HER2 overexpression is correlated with aggressive tumor behavior and poor clinical outcome. Therefore, HER2 has become an important prognostic and predictive factor, as well as a target for molecular ...therapies. The article reviews recent advances in molecular imaging of HER2 that could facilitate individual approaches to targeted therapy of HER2-positive breast cancers.
Because of the heterogeneity of breast cancer and possible discordance in HER2 status between primary tumors and distant metastases, assessment of HER2 expression by noninvasive imaging may become an important complement to immunohistochemistry or fluorescence in-situ hybridization analyses of biopsied tissue. Monoclonal antibodies such as trastuzumab and pertuzumab, or small scaffold proteins such as affibody molecules are used as HER2-targeting agents. For imaging purposes, these agents are labeled with positron or gamma-emitting radionuclides, optical dyes, or paramagnetic contrast molecules for positron emission tomography single photon emission tomography optical, and magnetic resonance imaging, respectively. HER2-specific molecular probes, combined with modern imaging techniques to provide information on HER2 expression not only in primary tumors but also in distant metastases not amenable to biopsy, may reduce problems with false negative results and, thereby, influence patient management by selecting patients that would benefit from HER2-targeted therapies.
The new 'image and treat' strategy, involving assessment of target presence and distribution in an individual patient followed by optimized, target-specific drug delivery, may potentially improve efficacy of cancer treatment while reducing side effects.
In April 2016, the National Cancer Institute hosted a multidisciplinary workshop to discuss the current knowledge of the radiobiological aspects of charged particles used in cancer therapy to ...identify gaps in that knowledge that might hinder the effective clinical use of charged particles and to propose research that could help fill those gaps. The workshop was organized into 10 topics ranging from biophysical models to clinical trials and included treatment optimization, relative biological effectiveness of tumors and normal tissues, hypofractionation with particles, combination with immunotherapy, "omics," hypoxia, and particle-induced second malignancies. Given that the most commonly used charged particle in the clinic currently is protons, much of the discussion revolved around evaluating the state of knowledge and current practice of using a relative biological effectiveness of 1.1 for protons. Discussion also included the potential advantages of heavier ions, notably carbon ions, because of their increased biological effectiveness, especially for tumors frequently considered to be radiation resistant, increased effectiveness in hypoxic cells, and potential for differentially altering immune responses. The participants identified a large number of research areas in which information is needed to inform the most effective use of charged particles in the future in clinical radiation therapy. This unique form of radiation therapy holds great promise for improving cancer treatment.
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.
HER2 overexpression has been associated with a poor prognosis and resistance to therapy in breast cancer patients. We are developing molecular probes for in vivo quantitative imaging of HER2 ...receptors using near-infrared (NIR) optical imaging. The goal is to provide probes that will minimally interfere with the studied system, that is, whose binding does not interfere with the binding of the therapeutic agents and whose effect on the target cells is minimal.
We used three different types of HER2-specific Affibody molecules monomer ZHER2:342, dimer (ZHER2:477)2, and albumin-binding domain-fused-(ZHER2:342)2 as targeting agents and labeled them with Alexa Fluor dyes. Trastuzumab was also conjugated, using commercially available kits, as a standard control. The resulting conjugates were characterized in vitro by toxicity assays, Biacore affinity measurements, flow cytometry, and confocal microscopy. Semiquantitative in vivo NIR optical imaging studies were carried out using mice with s.c. xenografts of HER2-positive tumors.
The HER2-specific Affibody molecules were not toxic to HER2-overexpressing cells and their binding to HER2 did interfere with neither binding nor effectives of trastuzumab. The binding affinities and specificities of the Affibody-Alexa Fluor fluorescent conjugates to HER2 were unchanged or minimally affected by the modifications. Pharmacokinetics and biodistribution studies showed the albumin-binding domain-fused-(ZHER2:342)2-Alexa Fluor 750 conjugate to be an optimal probe for optical imaging of HER2 in vivo.
Our results suggest that Affibody-Alexa Fluor conjugates may be used as a specific NIR probe for the noninvasive semiquantitative imaging of HER2 expression in vivo.
We previously reported the formulation and physical properties of HER2 (human epidermal growth factor receptor 2)-specific affibody (ZHER2:342-Cys) conjugated thermosensitive liposomes (HER2
...+affisomes). Here we examined localized delivery potential of these affisomes by monitoring cellular interactions, intracellular uptake, and hyperthermia-induced effects on drug delivery. We modified ZHER2:342-Cys by introducing a glycine–serine spacer before the C-terminus cysteine (called ZHER2-GS-Cys) to achieve accessibility to cell surface expressed HER2. This modification did not affect HER2-specific binding and ZHER2-GS-Cys retained its ability to conjugate to the liposomes containing dipalmitoyl phosphatidyl choline: DSPE-PEG2000-Malemide, 96:04 mole ratios (HER2
+affisomes). HER2
+affisomes were either (i) fluorescently labeled with rhodamine-PE and calcein or (ii) loaded with an anticancer drug doxorubicin (DOX). Fluorescently labeled HER2
+ affisomes showed at least 10-fold increase in binding to HER2
+ cells (SK-BR-3) when compared to HER2
− cells (MDA-MB-468) at 37
°C. A competition experiment using free ZHER2-GS-Cys blocked HER2
+ affisome–SK-BR-3 cell associations. Imaging with confocal microscopy showed that HER2
+ affisomes accumulated in the cytosol of SK-BR-3 cells at 37
°C. Hyperthermia-induced intracellular release experiments showed that the treatment of HER2
+ affisome/SK-BR-3 cell complexes with a 45
°C (±
1
°C) pre-equilibrated buffer resulted in cytosolic delivery of calcein. Substantial calcein release was observed within 20
min at 45
°C, with no effect on cell viability under these conditions. Similarly, DOX-loaded HER2
+affisomes showed at least 2- to 3-fold higher accumulation of DOX in SK-BR-3 cells as compared to control liposomes. DOX-mediated cytotoxicity was more pronounced in SK-BR-3 cells especially at lower doses of HER2
+affisomes. Brief exposure of liposome–cell complexes at 45
°C prior to the onset of incubations for cell killing assays resulted in enhanced cytotoxicity for affisomes and control liposomes. However, Doxil (a commercially available liposome formulation) showed significantly lower toxicity under identical conditions. Therefore, our data demonstrate that HER2
+affisomes encompass both targeting and triggering potential and hence may prove to be viable nanodrug delivery carriers for breast cancer treatment.
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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.
The Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) programs of the National Cancer Institute (NCI) are congressionally mandated set-aside programs that ...provide research funding to for-profit small businesses for the development of innovative technologies and treatments that serve the public good. These two programs have an annual budget of $159 million (in 2017) and serve as the NCI's main engine of innovation for developing and commercializing cancer technologies. In collaboration with the NCI's Radiation Research Program, the NCI SBIR Development Center published in 2015-2017 three separate requests for proposals from small businesses for the development of systemic targeted radionuclide therapy (TRT) technologies to treat cancer. TRT combines a cytotoxic radioactive isotope with a molecularly targeted agent to produce an anticancer therapy capable of treating local or systemic disease. This article summarizes the NCI SBIR funding solicitations for the development of TRTs and the research proposals funded through them.
Purpose
The expression of human epidermal growth factor receptor-2 (HER2) receptors in cancers is correlated with a poor prognosis. If assessed in vivo, it could be used for selection of appropriate ...therapy for individual patients and for monitoring of the tumor response to targeted therapies. We have radiolabeled a HER2-binding Affibody molecule with fluorine-18 for in vivo monitoring of the HER2 expression by positron emission tomography (PET).
Materials and methods
The HER2-binding Z
HER2:342
-Cys Affibody molecule was conjugated with
N
-2-(4-
18
Ffluorobenzamido)ethylmaleimide (
18
FFBEM). The in vitro binding of the resulting radioconjugate was characterized by receptor saturation and competition assays. For in vivo studies, the radioconjugate was injected into the tail vein of mice bearing subcutaneous HER2-positive or HER2-negative tumors. Some of the mice were pre-treated with non-labeled Z
HER2:342
−Cys. The animals were sacrificed at different times post-injection, and the radioactivity in selected tissues was measured. PET images were obtained using an animal PET scanner.
Results
In vitro experiments indicated specific, high-affinity binding to HER2. PET imaging revealed a high accumulation of the radioactivity in the tumor as early as 20 min after injection, with a plateau being reached after 60 min. These results were confirmed by biodistribution studies demonstrating that, as early as 1 h post-injection, the tumor to blood concentration ratio was 7.5 and increased to 27 at 4 h. Pre-saturation of the receptors with unlabeled Z
HER2:342
-Cys lowered the accumulation of radioactivity in HER2-positive tumors to the levels observed in HER2-negative ones.
Conclusion
Our results suggest that the
18
FFBEM-Z
HER2:342
radioconjugate can be used to assess HER2 expression in vivo.
Targeted radiopharmaceutical conjugates intended for therapeutic use often are made of three key components, a decaying radionuclide, a chemical chelator/linker, and a targeted molecular entity. The ...National Cancer Institute (NCI) Experimental Therapeutics Program has accepted four radiopharmaceutical drug products so far that fit the targeted radiopharmaceutical conjugate class. As the NCI sharpens its thinking about its role as an investigational new drug sponsor for radiopharmaceuticals in clinical development, it has considered the relative merits of modular radiopharmaceutical drug master files. Here, the NCI provides its perspective on modular radiopharmaceutical drug master files as it initiates a clinical development program for such agents and further organizes its radiopharmaceutical Small Business Innovation Research portfolio.
Positron emission tomography (PET) has become an indispensable tool in the study of cancer biology, as well as in the clinical management of patients with cancer. Quantitative measurements of tracer ...accumulation enable researchers to detect tumor changes much earlier than by conventional imaging modalities. ¹⁸F-FDG has been widely utilized for staging and restaging of cancer, evaluation of response to the treatment, and assessment of prognosis; however, recently target-specific PET tracers have raised even more attention. This overview discusses the current status of PET imaging in optimization of cancer therapies in preclinical and clinical studies.
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