging Physics, is collab-orating with Jason Stafford, Ph.D.(right) and Kamran Ahrar, M.D., on the devel-opment of novel MRI tech-niques to monitor non-invasive or minimally invasive thermal therapies

“Again with imaging,” Gelovani says, “we can better assess non-invasively how much of a drug (specifically, ganciclovir) is needed to induce tumor stromal collapse, based on the percentage of stem cells seen in the tumor.”

With a dozen or so tracers under development, Gelovani is optimistic that new imaging agents will bring into sharper view various molecular abnormalities indicative of cancer and revolutionize the diagnosis and treatment of the disease.

Phasing in

“We’re beginning to transition into the clinical phase of evaluation with several of our tracer compounds,” Gelovani says, “which will initially focus on radiation dose absorption, biodistribution, metabolism and pharmacokinetics.”

Next, his team will validate tumor activity by comparing the imaging results with a tissue biopsy, hoping to confirm that what they see on the image does in fact reflect the magnitude and duration of expression of the targeted gene or protein.

Gelovani is quick to note that these early imaging studies are not intended to have any therapeutic effect, but are essential in establishing targeted tracers as a viable way for clinicians to understand early on what is happening at a molecular level in these tumors when a drug is given and to know whether it’s really affecting the target proteins.

The pairing of PET scans with CT scans is a tremendous advance in diagnostic imaging, according to Donald Podoloff, M.D., allowing radiologists to visualize various intracellular processes that promote cancer.

“The development of these imaging agents is imperative not only for monitoring therapies,” he says, “but also in ultimately helping to stratify patients towards therapies that will most likely be effective in their case — in other words to individualize therapies.”

Macapinlac takes it a step further saying, “we also have an opportunity to let patients know within days rather than weeks or months whether their treatment is working. Having this information upfront provides patients with hope, the fervor to continue the treatment despite the side effects.”

Image-Guided Precision

Marshall Hicks, M.D., and his team rely heavily on imaging technology to obtain biopsies and guide therapies.

Donald Podoloff, M.D., head of M. D. Anderson’s Division of Diagnostic Imaging and professor of nuclear medicine, tells the story of his grandmother to illustrate how far imaging technology has come in diagnosing and treating cancer.

“In 1955, my grandmother, who was then 60 years old, turned yellow over night. After a battery of tests, she underwent exploratory surgery, at which time her doctors found she was covered with cancer.

“Today, a CT scan would have picked that up and she would have had a simple biliary drainage procedure (to relieve pressure in bile ducts caused by an obstruction) and the whole thing would have been done in a matter of hours not the seven to 10 days she spent in the hospital.”

The exploratory laparotomy, which was a common operation 20 to 30 years ago, has virtually been replaced by CT or magnetic resonance imaging, Podoloff says, “because we can now look inside and see what’s going on without having to do surgery first.”

Interventional radiologists at M. D. Anderson rely heavily on CT and MRI imaging to obtain biopsies and guide therapies, according to Marshall Hicks, M.D., professor of diagnostic radiology and head of interventional radiology.

The generated images help them navigate during a procedure, allowing them to differentiate hard-to-see areas better and ensuring that they insert the needle in the right place.

Image-guided biopsies make up the bulk of the procedures. While most of these are done to determine stage of disease, Hicks and his team are increasingly being asked to sample various spots within a tumor to verify that an investigational drug is actually reaching its target and being expressed in the tissue.

“The Food and Drug Administration is now saying that if you want to bring a new drug to market, we need to know where that drug goes, we need to see it and you need to prove the drug is there,” says Podoloff, noting that interventional radiologists are being besieged with questions that need answering.

Beyond biopsies, interventional radiologists are performing procedures using imaging to block off the tumor’s blood supply, guide probes that can be heated or cooled to destroy tumors and to place infusion catheters into organs for drug delivery, among others.

“The sophistication of the imaging is critical for what we do,” says Hicks, whose team is working collaboratively with colleagues throughout M. D. Anderson to develop novel and more sensitive image-guided drug and thermal delivery approaches, devices that can be used for diagnosis, palliation and treatment, and non-invasive ways to image tumor cell death.

“We’re continually enhancing our techniques,” Hicks says, “so that we can shorten the time when newer applications can benefit our patients.”

© 2015 The University of Texas MD Anderson Cancer Center