Abstract
Novel technologies are being developed to improve patient therapy through the identification of targets and surrogate molecular signatures that can help direct appropriate treatment regimens for efficacy and drug safety. This is particularly the case in oncology whereby patient tumor and biofluids are routinely isolated and analyzed for genetic, immunohistochemical, and/or soluble markers to determine if a predictive biomarker signature (i.e., mutated gene product, differentially expressed protein, altered cell surface antigen, etc.) exists as a means for selecting optimal treatment. These biomarkers may be drug-specific targets and/or differentially expressed nucleic acids, proteins, or cell lineage profiles that can directly affect the patient’s disease tissue or immune response to a therapeutic regimen. Improvements in diagnostics that can prescreen predictive response biomarker profiles will continue to optimize the ability to enhance patient therapy via molecularly defined disease-specific treatment. Conversely, patients lacking predictive response biomarkers will no longer needlessly be exposed to drugs that are unlikely to provide clinical benefit, thereby enabling patients to pursue other therapeutic options and lowering overall healthcare costs by avoiding futile treatment. While patient molecular profiling offers a powerful tool to direct treatment options, the difficulty in identifying disease-specific targets or predictive biomarker signatures that stratify a significant fraction within a disease indication remains challenging. A goal for drug developers is to identify and implement new strategies that can rapidly enable the development of beneficial disease-specific therapies for broad patient-specific targeting without the need of tedious predictive biomarker discovery and validation efforts, currently a bottleneck for development timelines. Successful strategies may gain an advantage by employing repurposed, less-expensive existing agents while potentially improving the therapeutic activity of novel, target-specific therapies that may otherwise have off-target toxicities or less efficacy in cells exhibiting certain pathways. Here, we discuss the use of co-developing diagnostic-targeting vectors to identify patients whose malignant tissue can specifically uptake a targeted anti-cancer drug vector prior to treatment. Using this system, a patient can be predetermined in real-time as to whether or not their tumor(s) can specifically uptake a drug-linked diagnostic vector, thus inferring the uptake of a similar vector linked to an anti-cancer agent. If tumor-specific uptake is observed, then the patient may be suitable for drug-linked vector therapy and have a higher likelihood of clinical benefit while patients with no tumor uptake should consider other therapeutic options. This approach offers complementary opportunities to rapidly develop broad tumor-specific agents for use in personalized medicine.
Highlights
Novel technologies are being developed to improve patient therapy through the identification of targets and surrogate molecular signatures that can help direct appropriate treatment regimens for efficacy and drug safety
Advances in therapeutic–theranostic co-development molecular target of an altered pathway or a sequence-specific gene product that in turn results in selective killing of malignant but not normal cells; (ii) inducing a host immune response against malignant cells; and (iii) enhancing specific uptake of an agent(s) in target cells for disease suppression. Based on their chemical or biochemical nature, targeted anti-cancer agents can be classified into small chemical entities (SCE) capable of disrupting cellular processes such as enzymatic reactions, tubulin polymerization and DNA replication; nucleic acids that can bind a gene product involved in tumor growth and metastasis; and cellular- and protein-based therapies that can target tumor-associated cell surface proteins or soluble ligands [2]
Monopayload, radiolabeled compounds could be used theranostically, whereby: (i) low, diagnostic doses are used for initial assessment of in vivo targeting; (ii) sub-therapeutic doses are administered for dosimetry, allowing precise dose selection, and for monitoring potential toxic effect; and (iii) higher, therapeutic doses are administered to continue to monitor toxicity in conjunction with tumor burden and tumor uptake
Summary
With the early success of antibody–cytotoxin conjugates using radionuclides (referred to as radioimmunotherapy, RIT), such as yttrium-90 (90Y)-labeled-ibritumomab tiuxetan [15] and iodine-131 (131I)-labeled tositumomab [16] in treating refractory lymphoma, as well as the recently approved ADC trastuzumabDM1 (T-DM1, Kadcyla®) [17], and brentuximab vedotin (SGN35, Adcetris®) [18], significant progress in personalized medicine has been attained [19] Part of this advancement is due to the improved therapeutic activity over the parental agents (the cytotoxic or targeting agent alone) resulting in a better clinical outcome while minimizing toxicity.
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