99m Tc-HisoDGR as a Potential SPECT Probe for Orthotopic Glioma Detection via Targeting of Integrin α 5 β 1

350

339

Integrins are key regulators of communication between cells and with their microenvironment. Eight members of the integrin superfamily recognize the tripeptide motif Arg-Gly-Asp (RGD) within extracelluar matrix (ECM) proteins. These integrins constitute an important subfamily and play a major role in cancer progression and metastasis via their tumor biological functions. Such transmembrane adhesion and signaling receptors are thus recognized as promising and well accessible targets for novel diagnostic and therapeutic applications for directly attacking cancer cells and their fatal microenvironment. Recently, specific small peptidic and peptidomimetic ligands as well as antibodies binding to distinct integrin subtypes have been developed and synthesized as new drug candidates for cancer treatment. Understanding the distinct functions and interplay of integrin subtypes is a prerequisite for selective intervention in integrin-mediated diseases. Integrin subtype-specific ligands labelled with radioisotopes or fluorescent molecules allows the characterization of the integrin patterns in vivo and later the medical intervention via subtype specific drugs. The coating of nanoparticles, larger proteins, or encapsulating agents by integrin ligands are being explored to guide cytotoxic reagents directly to the cancer cell surface. These ligands are currently under investigation in clinical studies for their efficacy in interference with tumor cell adhesion, migration/invasion, proliferation, signaling, and survival, opening new treatment approaches in personalized medicine.

Section: In Vivo Targeting Of Integrins For Cancer Imaging and Thementioning

confidence: 99%

Exploring the Role of RGD-Recognizing Integrins in Cancer

Nieberler

Reuning

Reichart

et al. 2017

350

339

“…The iso DGR derived cyclic peptide cyclo[phg- iso DGRk] (phg = d- phenylglycine; ligand 10 , Figure 7 ) was designed as a highly selective α5β1 (IC 50 = 8.7 nM) integrin ligand, which also displayed targeting of αvβ6 (IC 50 = 19 nM) [ 317 ]. This ligand was further developed and transformed into the 99m Tc-radiolabeled compound 99m Tc-HisoDGR for its use as a Single Photon Emission Computed Tomography (SPECT) imaging probe of α5β1-positive glioma (see Section 5 ) [ 351 , 352 ]. Regarding cancer therapy, no attempts were published, but the use of cyclo[phg-isoDGRk] as a drug vehicle is conceivable.…”

Section: Design and Development Of Rgd-based Integrin Ligands For mentioning

confidence: 99%

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

Ludwig

Kessler

Kossatz

et al. 2021

144

116

Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.

“…In spite of these interesting results, the clinical value of the in vivo mapping of αVβ3 to quantify tumor angiogenesis has not been clinically validated yet, as αVβ3 expression itself does not necessarily correspond to angiogenic activity in tumor tissues [200,206]. Integrin α5β1 has also been explored for PET and SPECT-based imaging of experimental tumors using peptidomimetic, linear, or cyclic peptides [207,208,209], while α5β1-based imaging in human has not been reported yet [28]. αVβ6-based imaging may be attractive, as it is associated with the invasion and activation of the TGFβ pathway in tumor cells.…”

Section: Targeting Integrins In Cancermentioning

confidence: 99%

Are Integrins Still Practicable Targets for Anti-Cancer Therapy?

Alday-Parejo

Stupp

Rüegg

2019

138

127

Correlative clinical evidence and experimental observations indicate that integrin adhesion receptors, in particular those of the αV family, are relevant to cancer cell features, including proliferation, survival, migration, invasion, and metastasis. In addition, integrins promote events in the tumor microenvironment that are critical for tumor progression and metastasis, including tumor angiogenesis, matrix remodeling, and the recruitment of immune and inflammatory cells. In spite of compelling preclinical results demonstrating that the inhibition of integrin αVβ3/αVβ5 and α5β1 has therapeutic potential, clinical trials with integrin inhibitors targeting those integrins have repeatedly failed to demonstrate therapeutic benefits in cancer patients. Here, we review emerging integrin functions and their proposed contribution to tumor progression, discuss preclinical evidence of therapeutic significance, revisit clinical trial results, and consider alternative approaches for their therapeutic targeting in oncology, including targeting integrins in the other cells of the tumor microenvironment, e.g., cancer-associated fibroblasts and immune/inflammatory cells. We conclude that integrins remain a valid target for cancer therapy; however, agents with better pharmacological properties, alternative models for their preclinical evaluation, and innovative combination strategies for clinical testing (e.g., together with immuno-oncology agents) are needed.