Theranostics, Nuclear medicine at it’s best

In this new issue of Pangea-ePatient we are starting a series of    articles on radio- pharmaceuticals that are used for diagnostic and therapeutic procedures that are now commonly called Theranostics.

Theranostics, the new buzz word in medicine was coined in the early 2000’s by the CEO of PhamaNetics to define the vision for his company. It stems from the contraction of two words: therapeutics and diagnostics. Theranostics are one of the significant outcomes of the Human Genome Project. In the medical era of the omics, it is directly related to, if not synonym to, personalized medicine where diagnostic and therapeutic procedures are individually carved out for patients based on their genotype and phenotype. Most commonly, it refers to the use of a single agent/compound to diagnose and treat a specific disease.

While fitting well with the medical vocabulary of the new millennium, Theranostics are not new to nuclear medicine practitioners. In fact, it has been intimately part of our day to day practice for a long time. Way before the sequencing of the sodium iodine symporter gene in 1996 which characterized the cellular membrane transporter for iodine., nuclear medicine had already used the same physiologic 131 iodine molecule to diagnose and to treat patients with thyroid cancer for a few decades. Radioiodine imaging of the thyroid gland was in fact initiated by Benedict Cassen in 1950 already at UCLA using, at the time, a rectilinear scanner. To this day, the accumulation or lack of uptake of radioiodine by the thyroid gland represents a key non-invasive tool for the diagnosis and treatment of thyroid cancers.

The visualization, description and quantification of the molecular processes in normal and abnormal cells through molecular techniques has exploded since the late 1990s. Modern therapy of cancers, neurological and cardiac conditions now relies on the identification and targeting of specific cellular molecules. At the intersection of molecular biology and imaging, molecular imaging and nuclear medicine have grown exponentially as the complex biochemical and molecular secrets of the cell were being unraveled. The number of articles and references already published on the subject is striking: in less than 1 second a Google search for the words molecular imaging yields more than 8.6 million hits.

Using specific probes and labeling them with diagnostic and/or killer medical isotopes, nuclear medicine offers the most attractive and quintessential tool in theranostic medicine. Besides iodine, the second class of nuclear medicine compounds that can fall into theranostic nuclear medicine are the radiolabeled monoclonal antibodies and  their fragments’  variations. Unfortunately, and albeit having an exquisite specificity to targets, their high molecular weight, slow clearance and poor diffusion in the tissues did severely limit their clinical usefulness. In vogue in the 80’s and early 90’s the only three “survivors” of that chapter of nuclear medicine that are in clinical use today are the anti CD20 idodine-131 labeled tositumomab (Iodine-131 Bexxar) and Y-90 ibritumomab tiuxetan (Zevalin) and the almost defunct Indium-111 Capromab pentedite monoclonal antibodies.

The modern landmark for theranostic nuclear medicine originated in the seventies with the discovery of Somatostatin. Somatostatin, a 14-amino acid Cystin bridge-containing peptide, was first discovered in 1973. The elucidation of its three-dimensional structure, its metabolism and biological activity site in the following years rapidly lead to the synthesis of a large number of analogs. Identified as the most stable and active in inhibiting the effect of the growth hormone, Octreotide, one of the derivatives, demonstrated enough in vivo stability to obtain regulatory approval in 1988 for the treatment of acromegaly and carcinoid tumors.

The coupling of Octreotide to gamma emitting isotopes in the late 80’s and early 90’s represented a major breakthrough to what we call now molecular targeted imaging. Furthermore, its labeling with yttrium 90 and lutetium 177 in the early 2000’s started the modern era of theranostic nuclear medicine by introducing the fast-growing field of peptide receptor radionuclide therapy (PRRT). In PRRT, specific receptors present at the surface of tumors can now be detected, imaged, treated and followed up with the same peptidomimetic labeled with either imaging or killer isotopes. Labeled with gallium 68, a positron emitter and lutetium 177 a gamma and beta emitter, the somatostatin analog dotatate has recently emerged as a prime tool to diagnose, treat and follow up the treatment efficacy of neuroendocrine tumors overexpressing the somatostatin receptor.

High throughput platforms such as phage, bacterial and aptamers display libraries, protein, RNA and DNA microarrays, fluorescence, spectroscopy are now routinely used to identify and to develop small molecular probes to image and potentially treat these specific receptors targets. Tagged with bifunctional chelating agents, native peptides, hormones, neurotransmitters and peptidomimetics are now emerging as suitable molecules for site-directed targeted imaging and therapy. Among the most promising of these compounds in nuclear medicine are the inhibitors of the prostate specific membrane antigen (PSMA).

PSMA is a membrane glycoprotein with peptidase activity which is significantly over-expressed in prostate cancers. Its expression increases with tumor aggressiveness, androgen-independence, metastatic disease, and disease recurrence. Evidence suggests that PSMA may perform multiple physiological functions within the cell: a role in signal transduction, cell migration, receptor function for an unidentified ligand and nutrient uptake such as glutamate and folate have been suggested.

Having a sensitive and specific biomarker to localize primary and metastatic prostate cancer would greatly improve the algorithm for the diagnosis and management of prostate cancer. Other than skin cancer, prostate cancer is the most common cancer in North America. There are about 180,890 new cases of prostate cancer every year in the US. About one out of seven men will be diagnosed from prostate cancer during his lifetime.

Since 2012, the number of clinical studies using urea- based PSMA ligands, such as 123, 124, 131 labeled IMIP- 1072/-1095, 99mTc labeled MIP-1404/-1405, 68Ga labeled HBED-PSMA,   18F labeled DCFBC and DCFPyl, has exponentially increased. Among these agents, the 68Ga- and 18F- labeled compounds have attracted the most attention, as these compounds can be used for PET/CT imaging. However, the availability of 123I or 99mTc also will allow SPECT/CT imaging in centers without facilities for PET. Based on these studies, the promising uses of imaging with labeled PSMA ligands in the management of prostate carcinoma include: the primary staging of high risk cancer disease, the biochemical recurrence with low PSA levels (as low as 0.2 ng/ml), identification of lesions for biopsy targeting after negative previous biopsy, the monitoring of systemic treatment in metastatic disease, the active surveillance and the treatment monitoring after 177Lu-PSMA ligand therapy.

Because of their ability to characterize cellular physiology and dysfunction, the radio- pharmaceuticals used in nuclear medicine offer a very unique and specific window on disease that can exploited both for diagnostic and therapeutic purposes. During the past two decades, numerous ligands that bind to specific molecular targets, particularly in cancers, have been identified and characterized. Their labeling with single photon and positron emitters and alpha or beta particles has opened up a new era in nuclear medicine. While still in its infancy, nuclear diagnostic and therapeutic targeting (nuclear theranostics) is rapidly becoming a cornerstone in personalized oncology  medicine.

The lack of concerted efforts in research and development of new radio-pharmaceuticals in the last part of the 20th century created a climate of uncertainty about the field of nuclear medicine at the eve of the 21st century. In a very interesting and remarkable turn of events, theranostics have the potentials of becoming the new holy grail of nuclear medicine.

In this issue, we will first look at the treatment of thyroid cancers with radioiodine. The upcoming June 2018 issue will illustrate the use of Theranostics in neuroendocrine tumors. In the October 2018 edition, we will describe and illustrate the very exciting new radiopharmaceuticals for the diagnosis and treatment of prostate cancers.