Theranostics Dissected

Recent developments in theranostics could usher in an era that helps drive personalized medicine from research to reality. The practice of theranostics harnesses molecular imaging to target drug delivery to specific cellular features characteristic of an individual patient’s disease. However, individualized medicine also may be its Achilles’ heel.

The potential for a pharmaceutical blockbuster is next to nil because each treatment targets a select group of patients. While some researchers explore the clinical potential in areas from prostate cancer to diabetes, others are troubleshooting regulatory and economic hurdles.

Theranostics is complex, but all the varied, but necessary, parts are working in the research setting, says Daniel Y. Lee, MD, PhD, director of the PET Center at The Methodist Hospital Research Institute in Houston. But, the entire system required to translate theranostics to clinical practice is not yet working together.  

As the pace of research accelerates, investigators need to prepare for other challenges. In fact, regulatory issues, rather than scientific challenges, present the primary barrier to catalyzing theranostic drug platforms, says Lee.

Theranostics in Action

A single-entity theranostic system combines initial staging with an imaging version of specific probe (green sunburst), followed by therapy with the therapeutic version of the probe (red lightning bolt). Restaging exams are performed with the imaging probe. Patients with positive imaging results (red lesion) can be treated with the therapeutic agent. Patients with negative results will not be treated with the agent.

© 2011 by American Roentgen Ray Society / Lee D Y , Li K C P AJR 2011;197:318-324

The basics

Theranostics is best exemplified by the use of radioactive iodine to image and treat thyroid diseases. This dual function is possible because of the characteristics of the radioactive element and the natural mechanism of concentrating iodine by thyroid cells. When this biochemical mechanism is lost as in certain forms of aggressive thyroid cancers, then radioiodine therapy is no longer effective, underscoring the need for active targeting. Modern theranostics promises to target treatment to the appropriate tissue.

One-half of the theranostics equation is the new class of drugs based on molecular targeting. These drugs are designed to take action on a specific receptor or other gene product characteristic of the disease. For example, women with breast cancer are tested to assess the status of human epidermal growth factor receptor 2 (HER2). Women with positive results are candidates for trastuzumab (Herceptin, Genentech) therapy, a biological drug that specifically targets HER2.

Molecular imaging can be leveraged to combine noninvasive imaging and targeted drug delivery. Imaging agents are typically small molecules or biologics with tumor-seeking properties. Combining these agents with disease-destroying payloads, such as radioisotopes or drugs, can produce customized theranostics.

Nanometer-sized materials are the newest additions to this platform. The composition and size of these nanomedicines allow for multiple components to be carried. By choosing the correct combination of targeting, imaging and therapeutic payloads these nanomedicines provide opportunities for drug development. “We are on the cusp of creating new nanoparticle-based, multipurpose targeting vehicles,” confirms Lee. 

Using the analogy of a car model, the nanoparticle serves as the platform for theranostics, but it can be accessorized differently depending on the patient’s specific disease. Some nanoparticles require GPS for guidance; others require a larger trunk with remote control operation; and still others require sophisticated communication tools, such as headlights that flash to indicate a car’s location.

Imaging with a theranostic agent can visualize receptors or proteins in a disease process to determine if a patient is responding to therapy.

Although the last two decades have brought progress in nanomedicine, significant challenges remain. While researchers are progressing with nanoparticle development, the capability to activate drug delivery has lagged. “We need to control the trigger, so the drug is delivered to the appropriate target. The challenge is finding the right combination of targeting agents, vehicles and control elements to make the trigger work,” says Lee. “These are solvable problems.”

In the research lab

Zaver Bhujwalla, PhD, director of the molecular imaging program at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, has turned to theranostics with the goal of treating metastatic prostate cancer.

Although there are multiple treatment options for primary prostate tumors, the window begins to close after the cancer metastasizes. “We are trying to figure out how to target cancer cells without damaging normal tissue,” Bhujwalla explains.

Her team’s preclinical project has equipped a nanoparticle with an inactive form of chemotherapy and an enzyme. The theranostic cocktail includes an agent of prostate-specific membrane antigen expressed on the surface of aggressive, castrate-resistant prostate cancer.

The particle sticks to cells expressing the antigen, making it highly specific for cancer cells. In addition, the particle passes the trigger test. The drug-protein complex binds to the cell’s surface, allowing it to get inside the cancerous cell, where the enzyme slowly activates chemotherapy.

The nanoparticle can be radiolabelled with a SPECT or PET radiolabel for targeting. The conversion process in which the chemotherapy is activated is detected by MR spectroscopy.

The new technique may work against any cancer in which tumors elevate production of certain cell surface proteins, says Bhujwalla. Examples include certain breast, liver, lung and kidney cancers. The team plans to complete toxicity studies and translate the process to humans.

Although cancer has taken center stage in theranostics research, the platform offers potential for other diseases. Researchers at the Molecular Imaging Laboratory at Massachusetts General Hospital/Harvard Medical School in Boston are working with type 1 diabetes. Specifically, Anna Moore, PhD, and colleagues are leveraging MRI to target and monitor transplanted islet cells.

Although islet transplantation has emerged as a promising treatment for type 1 diabetes, there is a shortage of islet donors. The shortage is exacerbated by a fairly high death rate among transplanted islet cells. “Histological studies show up to 60 percent of islets die during the first two weeks after transplantation,” says Moore.

Moore and her team aim to use theranostics to protect islets prior to cell death, which involves silencing the genes responsible for damage and death. They incubated islet cells with a conjugate designed to silence one of the offending genes and used magnetic nanoparticles to label and monitor the islets. MRI showed better survival among grafts produced with the protected islet cells. Moore and colleagues further boosted islet survival by using a similar process to silence a protein associated with the histocompatibility complex that causes T-cells to attack the transplanted islets.

“Silencing one gene still leads to graft failure, but that failure is delayed. The idea is to combine multiple nanoparticles in a cocktail and silence multiple genes linked with graft failure,” says Moore. Their next step will center on replicating these experiments with nonhuman primates.

Beyond science

Translating theranostics from bench to bedside likely hinges on re-framing the conventional drug development process, which requires investing billions of dollars into the development of a blockbuster drug with a large target market.

With individualized treatment, the target market is relatively microscopic. Each agent is customized for a subset of patients whose cancer contains very specific proteins or receptors. Thus, development needs to be approached from a different perspective, says Lee.

Several avenues are possible. One promising path is a rapid mechanism for testing new radiopharmaceuticals in a Phase 0 clinical trial. With radioactive imaging agents, a Phase 0 trial allows first-in-human experiments, because the material is used at a dose that is too low to cause any drug effects. This pathway dramatically condenses the cost and time of a traditional trial from up to one decade to one to two years.

“With substantially reduced costs, theranostics make economic sense,” says Lee. According to the leading scientists in the field, theranostics is not a matter of if, but when. As research advances, stakeholders need to overcome economic and regulatory hurdles and connect with clinicians to help them understand these new tools.