The concept of personalized medicine has been influencing patient care since at least the dawn of Western medicine more than 2,000 years ago.

Hippocrates, an early proponent of this concept, is said to have observed, "It's far more important to know what person the disease has than what disease the person has."

It was not until the 19th century that developments in chemistry, histochemistry and microscopy enabled scientists to understand the underlying causes of diseases. Those breakthroughs ushered in the innovations of the pharmaceutical and medical device industries of the 20th century and gave rise to genetics, imaging and data mining.

More recently, the ability to sequence the human genome finally put the concept of personalized medicine into practice, making it possible for scientists to develop technology that curates diagnosis and treatment for each individual patient.

Theranostics, a combination of therapy and diagnostics, is a form of personalized medicine. While it usually refers to genome and RNA sequencing, molecular theranostics is a uniquely promising specialty that is gaining momentum.

“Theranostics involving molecular nuclear medicine is a very small field within the whole field of medicine, but I think it has the most interesting, practical applications for theranostics," says Dr. Richard Baum, professor of nuclear medicine and chairman and clinical director of the Theranostics Center for Molecular Imaging and Molecular Radiotherapy at Frankfurt University Hospital in Germany.

Molecular theranostics typically involves a PET/CT exam in combination with a diagnostic radiotracer to determine whether a cancer patient would benefit from a specific therapeutic drug.

The field is not new, but it didn't gain traction until recently. The radiotracer iodine-131 was used in 1941 at the Massachusetts Institute of Technology to treat metastatic thyroid cancer, but it wasn't until 2011 that Frankfurt University Hospital launched the first world congress for molecular theranostics.

To date, the Theranostic World Congress has been held four times. In 2013, it was held in India. In 2015, it took place in the U.S. Last November it was in Australia.

The current gold standard
Most cancer patients are still treated based on their symptoms. The physician makes a diagnosis and then selects the treatment using data from large clinical trials, which predict with some certainty if the patient will respond to the treatment.

“It is common for physicians to use a trial-and-error strategy until they find the treatment therapy that is most effective for the individual patient,” says Baum.

Following chemotherapy, lab testing and CT or MR exams are performed after several weeks or months to determine if the cancer is shrinking. In many cases, the therapy doesn’t work and the patient has to endure another round of chemotherapy.

“Of course, it is based off of large clinical trials with thousands of patients where you know the drug is working in 70 out of 100 patients,” says Baum. “But if you are the individual patient, no one knows if you belong to the 70 percent or to the 30 percent that are not responding.”

The difference between the standard approach and the theranostic approach is that a test is performed before the therapy is administered. That informs the physicians that the drug will bind to the cancer cell, which means the treatment should be effective.

Baum explains to his patients that the diagnostic radiotracer fits like a key in a lock into the tumor cell, which allows him to predict if the same peptide will carry the therapeutic radioisotope into the tumor cell and kill it.

Neuroendocrine tumors
Each year, about 8,000 people in the U.S. are diagnosed with a neuroendocrine tumor, according to the American Society of Clinical Oncology. These tumors originate in the gastrointestinal tract and frequently localize in the lung, pancreas and small intestine.

The research on treating neuroendocrine tumors with molecular theranostics was pioneered in Europe. The diagnostic compounds are labeled with gallium-68 (Ga-68) and the therapeutic compounds are labeled with lutetium-177 (Lu-177).

"That targets these neuroendocrine tumors and has been shown to be very successful even in delaying disease progression,” says Dr. Johannes Czernin, editor-in-chief of the Journal of Nuclear Medicine and professor in the department of molecular and medical pharmacology and chief of the Ahmanson Translational Imaging division at UCLA.

The physician has the patient undergo a Ga-68-DOTATATE PET/CT exam to see if the target is expressed in the body. If it’s expressed, the patient then qualifies for therapy and is treated with the Lu-177-DOTATATE compound, which is on the market as Lutathera.

To date, major studies investigating this therapy have been published and Czernin expects it to be approved by the FDA later this year.

Prostate cancer
Prostate cancer is far more prevalent than neuroendocrine tumors. The American Cancer Society estimates that there will be about 161,360 new cases of prostate cancer and about 26,730 deaths from the disease this year.

"When talking about prostate cancer that recurs and becomes hormone resistant, you have to lock all of the hormones in the body, which is usually done with medication, but even with these medications the tumors reoccur,” says Czernin.

The prostate-specific membrane antigen (PSMA) protein, which is found on the surface of prostate cancer and metastatic cells, was first discovered in the 1980s. It was originally labeled with Ga-68 and only used for diagnostic purposes, but eventually it was labeled with Lu-177 to also be used to treat metastatic prostate cancer.

A study from June 2015 investigating a PSMA-inhibiting theranostic agent called PSMA-617 was presented at the 2015 Annual Meeting of the Society of Nuclear Medicine and Molecular Imaging. The researchers imaged mice with Ga-68 to assess the diagnostic value of PSMA-617.

They then used Lu-177 to deliver a more powerful dose of radiation to penetrate and destroy the tumor cells when combined with PSMA-617. That preclinical research was followed by the first in-human clinical trial, which found that this therapy can reduce the prostate-specific antigen (PSA) level from 38 to 4.6 nanograms per milliliter.

Pioneering the PSMA-targeted theranostic field in Europe, a research group in Germany produced the imaging and therapeutic compounds and they were later approved for clinical use. They have been used to image thousands and treat over 1,000 patients with prostate cancer.

There’s a single-center trial underway at Frankfurt University Hospital that’s investigating PSMA for imaging and therapy, and a multi-center trial will soon begin in Germany. Most of the university hospitals in Germany are now offering this therapy to patients, says Baum.

“It’s a specific situation in Germany because we can use new radiopharmaceuticals in hospitals, especially in university hospitals, without approval by German authorities because we have a law that allows us to administer new radiopharmaceuticals to end-stage cancer patients,” he adds.

This hasn’t been approved for use in the U.S. due to the FDA’s strict regulatory requirements. UCLA and Stanford University are performing Ga-68 PSMA PET/CT exams, but therapy cannot be performed.

"We are sending out patients to Europe for treatment, which is unfortunate,” says Czernin. “There is no question that we will get [approval] fairly quickly, which will make life much easier for patients.”

This therapy has a response rate of over 80 percent, even among end-stage cancer patients, according to Baum. In addition, there are no adverse effects, which is one of the main advantages of theranostics.

“The therapy is really a cancer-targeted therapy, which means that it really hits the tumor cells and is not affecting normal tissue, [as] opposed to chemotherapy, which affects all dividing cells,” Baum adds.

What about other cancers?
In 2013, 232,924 people in the U.S. were diagnosed with breast cancer, 212,584 with lung cancer and 136,119 with colon cancer, according to the Centers for Disease Control and Prevention.

There aren’t any markers specific enough to be used to treat those cancers. F-18 FDG, which is the main radiopharmaceutical used for PET/CT imaging, is an unspecific biomarker, says Baum.

“It just tells you that the cancer cells [have] increased metabolism,” says Baum. “It is very sensitive to find the disease, but it cannot determine if it’s a breast cancer cell, lung cancer cell or lymphoma cell because they all take up FDG very heavily.”

Since most tumors don’t express cancer cell-specific receptors, there is an increasing need to find other ways to deliver image-guided targeted molecular medicine. Sources such as metabolism, angiogenesis, inflammation, the tumor microenvironment and stromal cell receptors are being explored, according to a study published in the European Journal of Radiology.

The researchers concluded that although cancer cell receptors are the easiest targets for theranostics, future areas will include targeting specific microenvironments, cancer stem cells and imaging, and targeting preventive microenvironmental niches for cancer stem cells.