Germany-Austria-Nethelands FYI Tilmanocept mentioned in study
Development of Radiotracers for Breast Cancer—TheTumor Microenvironment as an Emerging Target
Amelie Heesch1, Jochen Maurer2, Elmar Stickeler2, Mohsen Beheshti1,3,Felix M. Mottaghy1,4and Agnieszka Morgenroth1,*1Department of Nuclear Medicine, University Hospital Aachen, RWTH Aachen University, 52074 Aachen,Germany; firstname.lastname@example.org (A.H.); email@example.com (M.B.); firstname.lastname@example.org (F.M.M.)2Department of Obstetrics and Gynecology, University Hospital Aachen (UKA), 52074 Aachen, Germany;email@example.com (J.M.); firstname.lastname@example.org (E.S.)3Department of Nuclear Medicine, University Hospital Salzburg, Paracelsus Medical University,5020 Salzburg, Austria4Department of Radiology and Nuclear Medicine, Maastricht University Medical Center (MUMC+),6202 Maastricht, The Netherlands*Correspondence: email@example.comReceived: 24 September 2020; Accepted: 19 October 2020; Published: 21 October 2020
Molecular imaging plays an increasingly important role in the diagnosis and treatment of different malignancies. Radiolabeled probes enable the visualization of the primary tumor as well as the metastases and have been also employed in targeted therapy and theranostic approaches.With breast cancer being the most common malignancy in women worldwide it is of special interest to develop novel targeted treatments. However, tumor micro environment and escape mechanisms often limit their therapeutic potential. Addressing tumor stroma associated targets provides a promising option to inhibit tumor growth and angiogenesis and to disrupt tumor tissue architecture.This review describes recent developments on radiolabeled probes used in diagnosis and treatment of breast cancer especially in triple negative type with the focus on potential targets offered by the tumor microenvironment, like tumor associated macrophages, cancer associated fibroblasts,and endothelial cells
Targeting e.g., tumor cells and angiogenesis at the same time provides a
larger number of potential binding sites for the respective radiotracer. Nevertheless, most targets are specific for one cell type. A combined approach to target dierent cellular compartments in the tumor would be conceivable for future tracer design. Meanwhile, the role of nuclear medicine in cancer care is indispensable as it holds a tremendous potential for novel theranostic strategies (with a). Imaging tracer
which show a high accumulation in the target can be labeled with therapeutic moieties and thus be implicated in individual therapy design. The challenge is to develop a theranostic radiopharmaceutical with high affinity, low unspecific binding, adequate half-life, low cytotoxic offsite effects, and high target-specificity. By combining molecular biology, chemistry and imaging technologies in an attempt to develop specific stroma- and angiogenesis-targeting agents for BCa, not only patient prognosis and
therapy but overall life quality could improve significantly.
....Inflammation is one of the hallmarks of cancer progression. Here, TAMs play an important role in promoting tumor growth through pro-angiogenic behavior, inhibiting the antitumor immune response and remodeling the ECM [91,92]. Moreover, a high TAM infiltrate density in the primary breast tumor correlates with a worse prognosis . TAMs are the most abundant immune-related cells in the tumor stroma. Cancer cells that underwent EMT are known to activate macrophages to a TAM-like phenotype which in turn produce chemokines to again induce EMT in cancer cells forming a positive feedback-loop . Macrophages are phagocytic immune cells which are involved in tissue homoeostasis, defense mechanisms, and wound healing. Due to micro environmental stimuli they are polarized to form a heterogeneous population with diverse functions and characteristics. They are subdivided in proinflammatory M1 or anti-inflammatory M2 macrophages. M1 macrophages secrete reactive oxygen
species (ROS) and cytokines and are therefore termed as “fight” macrophages. M2 macrophages repair and remodel injured tissue and are involved in debris scavenging and immune modulation. In cancer they act pro-angiogenic by secreting adrenomedullin and VEGFs and suppress the immune response in favor of the tumor .
Previous studies have shown that a high number of M2 TAMs in tumor entails chemoresistance and radioprotective effects leading to therapy failure . Targeting TAMs therefore is not only advantageous in inhibiting angiogenesis but also has potential to improve therapeutic eefficacy by preventing development of chemoresistance. Up to date several TAM markers for M2 macrophages
are known including the mannose receptor C type 1 CD206 and the macrophage scavenger receptors CD204, and CD163 .
One common tracer is [99mTc]Tc-tilmanocept which is already approved by the U.S. Food and Drug Administration for lymphatic mapping and sentinel lymph node localization in different malignancies including BCa. The agent binds to the CD206 receptor on the surface of TAMs and dendritic cells which are numerously present in lymphatic tissue resulting in a strong tracer accumulation in this area . Different clinical trials demonstrated that [99mTc]Tc-tilmanocept is superior to[99mTc]Tc-sulfur colloid (SC) due to a faster injection site clearance while primary sentinel node uptake was equivalent [39,99–101]. Another group developed macrophage mannose receptor (MMR) targeting nanobodies(99mTc-labeledα-MMR Nb). SPECT analysis in mammary carcinoma mouse model demonstrated the potential ofα-MMR Nb as MMR specific approach for efficient targeting of TAMs in solid tumors . Addressing TAMs is also possible with tracer targeting the high-density lipoprotein (HDL)which is specific for macrophages. For this, two89Zr-modified reconstituted HDL (rHDL) have been designed as PET tracers and evaluated in an orthotopic breast cancer mouse model. For design of[89Zr]Zr-AI-HDL, only the protein component apoA of HDL was labeled whereas for [89Zr]Zr-PL-HDL,only the phospholipid load was labeled. Interestingly, the blood half-life of [89Zr]Zr-AI-HDL was nearly three times longer than that of [89Zr]Zr-PL-HDL. Tumor uptake was high for both tracer and the specificity was additionally confirmed by localization of radiotracer in ionized calcium-binding adapter molecule 1 (Iba1)-positive areas. Ex vivo histological and flow cytometric analyses validated TAMs as the main target for both radiotracers . A recent study from Mason et al. used [89Zr]Zr-HDLto monitor the response to immunotherapy. The mice were administered pexidartinib, an inhibitor of colony-stimulating factor 1 receptor (CSF1R), which is overexpressed on TAMs. PET/CT and also ex vivo analyses demonstrated a correlation between macrophage density and [89Zr]Zr-HDL accumulation. Unfortunately, the tracer also highly accumulated in the liver which blurred the delineation of hepatic lesions. However, this study clearly evidences the potential of [89Zr]Zr-HDL nanoparticles as macrophage-avid PET tracer for detection of early responses to therapies in tumor micro environmental-guided approaches ....