National Cancer Institute support for targeted alpha-emitter therapy.

BACKGROUND: Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. METHODS: This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. RESULTS: NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. CONCLUSION: Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

Active targeting using HER-2-affibody-conjugated nanoparticles enabled sensitive and specific imaging of orthotopic HER-2 positive ovarian tumors.

Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER-2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery.

The United States Department of Energy and National Institutes of Health Collaboration: Medical Care Advances by Discovery in Radiation Detection.

A National Institutes of Health (NIH) and U.S. Department of Energy (DOE) Office of Science virtual workshop on shared general topics was held in July of 2021 and reported on in this publication in January of 2023. Following the inaugural 2021 joint meeting representatives from the DOE Office of Science and NIH met to discuss organizing a second joint workshop that would concentrate on radiation detection to bring together teams from both agencies and their grantee populations to stimulate collaboration and efficiency. To meet this scientific mission within the NIH and DOE radiation detection space, the organizers assembled workshop sessions covering the state-of-the-art in cameras, detectors, and sensors for radiation external and internal (diagnostic and therapeutic) to human, data acquisition and electronics, image reconstruction and processing, and the application of artificial intelligence. NIH and DOE are committed to continuing the process of convening a joint workshop every 12-24 months. This Special Report recaps the findings of this second workshop. Beyond showing only the innovations and areas of success, important gaps in our knowledge were defined and presented. We summarize by defining four areas of greatest opportunity and need that emerged from the unique, dynamic dialogue the in-person workshop provided the attendees.

The United States Department of Energy and National Institutes of Health Collaboration: Medical Care Advances via Discovery in Physical Sciences.

Over several months, representatives from the U.S. Department of Energy (DOE) Office of Science and National Institutes of Health (NIH) had a number of meetings that lead to the conclusion that innovations in the Nation's health care could be realized by more directed interactions between NIH and DOE. It became clear that the expertise amassed and instrumentation advances developed at the DOE physical science laboratories to enable cutting-edge research in particle physics could also feed innovation in medical healthcare. To meet their scientific mission, the DOE laboratories created advances in such technologies as particle beam generation, radioisotope production, high-energy particle detection and imaging, superconducting particle accelerators, superconducting magnets, cryogenics, high-speed electronics, artificial intelligence, and big data. To move forward, NIH and DOE initiated the process of convening a joint workshop which occurred on July 12th and 13th, 2021. This Special Report presents a summary of the findings of the collaborative workshop and introduces the goals of the next one.

In vivo method to monitor changes in HER2 expression using near-infrared fluorescence imaging.

Human epidermal growth factor receptor type 2 (HER2) is a well-known biomarker that is overexpressed in many breast carcinomas. HER2 expression level is an important factor to optimize the therapeutic strategy and monitor the treatment. We used albumin binding domain-fused HER2-specific Affibody molecules, labeled with Alexa Fluor750 dye, to characterize HER2 expression in vivo. Near-infrared optical imaging studies were carried out using mice with subcutaneous HER2-positive tumors. Animals were divided into groups of five: no treatment and 12 hours and 1 week after treatment of the tumors with the Hsp90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). The compartmental ligands-receptor model, describing binding kinetics, was used to evaluate HER2 expression from the time sequence of the fluorescence images after the intravenous probe injection. The normalized rate of accumulation of the specific fluorescent biomarkers, estimated from this time sequence, linearly correlates with the conventional ex vivo enzyme-linked immunosorbent assay (ELISA) readings for the same tumor. Such correspondence makes properly arranged fluorescence imaging an excellent candidate for estimating HER2 overexpression in tumors, complementing ELISA and other ex vivo assays. Application of this method to the fluorescence data from HER2-positive xenografts reveals that the 17-DMAG treatment results in downregulation of HER2. Application of the AngioSense 750 probe confirmed the antiangiogenic effect of 17-DMAG found with Affibody-Alexa Fluor 750 conjugate.

The role of nuclear medicine in modern therapy of cancer.

Nuclear medicine is a multidisciplinary field that develops and uses instrumentation and tracers (radiopharmaceuticals) to study physiological processes and noninvasively diagnose, stage, and treat diseases. Particularly, it offers a unique means to study cancer biology in vivo and to optimize cancer therapy for individual patients. A tracer is either a radionuclide alone, such as iodine-131 or a radiolabel in a carrier molecule such as (18)F in fluorodeoxyglucose ((18)F-FDG), or other feasible radionuclide attached to a drug, a protein, or a peptide, which when introduced into the body, would accumulate in the tissue of interest. Nuclear medicine imaging, including single-photon emission computer tomography and positron emission tomography, can provide important quantitative and functional information about normal tissues or disease conditions, in contrast to conventional, anatomical imaging techniques such as ultrasound, computed tomography, or magnetic resonance imaging. For treatment, tumor-targeting agents, conjugated with therapeutic radionuclides, may be used to deposit lethal radiation at tumor sites. This review outlines the role of nuclear medicine in modern cancer therapy.

The State of Preclinical Modeling for Early Phase Cancer Trials Using Molecularly Targeted Agents with Radiation.

Preclinical studies inform and guide the development of novel treatment combination strategies that bridge the laboratory with the clinic. We aimed to evaluate approaches cancer researchers used to justify advancing new combinations of molecularly targeted agents and radiation treatment into early-phase human clinical trials. Unsolicited early phase clinical trial proposals submitted to the National Cancer Institute's Cancer Therapy Evaluation Program between January 2016 and July 2020 were curated to quantify key characteristics and proportion of preclinical data provided by trialists seeking to conduct molecularly targeted agent-radiation combination studies in cancer patients. These data elucidate the current landscape for how the rationale for a molecularly targeted agent-radiation combination therapy is supported by preclinical research and illustrate unique challenges faced in translation at the intersection of precision medicine and radiation oncology.

SimBoolNet--a Cytoscape plugin for dynamic simulation of signaling networks.

SUMMARY: SimBoolNet is an open source Cytoscape plugin that simulates the dynamics of signaling transduction using Boolean networks. Given a user-specified level of stimulation to signal receptors, SimBoolNet simulates the response of downstream molecules and visualizes with animation and records the dynamic changes of the network. It can be used to generate hypotheses and facilitate experimental studies about causal relations and crosstalk among cellular signaling pathways. AVAILABILITY: SimBoolNet package (with manual) is freely available at http://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/SimBoolNet

68Ga-DOTA-affibody molecule for in vivo assessment of HER2/neu expression with PET.

PURPOSE: Overexpression of HER2/neu in breast cancer is correlated with a poor prognosis. It may vary between primary tumors and metastatic lesions and change during the treatment. Therefore, there is a need for a new means to assess HER2/neu expression in vivo. In this work, we used (68)Ga-labeled DOTA-Z(HER2:2891)-Affibody to monitor HER2/neu expression in a panel of breast cancer xenografts. METHODS: DOTA-Z(HER2:2891)-Affibody molecules were labeled with (68)Ga. In vitro binding was characterized by a receptor saturation assay. Biodistribution and PET imaging studies were conducted in athymic nude mice bearing subcutaneous human breast cancer tumors with three different levels of HER2/neu expression. Nonspecific uptake was analyzed using non-HER2-specific Affibody molecules. Signal detected by PET was compared with ex vivo assessment of the tracer uptake and HER2/neu expression. RESULTS: The (68)Ga-DOTA-Z(HER2:2891)-Affibody probe showed high binding affinity to MDA-MB-361 cells (K (D) = 1.4 ± 0.19 nM). In vivo biodistribution and PET imaging studies demonstrated high radioactivity uptake in HER2/neu-positive tumors. Tracer was eliminated quickly from the blood and normal tissues, resulting in high tumor-to-blood ratios. The highest concentration of radioactivity in normal tissue was seen in the kidneys (227 ± 14%ID/g). High-contrast PET images of HER2/neu-overexpressing tumors were recorded as soon as 1 h after tracer injection. A good correlation was observed between PET imaging, biodistribution estimates of tumor tracer concentration, and the receptor expression. CONCLUSION: These results suggest that PET imaging using (68)Ga-DOTA-Z(HER2:2891)-Affibody is sensitive enough to detect different levels of HER2/neu expression in vivo.

Sarcosine induces increase in HER2/neu expression in androgen-dependent prostate cancer cells.

Increasing evidence suggests that Human epidermal growth factor receptor 2 (HER2/neu) is involved in progression of prostate cancer. Recently, sarcosine was reported to be highly increased during prostate cancer progression, and exogenous sarcosine induces an invasive phenotype in benign prostate epithelial cells. The aim of this work was to investigate the effect of sarcosine on HER2/neu expression in prostate cancer cell lines LNCaP (androgen dependent), PC-3 and DU145 (both androgen independent). Relative amounts of HER2/neu and androgen receptor (AR) transcripts were determined using RT-qPCR. Total expression of HER2/neu was confirmed by Western blot (WB). HER2/neu protein on the surface of living LNCaP cells was visualized by confocal microscopy using a HER2/neu-specific fluorescent probe. Exposure of LNCaP cells to 50 µM sarcosine for 24 h resulted in a 58% increase of the HER2/neu mRNA level (P < 0.001) indicating that sarcosine effects HER2/neu expression on the level of transcription. Control experiments with alanine, an isomer of sarcosine, showed no significant effect on HER2/neu transcription. The upregulation of HER2/neu mRNA preceded the corresponding increment of the protein level after the 48-h exposure to sarcosine as shown by WB and confocal microscopy. Interestingly, sarcosine had no effect on the activated (phosphorylated) form of HER2/neu. No significant change in AR expression was observed after exposure to sarcosine. This is the first report indicating that sarcosine is involved in the regulation of the oncoprotein HER2/neu. Thus, sarcosine may induce prostate cancer progression by increased HER2/neu expression. However, detailed information on cellular mechanisms remains to be elucidated.

A New Generation of "Magic Bullets" for Molecular Targeting of Cancer.

A two-step molecular targeting approach involving a self-assembling and disassembling (SADA) bispecific antibody platform and DOTA-radioconjugates allows tumor-specific delivery of diagnostic and therapeutic payloads. Low immunogenicity and the modular nature of SADA allow its optimization to safely and repeatedly deliver a variety of payloads to tumors expressing diverse tumor-specific antigens.See related article by Santich et al., p. 532.

Radiopharmaceutical Delivery for Theranostics: Pharmacokinetics and Pharmacodynamics.

Theranostics is a new and evolving combination diagnostic and/or therapeutic approach that is demonstrating efficacy for treatment of a growing number of cancers. In this approach, a diagnostic radiopharmaceutical is used in concert with positron-emission tomography (PET) or single photon emission computed tomography (SPECT) imaging to identify whether a cancer-specific membrane protein is strongly expressed on a patient's tumors. If the molecular target is detected with sufficient specificity and uptake, a therapeutic radiopharmaceutical, nearly identical to the diagnostic radiopharmaceutical except labeled with a longer-lived alpha or beta-emitting radionuclide, is administered at a therapeutic dose level to treat the cancer. Quantitative imaging methods are being used to elucidate patient-specific pharmacokinetics to select patients for whom the therapeutic radiopharmaceutical would be most beneficial. Similarly, quantitative imaging of the therapeutic radionuclide is being used to image pharmacodynamic response to therapy (cell kill) to guide personalized, patient-specific dosages designed to both reduce radiation toxicities and optimize radiotherapeutic benefit.

Dosimetry for Radiopharmaceutical Therapy: Current Practices and Commercial Resources.

With the ongoing dramatic growth of radiopharmaceutical therapy, research and development in internal radiation dosimetry continue to advance both at academic medical centers and in industry. The basic paradigm for patient-specific dosimetry includes administration of a pretreatment tracer activity of the therapeutic radiopharmaceutical; measurement of its time-dependent biodistribution; definition of the pertinent anatomy; integration of the measured time-activity data to derive source-region time-integrated activities; calculation of the tumor, organ-at-risk, and/or whole-body absorbed doses; and prescription of the therapeutic administered activity. This paper provides an overview of the state of the art of patient-specific dosimetry for radiopharmaceutical therapy, including current methods and commercially available software and other resources.

Dosimetry in Clinical Radiopharmaceutical Therapy of Cancer: Practicality Versus Perfection in Current Practice.

The use of radiopharmaceutical therapies (RPTs) in the treatment of cancers is growing rapidly, with more agents becoming available for clinical use in last few years and many new RPTs being in development. Dosimetry assessment is critical for personalized RPT, insofar as administered activity should be assessed and optimized in order to maximize tumor-absorbed dose while keeping normal organs within defined safe dosages. However, many current clinical RPTs do not require patient-specific dosimetry based on current Food and Drug Administration-labeled approvals, and overall, dosimetry for RPT in clinical practice and trials is highly varied and underutilized. Several factors impede rigorous use of dosimetry, as compared with the more convenient and less resource-intensive practice of empiric dosing. We review various approaches to applying dosimetry for the assessment of activity in RPT and key clinical trials, the extent of dosimetry use, the relative pros and cons of dosimetry-based versus fixed activity, and practical limiting factors pertaining to current clinical practice.

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.

Current Status of Radiopharmaceutical Therapy.

In radiopharmaceutical therapy (RPT), a radionuclide is systemically or locally delivered with the goal of targeting and delivering radiation to cancer cells while minimizing radiation exposure to untargeted cells. Examples of current RPTs include thyroid ablation with the administration of 131I, treatment of liver cancer with 90Y microspheres, the treatment of bony metastases with 223Ra, and the treatment of neuroendocrine tumors with 177Lu-DOTATATE. New RPTs are being developed where radionuclides are incorporated into systemic targeted therapies. To assure that RPT is appropriately implemented, advances in targeting need to be matched with advances in quantitative imaging and dosimetry methods. Currently, radiopharmaceutical therapy is administered by intravenous or locoregional injection, and the treatment planning has typically been implemented like chemotherapy, where the activity administered is either fixed or based on a patient's body weight or body surface area. RPT pharmacokinetics are measurable by quantitative imaging and are known to vary across patients, both in tumors and normal tissues. Therefore, fixed or weight-based activity prescriptions are not currently optimized to deliver a cytotoxic dose to targets while remaining within the tolerance dose of organs at risk. Methods that provide dose estimates to individual patients rather than to reference geometries are needed to assess and adjust the injected RPT dose. Accurate doses to targets and organs at risk will benefit the individual patients and decrease uncertainties in clinical trials. Imaging can be used to measure activity distribution in vivo, and this information can be used to determine patient-specific treatment plans where the dose to the targets and organs at risk can be calculated. The development and adoption of imaging-based dosimetry methods is particularly beneficial in early clinical trials. In this work we discuss dosimetric accuracy needs in modern radiation oncology, uncertainties in the dosimetry in RPT, and best approaches for imaging and dosimetry of internal radionuclide therapy.

Moving Forward in the Next Decade: Radiation Oncology Sciences for Patient-Centered Cancer Care.

In a time of rapid advances in science and technology, the opportunities for radiation oncology are undergoing transformational change. The linkage between and understanding of the physical dose and induced biological perturbations are opening entirely new areas of application. The ability to define anatomic extent of disease and the elucidation of the biology of metastases has brought a key role for radiation oncology for treating metastatic disease. That radiation can stimulate and suppress subpopulations of the immune response makes radiation a key participant in cancer immunotherapy. Targeted radiopharmaceutical therapy delivers radiation systemically with radionuclides and carrier molecules selected for their physical, chemical, and biochemical properties. Radiation oncology usage of "big data" and machine learning and artificial intelligence adds the opportunity to markedly change the workflow for clinical practice while physically targeting and adapting radiation fields in real time. Future precision targeting requires multidimensional understanding of the imaging, underlying biology, and anatomical relationship among tissues for radiation as spatial and temporal "focused biology." Other means of energy delivery are available as are agents that can be activated by radiation with increasing ability to target treatments. With broad applicability of radiation in cancer treatment, radiation therapy is a necessity for effective cancer care, opening a career path for global health serving the medically underserved in geographically isolated populations as a substantial societal contribution addressing health disparities. Understanding risk and mitigation of radiation injury make it an important discipline for and beyond cancer care including energy policy, space exploration, national security, and global partnerships.

Overview of the First NRG Oncology-National Cancer Institute Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy.

In 2018, the National Cancer Institute and NRG Oncology partnered for the first time to host a joint workshop on systemic radiopharmaceutical therapy (RPT) to specifically address dosimetry issues and strategies for future clinical trials. The workshop focused on current dosimetric approaches for clinical trials, strategies under development that would optimize dose reporting, and future desired or optimized approaches for novel emerging radionuclides and carriers in development. In this article, we review the main approaches that are applied clinically to calculate the absorbed dose. These include absorbed doses calculated over a variety of spatial scales, including whole body, organ, suborgan, and voxel, the last 3 of which are achievable within the MIRD schema (S value) and can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This article will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biologic effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We also briefly discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.

Quantitative analysis of Her2 receptor expression in vivo by near-infrared optical imaging.

Human epidermal growth factor receptor 2 (HER2) overexpression in breast cancers is associated with poor prognosis and resistance to therapy. Current techniques for estimating this important characteristic use ex vivo assays that require tissue biopsies. We suggest a novel noninvasive method to characterize HER2 expression in vivo, using optical imaging, based on HER2-specific probes (albumin-binding domain-fused-(ZHER2:342)2-Cys Affibody molecules [Affibody AB, Solna, Sweden], labeled with Alexa Fluor 750 [Molecular Probes, Invitrogen, Carlsbad, CA]) that could be used concomitantly with HER2-targeted therapy. Subcutaneous tumor xenografts, expressing different levels of HER2, were imaged with a near-infrared fluorescence small-animal imaging system at several times postinjection of the probe. The compartmental ligand-receptor model was used to calculate HER2 expression from imaging data. Correlation between HER2 amplification/overexpression in tumor cells and parameters, directly estimated from the sequence of optical images, was observed (eg, experimental data for BT474 xenografts indicate that initial slope, characterizing the temporal dependence of the fluorescence intensity detected in the tumor, linearly depends on the HER2 expression, as measured ex vivo by an enzyme-linked immunosorbent assay for the same tumor). The results obtained from tumors expressing different levels of HER2 substantiate a similar relationship between the initial slope and HER2 amplification/overexpression. This work shows that optical imaging, combined with mathematical modeling, allows noninvasive monitoring of HER2 expression in vivo.

'Image and treat': an individualized approach to urological tumors.

PURPOSE OF REVIEW: The current treatment options for advanced urologic cancers demonstrate limited efficacy. To obtain optimal clinical results, there is a need for new, individualized, therapeutic strategies, which have only recently been applied to these malignancies. Nuclear medicine plays an important role in establishing imaging biomarkers necessary for personalized medicine. This review focuses on the current status of the 'image and treat' approach combining molecular imaging with targeted radionuclide therapy of urological malignancies RECENT FINDINGS: Tumor-specific targets in uro-oncology are showing promising results for development of personalized therapy using positron emission tomography/computed tomography (PET/CT) molecular imaging and radioimmunotherapy. The antibody cG250, which binds to carbonic anhydrase IX, is being evaluated as a radiolabeled imaging and therapeutic agent in clear-cell renal cell carcinoma. I-cG250 PET/CT has demonstrated excellent targeting of clear-cell renal cell carcinoma. Prostate-specific membrane antigen is a promising target for both PET/CT and radioimmunotherapy of prostate cancer. HER2 may be another potential target in bladder and prostate cancer. SUMMARY: Tumor-specific targets and biomarkers are being studied for PET/CT and radioimmunotherapy. This may lead to development of new therapeutic strategies. However, considerable investment in new research will be required for personalized medicine to be routinely used in uro-oncology.