Beyond Cancer Imaging
Exploring the new world of theranostics that integrates cancer diagnosis with treatment
Zaver M. Bhujwalla |
At the interface of diagnosis and therapy, theranostic imaging is showing real promise in the rapidly expanding field of precision medicine. As we know, when administering cancer therapy, it is critical to minimize damage to normal tissue. Molecular imaging provides this crucial support by identifying disease-specific targets, contributing to the design of agents against these targets, visualizing their delivery, and monitoring their therapeutic effect. And now that genomic and proteomic profiling can provide an extensive “fingerprint” of each tumor, it is possible to design personalized cancer theranostics which minimize damage to normal tissue. The importance of these advances must not be underestimated; the effective application of theranostic agents may achieve the goal that has remained elusive for so many malignancies – a cure for cancer.
So, let’s look at how we can define a theranostic. It is the integration of a diagnostic and therapeutic agent to deliver a highly-targeted treatment.
If we focus first on diagnosis, this is categorized according to the imaging modality that is used and the cancer-associated target that is being exploited. Several technologies that span bench to bedside – such as magnetic resonance imaging/spectroscopy, positron emission tomography, single photon emission computerized tomography, and optical imaging for intra-operative imaging – are applicable to theranostic imaging. But there is also a rapid expansion of innovative nanoplatforms for theranostics, too, which are based on the application of nanotechnology to imaging modality, therapeutic cargo, or target. Examples include liposomes, nanoparticles, micelles and viral vectors that display imaging reporters, and deliver either conventional therapy or nucleic acid-based interventions, such as complementary DNA or small interfering RNA. There is an increasing trend to combine imaging modalities and, as a result, the nanoplatforms may carry multi-modal imaging reporters. Innovative strategies such as pH-responsive micelles that show pH-dependent demicellization below pH 6.5 have also been developed.
If we take a look at targets, cancer theranostics involve the delivery of a therapeutic cargo to tumor targets that can be non-invasively imaged, and therefore cancer-associated cell surface antigens provide useful targets. For example, 20 to 30 percent of breast cancers express the human epidermal growth factor receptor (HER2). Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER2, was a breakthrough treatment for this population of patients. Good responses are also seen with the dual tyrosine kinase inhibitor lapatinib, which inhibits EGFR/ErbB1 and HER2/ErbB2. However, a large percentage of patients develop drug resistance due to adaptation of signaling pathways; hence, theranostic imaging is an attractive option for identifying and monitoring the outgrowth of drug-resistant tumors. Theranostic imaging can also exploit prostate-specific membrane antigen, a type II integral membrane protein expressed abundantly on the surface of androgen-independent, advanced prostate cancer, and CD44, a transmembrane glycoprotein that is important in metastasis and in stem-like breast, prostate, pancreatic, ovarian and colorectal cancers.
Most tumors, however, do not express cancer-specific cell surface antigens; developing theranostic tools for these malignancies therefore requires investigators to mine other aspects of the tumor: metabolism, angiogenesis, inflammation, tumor microenvironment (TME), and stromal cell receptors. The physiological environment of the tumor is usually characterized by hypoxia, acidic extracellular pH, and substrate deprivation; none of these features are typical of non-malignant tissues. Similarly, the TME – comprising the extracellular matrix, cancer-associated fibroblasts, adipocytes, pericytes, vascular and lymphatic endothelial cells, and multiple immune cells such as tumor-associated macrophages – also tends to differ from the non-cancerous extracellular environment. These points of difference provide opportunities for theranostic imaging.
In my view, a major challenge is the need to rapidly translate and clinically implement the most promising theranostic agents. Quantitative image analysis, the cost of synthesizing theranostic agents, immune responses to these agents, challenges with good manufacturing synthesis, difficulties in obtaining US Food and Drug Administration/European Medicines Agency/Institutional Review Board approval, and the cost of clinical trials are some of the challenges in this field. Despite these challenges, innovations in theranostics occurring at the interface of chemistry, molecular biology, and imaging will provide major advances in the field of cancer treatment.