Targeted Radionuclide Therapy: Practical Applications and Future Prospects

In recent years, there has been a proliferation in the development of targeted radionuclide cancer therapy. It is now possible to use baseline clinical and imaging assessments to determine the most effective therapy and to tailor this therapy during the course of treatment based on radiation dosimetry and tumor response. Although this personalized approach to medicine has the advantage of maximizing therapeutic effect while limiting toxicity, it can be challenging to implement and expensive. Further, in order to use targeted radionuclide therapy effectively, there is a need for multidisciplinary awareness, education, and collaboration across the scientific, industrial, and medical communities. Even more important, there is a growing understanding that combining radiopharmaceuticals with conventional treatment such as chemotherapy and external beam radiotherapy may limit patient morbidity while improving survival. Developments in radiopharmaceuticals as biomarkers capable of predicting therapeutic response and targeting disease are playing a central role in medical research. Adoption of a practical approach to manufacturing and delivering radiopharmaceuticals, assessing patient eligibility, optimizing post-therapy follow-up, and addressing reimbursement issues will be essential for their success

Radiopharmaceuticals for Relapsed or Refractory Leukemias

Radiopharmaceuticals, meaning drugs that hold a radionuclide intended for use in cancer patients for treatment of their disease or for palliation of their disease-related symptoms, have gained new interest for clinical development in adult patients with relapsed or refractory leukemia. About one-third of adult patients outlive their leukemia, with the remainder unable to attain complete remission status following the first phase of treatment due to refractory bone marrow or blood residual microscopic disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 49 phase 1-1b trials in adult patients with leukemia between 1986 and 2017 in an effort to discover tolerated and effective therapeutic drug combinations intended to improve remission and mortality rates. None of these trials involved radiopharmaceuticals. In this article, the NCI perspective on the challenges encountered in and on the future potential of radiopharmaceuticals alone or in combination for adult patients with relapsed or refractory leukemia is discussed. An effort is underway already to build-up the NCI's clinical trial enterprise infrastructure for radiopharmaceutical clinical development

The crosstalk between EGF, IGF, and Insulin cell signaling pathways - computational and experimental analysis

<p>Abstract</p> <p>Background</p> <p>Cellular response to external stimuli requires propagation of corresponding signals through molecular signaling pathways. However, signaling pathways are not isolated information highways, but rather interact in a number of ways forming sophisticated signaling networks. Since defects in signaling pathways are associated with many serious diseases, understanding of the crosstalk between them is fundamental for designing molecularly targeted therapy. Unfortunately, we still lack technology that would allow high throughput detailed measurement of activity of individual signaling molecules and their interactions. This necessitates developing methods to prioritize selection of the molecules such that measuring their activity would be most informative for understanding the crosstalk. Furthermore, absence of the reaction coefficients necessary for detailed modeling of signal propagation raises the question whether simple parameter-free models could provide useful information about such pathways.</p> <p>Results</p> <p>We study the combined signaling network of three major pro-survival signaling pathways: <b>E</b>pidermal <b>G</b>rowth <b>F</b>actor <b>R</b>eceptor (EGFR), <b>I</b>nsulin-like <b>G</b>rowth <b>F</b>actor-1 <b>R</b>eceptor (IGF-1R), and <b>I</b>nsulin <b>R</b>eceptor (IR). Our study involves static analysis and dynamic modeling of this network, as well as an experimental verification of the model by measuring the response of selected signaling molecules to differential stimulation of EGF, IGF and insulin receptors. We introduced two novel measures of the importance of a node in the context of such crosstalk. Based on these measures several molecules, namely Erk1/2, Akt1, Jnk, p70S6K, were selected for monitoring in the network simulation and for experimental studies. Our simulation method relies on the Boolean network model combined with stochastic propagation of the signal. Most (although not all) trends suggested by the simulations have been confirmed by experiments.</p> <p>Conclusion</p> <p>The simple model implemented in this paper provides a valuable first step in modeling signaling networks. However, to obtain a fully predictive model, a more detailed knowledge regarding parameters of individual interactions might be necessary.</p

Radiopharmaceutical Validation for Clinical Use

Radiopharmaceuticals are reemerging as attractive anticancer agents, but there are no universally adopted guidelines or standardized procedures for evaluating agent validity before early-phase trial implementation. To validate a radiopharmaceutical, it is desirous for the radiopharmaceutical to be specific, selective, and deliverable against tumors of a given, molecularly defined cancer for which it is intended to treat. In this article, we discuss four levels of evidence—target antigen immunohistochemistry, in vitro and in vivo preclinical experiments, animal biodistribution and dosimetry studies, and first-in-human microdose biodistribution studies—that might be used to justify oncology therapeutic radiopharmaceuticals in a drug-development sequence involving early-phase trials. We discuss common practices for validating radiopharmaceuticals for clinical use, everyday pitfalls, and commonplace operationalizing steps for radiopharmaceutical early-phase trials. We anticipate in the near-term that radiopharmaceutical trials will become a larger proportion of the National Cancer Institute Cancer Therapy Evaluation Program (CTEP) portfolio

Radiopharmaceuticals for Relapsed or Refractory Ovarian Cancers

Targeted radiopharmaceuticals for therapeutic use deliver radionuclides directly to tumor anywhere in the body, and therefore, have renewed interest for clinical development in women with disseminated chemorefractory ovarian cancers. About two in every five women with advanced stage ovarian cancer outlive their disease after the first treatment phase, with the rest rendered incurable due to the chemorefractory nature of their disease. The National Cancer Institute (NCI) Cancer Therapy Evaluation Program conducted 67 phase I or phase Ib trials among women with relapsed or refractory ovarian cancer between 1989 and 2017 in an effort to uncover tolerable and effective drug combinations intended to increase survival rates. None of these early clinical development phase trials involved radiopharmaceuticals. Here, the NCI provides its perspective on targeted radiopharmaceutical conjugates alone or in combination with its experimental therapeutics portfolio for women with relapsed or refractory ovarian cancer. An infrastructure build for Federal radiopharmaceutical medical monitoring and adverse event reporting has begun

Clinical Outcome Assessments Toolbox for Radiopharmaceuticals.

For nearly 40 years, the U.S. National Cancer Institute (NCI) has funded health-related quality-of-life (HRQOL) and symptom management in oncology clinical trials as a method for including a cancer patient\u27s experience during and after treatment. The NCI\u27s planned scope for HRQOL, symptom and patient-reported outcomes management research is explained as it pertains to radiopharmaceutical clinical development. An effort already underway to support protocol authoring via an NCI Cancer Therapy Evaluation Program (CTEP) Centralized Protocol Writing Service (CPWS) is described as this service aids incorporation of HRQOL, symptom and patient-reported outcomes management research into sponsored protocols

In Vivo Fluorescence Lifetime Imaging Monitors Binding of Specific Probes to Cancer Biomarkers

One of the most important factors in choosing a treatment strategy for cancer is characterization of biomarkers in cancer cells. Particularly, recent advances in Monoclonal Antibodies (MAB) as primary-specific drugs targeting tumor receptors show that their efficacy depends strongly on characterization of tumor biomarkers. Assessment of their status in individual patients would facilitate selection of an optimal treatment strategy, and the continuous monitoring of those biomarkers and their binding process to the therapy would provide a means for early evaluation of the efficacy of therapeutic intervention. In this study we have demonstrated for the first time in live animals that the fluorescence lifetime can be used to detect the binding of targeted optical probes to the extracellular receptors on tumor cells in vivo. The rationale was that fluorescence lifetime of a specific probe is sensitive to local environment and/or affinity to other molecules. We attached Near-InfraRed (NIR) fluorescent probes to Human Epidermal Growth Factor 2 (HER2/neu)-specific Affibody molecules and used our time-resolved optical system to compare the fluorescence lifetime of the optical probes that were bound and unbound to tumor cells in live mice. Our results show that the fluorescence lifetime changes in our model system delineate HER2 receptor bound from the unbound probe in vivo. Thus, this method is useful as a specific marker of the receptor binding process, which can open a new paradigm in the “image and treat” concept, especially for early evaluation of the efficacy of the therapy

Workshop Report for Cancer Research: Defining the Shades of Gy: Utilizing the Biological Consequences of Radiotherapy in the Development of New Treatment Approaches—Meeting Viewpoint

The ability to physically target radiotherapy using image-guidance is continually improving with photons and particle therapy that include protons and heavier ions such as carbon. The unit of dose deposited is the gray (Gy); however, particle therapies produce different patterns of ionizations, and there is evidence that the biological effects of radiation depend on dose size, schedule, and type of radiation. This National Cancer Institute (NCI)–sponsored workshop addressed the potential of using radiation-induced biological perturbations in addition to physical dose, Gy, as a transformational approach to quantifying radiation

Radiopharmaceutical Switch Maintenance for Relapsed Ovarian Carcinoma

Switch maintenance, or using alternative therapeutic agents that were not administered during a prior course of cancer treatment, has emerged as an active clinical research and regulatory agency-approvable path in the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) drug-development sequence. To better inform the design of therapeutic radiopharmaceutical trials, we reviewed academic scholarship discussing the clinical use of maintenance approaches to cancer treatment. Women with advanced-stage primary platinum-refractory or platinum-resistant ovarian carcinoma and their courses of treatment provide context for our discussion. Twenty-four (10%) out of 244 trials for women with ovarian carcinoma fit our search terms for maintenance trials. Five (2%) trials studied radiopharmaceuticals as switch maintenance. In our opinion, radiopharmaceutical switch maintenance merits further testing in prospective trials for women with advanced-stage primary platinum recurrent or refractory ovarian carcinoma