The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Jonathan D. Cheng - One of the best experts on this subject based on the ideXlab platform.
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selective inhibitors of Fibroblast Activation Protein fap with a xanthine scaffold
MedChemComm, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Annemarie Lambeir, Ingrid De Meester, Koen Augustyns, Hans De Winter, Pieter Van Der VekenAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
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extended structure activity relationship and pharmacokinetic investigation of 4 quinolinoyl glycyl 2 cyanopyrrolidine inhibitors of Fibroblast Activation Protein fap
Journal of Medicinal Chemistry, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Robert Verkerk, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure–activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral ...
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selective inhibitors of Fibroblast Activation Protein fap with a 4 quinolinoyl glycyl 2 cyanopyrrolidine scaffold
ACS Medicinal Chemistry Letters, 2013Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Oxana Ryabtsova, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
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identification of inhibitory scfv antibodies targeting Fibroblast Activation Protein utilizing phage display functional screens
The FASEB Journal, 2013Co-Authors: Jiping Zhang, Hyung-ok Lee, Matthildi Valianou, Louis M Weiner, Heidi H Simmons, Matthew K Robinson, Stefanie R Mullins, Wayne A Marasco, Gregory P Adams, Jonathan D. ChengAbstract:Fibroblast Activation Protein (FAP) is a serine protease selectively expressed on tumor stromal Fibroblasts in epithelial carcinomas and is important in cancer growth, adhesion, and metastases. As FAP enzymatic activity is a potent therapeutic target, we aimed to identify inhibitory antibodies. Using a competitive inhibition strategy, we used phage display techniques to identify 53 single-chain variable fragments (scFvs) after three rounds of panning against FAP. These scFvs were expressed and characterized for binding to FAP by surface plasmon resonance and flow cytometry. Functional assessment of these antibodies yielded an inhibitory scFv antibody, named E3, which could attenuate 35% of FAP cleavage of the fluorescent substrate Ala-Pro-7-amido-4-trifluoromethylcoumarin compared with nonfunctional scFv control. Furthermore, a mutant E3 scFv was identified by yeast affinity maturation. It had higher affinity (4-fold) and enhanced inhibitory effect on FAP enzyme activity (3-fold) than E3. The application ...
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activatable near infrared fluorescent probe for in vivo imaging of Fibroblast Activation Protein alpha
Bioconjugate Chemistry, 2012Co-Authors: Kai Chen, Jonathan D. Cheng, Jiping Zhang, Hongguang Liu, Kai Cheng, Meng Yang, Yan Zhang, Zhen ChengAbstract:Fibroblast Activation Protein-alpha (FAPα) is a cell surface glycoProtein which is selectively expressed by tumor-associated Fibroblasts in malignant tumors but rarely on normal tissues. FAPα has also been reported to promote tumor growth and invasion and therefore has been of increasing interest as a promising target for designing tumor-targeted drugs and imaging agents. Although medicinal study on FAPα inhibitors has led to the discovery of many FAPα-targeting inhibitors including a drug candidate in a phase II clinical trial, the development of imaging probes to monitor the expression and activity of FAPα in vivo has largely lagged behind. Herein, we report an activatable near-infrared (NIR) fluorescent probe (ANP(FAP)) for in vivo optical imaging of FAPα. The ANP(FAP) consists of a NIR dye (Cy5.5) and a quencher dye (QSY21) which are linked together by a short peptide sequence (KGPGPNQC) specific for FAPα cleavage. Because of the efficient fluorescence resonance energy transfer (FRET) between Cy5.5 and QSY21 in ANP(FAP), high contrast on the NIR fluorescence signal can be achieved after the cleavage of the peptide sequence by FAPα both in vitro and in vivo. In vitro assay on ANP(FAP) indicated the specificity of the probe to FAPα. The in vivo optical imaging using ANP(FAP) showed fast tumor uptake as well as high tumor to background contrast on U87MG tumor models with FAPα expression, while much lower signal and tumor contrast were observed in the C6 tumor without FAPα expression, demonstrating the in vivo targeting specificity of the ANP(FAP). Ex vivo imaging also demonstrated ANP(FAP) had high tumor uptake at 4 h post injection. Collectively, these results indicated that ANP(FAP) could serve as a useful NIR optical probe for early detection of FAPα expressing tumors.
Uwe Haberkorn - One of the best experts on this subject based on the ideXlab platform.
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the latest developments in imaging of Fibroblast Activation Protein
The Journal of Nuclear Medicine, 2021Co-Authors: Uwe Haberkorn, Annette Altmann, Jens T SivekeAbstract:Fibroblast Activation Protein (FAP), a membrane-anchored peptidase, is highly expressed in cancer-associated Fibroblasts in more than 90% of epithelial tumors and contributes to progression and worse prognosis of different cancers. Therefore, FAP is considered a promising target for radionuclide-based approaches for diagnosis and treatment of tumors and for the diagnosis of nonmalignant diseases associated with a remodeling of the extracellular matrix. Accordingly, a variety of quinolone-based FAP inhibitors (FAPIs) coupled to chelators were developed displaying specific binding to human and murine FAP with a rapid and almost complete internalization. Because of a high tumor uptake and a very low accumulation in normal tissues, as well as a rapid clearance from the circulation, a high contrast is obtained for FAPI PET/CT imaging even at 10 min after tracer administration. Moreover, FAPI PET/CT provides advantages over 18F-FDG PET/CT in several tumor entities for initial staging and detection of tumor recurrence and metastases, including peritonitis carcinomatosa.
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clinical results of Fibroblast Activation Protein fap specific pet and implications for radiotherapy planning systematic review
Cancers, 2020Co-Authors: Paul Windisch, Uwe Haberkorn, Frederik L Giesel, Daniel R Zwahlen, Stefan A Koerber, Jurgen Debus, Sebastian AdebergAbstract:Small molecules targeting Fibroblast Activation Protein (FAP) have emerged as a new group of tracers for positron emission tomography (PET) in 2018. The purpose of this systematic review is therefore to summarize the evidence that has been gathered to date in patients and to discuss its possible implications for radiotherapy planning. The MEDLINE database was searched for the use of FAP-specific PET in cancer patients and the records were screened according to PRISMA guidelines. Nineteen studies were included. While dedicated analyses of FAP-specific PET for radiotherapy planning were available for glioblastoma, head and neck cancers, lung cancer, and tumors of the lower gastrointestinal tract, there is still very limited data for several epidemiologically significant cancers. In conclusion, FAP-specific PET represents a promising imaging modality for radiotherapy planning that warrants further research.
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relationship between cardiac Fibroblast Activation Protein activity by positron emission tomography and cardiovascular disease
Circulation-cardiovascular Imaging, 2020Co-Authors: Markus B Heckmann, Finn Reinhardt, Daniel Finke, Hugo A Katus, Uwe Haberkorn, Florian Leuschner, Lorenz H LehmannAbstract:Background: FAP (Fibroblast Activation Protein) plays an important role in cardiac wound healing and remodeling. Although initially developed as a theranostic ligand for metastasized cancer, FAPI (...
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Fibroblast Activation Protein fap specific pet for advanced target volume delineation in glioblastoma
Radiotherapy and Oncology, 2020Co-Authors: Paul Windisch, Manuel Rohrich, Sebastian Regnery, Eric Tonndorfmartini, Thomas Held, Kristin Lang, Denise Bernhardt, Stefan Rieken, Frederik L Giesel, Uwe HaberkornAbstract:Abstract Fibroblast Activation Protein (FAP)-specific Positron Emission Tomography (PET) has shown promising results in various cancers. This pilot study compares FAP-specific PET to MRI for treatment planning in 13 Glioblastoma patients. The resulting incongruent volumes could provide additional information for radiotherapy or biopsy planning.
Koen Augustyns - One of the best experts on this subject based on the ideXlab platform.
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selective inhibitors of Fibroblast Activation Protein fap with a xanthine scaffold
MedChemComm, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Annemarie Lambeir, Ingrid De Meester, Koen Augustyns, Hans De Winter, Pieter Van Der VekenAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
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extended structure activity relationship and pharmacokinetic investigation of 4 quinolinoyl glycyl 2 cyanopyrrolidine inhibitors of Fibroblast Activation Protein fap
Journal of Medicinal Chemistry, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Robert Verkerk, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure–activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral ...
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selective inhibitors of Fibroblast Activation Protein fap with a 4 quinolinoyl glycyl 2 cyanopyrrolidine scaffold
ACS Medicinal Chemistry Letters, 2013Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Oxana Ryabtsova, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
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acylated gly 2 cyano pyrrolidines as inhibitors of Fibroblast Activation Protein fap and the issue of fap prolyl oligopeptidase prep selectivity
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Oxana Ryabtsova, Jonathan D. Cheng, Koen Jansen, Jurgen Joossens, Annemarie Lambeir, Ingrid De Meester, Koen Augustyns, Sebastiaan Van Goethem, Pieter Van Der VekenAbstract:A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of Fibroblast Activation Protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.
Koen Jansen - One of the best experts on this subject based on the ideXlab platform.
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selective inhibitors of Fibroblast Activation Protein fap with a xanthine scaffold
MedChemComm, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Annemarie Lambeir, Ingrid De Meester, Koen Augustyns, Hans De Winter, Pieter Van Der VekenAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanthine derivative linagliptin. In a broad literature screen amongst reported DPPIV inhibitors, linagliptin was the only druglike compound identified that possessed significant FAP potency. Hence, this compound served as a starting point for a SAR study that aimed to identify structural determinants that selectively increase FAP-potency of linagliptin analogues. By investigating the influence of the substitution pattern on N1, N7 and C8 of the xanthine scaffold, we managed to decouple DPPIV and FAP potency and identified the first selective xanthine-based FAP inhibitors with low micromolar potency. Furthermore, these compounds are the only known FAP-inhibitors that do not rely on a warhead functionality to obtain potencies in this range.
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extended structure activity relationship and pharmacokinetic investigation of 4 quinolinoyl glycyl 2 cyanopyrrolidine inhibitors of Fibroblast Activation Protein fap
Journal of Medicinal Chemistry, 2014Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Robert Verkerk, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure–activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral ...
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selective inhibitors of Fibroblast Activation Protein fap with a 4 quinolinoyl glycyl 2 cyanopyrrolidine scaffold
ACS Medicinal Chemistry Letters, 2013Co-Authors: Koen Jansen, Jonathan D. Cheng, Leen Heirbaut, Jurgen Joossens, Paul Cos, Louis Maes, Annemarie Lambeir, Ingrid De Meester, Oxana Ryabtsova, Koen AugustynsAbstract:Fibroblast Activation Protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp2 hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>103) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
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acylated gly 2 cyano pyrrolidines as inhibitors of Fibroblast Activation Protein fap and the issue of fap prolyl oligopeptidase prep selectivity
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Oxana Ryabtsova, Jonathan D. Cheng, Koen Jansen, Jurgen Joossens, Annemarie Lambeir, Ingrid De Meester, Koen Augustyns, Sebastiaan Van Goethem, Pieter Van Der VekenAbstract:A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of Fibroblast Activation Protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.
Samuel R Denmeade - One of the best experts on this subject based on the ideXlab platform.
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overcoming stromal barriers to immuno oncological responses via Fibroblast Activation Protein targeted therapy
Immunotherapy, 2021Co-Authors: Nathaniel W Brennen, Samuel R Denmeade, Daniel L J Thorek, Wen Jiang, Timothy E Krueger, Lizamma Antony, John T IsaacsAbstract:The tumor microenvironment contributes to disease progression through multiple mechanisms, including immune suppression mediated in part by Fibroblast Activation Protein (FAP)-expressing cells. Herein, a review of FAP biology is presented, supplemented with primary data. This includes FAP expression in prostate cancer and Activation of latent reservoirs of TGF-β and VEGF to produce a positive feedback loop. This collectively suggests a normal wound repair process subverted during cancer pathophysiology. There has been immense interest in targeting FAP for diagnostic, monitoring and therapeutic purposes. Until recently, this development has outpaced an understanding of the biology; impeding optimal translation into the clinic. A summary of these applications is provided with an emphasis on eliminating tumor-infiltrating FAP-positive cells to overcome stromal barriers to immuno-oncological responses.
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Review Rationale Behind Targeting Fibroblast Activation Protein–Expressing Carcinoma-Associated Fibroblasts as a Novel Chemotherapeutic Strategy
2016Co-Authors: Nathaniel W Brennen, John T Isaacs, Samuel R DenmeadeAbstract:The tumormicroenvironment has emerged as a novel chemotherapeutic strategy in the treatment of cancer. This is most clearly exemplified by the antiangiogenesis class of compounds. Therapeutic strategies that target Fibroblastswithin the tumor stroma offer another treatment option.However, despite promising data obtained in preclinical models, such strategies have not been widely used in the clinical setting, largely due to a lack of effective treatments that specifically target this population of cells. The identification of Fibroblast Activation Protein a (FAP) as a target selectively expressed on Fibroblasts within the tumor stroma or on carcinoma-associated Fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit. FAP is a membrane-bound serine protease of the prolyl oligopeptidase family with unique post-prolyl endopeptidase activity. Until recently, the majority of FAP-based therapeutic approaches focused on the development of small-molecule inhibitors of enzymatic activity. Evidence suggests, however, that FAP’s pathophysiological role in carcinogenesis may be highly contextual, depending on both the exact nature of the tumor microen-vironment present and the cancer type in question to determine its tumor-promoting or tumor-suppressing phenotype. As an alternative strategy, we are taking advantage of FAP’s restricted expression and unique substrate preferences to develop a FAP-activated prodrug to target the Activation of a cytotoxic compound within the tumor stroma. Of note, this strategy would be effective independently of FAP’s role in tumor progression because its therapeutic benefit would rely on FAP’s localization and activity within the tumor microenvironment rather than strictly on inhibition of its function.MolCancer Ther; 11(2); 257–66.2012AACR
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rationale behind targeting Fibroblast Activation Protein expressing carcinoma associated Fibroblasts as a novel chemotherapeutic strategy
Molecular Cancer Therapeutics, 2012Co-Authors: Nathaniel W Brennen, John T Isaacs, Samuel R DenmeadeAbstract:The tumor microenvironment has emerged as a novel chemotherapeutic strategy in the treatment of cancer. This is most clearly exemplified by the antiangiogenesis class of compounds. Therapeutic strategies that target Fibroblasts within the tumor stroma offer another treatment option. However, despite promising data obtained in preclinical models, such strategies have not been widely used in the clinical setting, largely due to a lack of effective treatments that specifically target this population of cells. The identification of Fibroblast Activation Protein α (FAP) as a target selectively expressed on Fibroblasts within the tumor stroma or on carcinoma-associated Fibroblasts led to intensive efforts to exploit this novel cellular target for clinical benefit. FAP is a membrane-bound serine protease of the prolyl oligopeptidase family with unique post-prolyl endopeptidase activity. Until recently, the majority of FAP-based therapeutic approaches focused on the development of small-molecule inhibitors of enzymatic activity. Evidence suggests, however, that FAP's pathophysiological role in carcinogenesis may be highly contextual, depending on both the exact nature of the tumor microenvironment present and the cancer type in question to determine its tumor-promoting or tumor-suppressing phenotype. As an alternative strategy, we are taking advantage of FAP's restricted expression and unique substrate preferences to develop a FAP-activated prodrug to target the Activation of a cytotoxic compound within the tumor stroma. Of note, this strategy would be effective independently of FAP's role in tumor progression because its therapeutic benefit would rely on FAP's localization and activity within the tumor microenvironment rather than strictly on inhibition of its function.
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targeting the cancer stroma with a Fibroblast Activation Protein activated promelittin protoxin
Molecular Cancer Therapeutics, 2009Co-Authors: Aaron M Lebeau, Nathaniel W Brennen, Saurabh Aggarwal, Samuel R DenmeadeAbstract:Fibroblast-Activation Protein-α (FAP) is a membrane-bound serine protease that is expressed on the surface of reactive stromal Fibroblasts present within the majority of human epithelial tumors but is not expressed by normal tissues. FAP is a postprolyl peptidase that differs from other dipeptidyl prolyl peptidases such as diprolylpeptidase 4 in that it also has gelatinase and collagenase endopeptidase activity. Therefore, FAP represents a potential pan-tumor target whose enzymatic activity can be exploited for the intratumoral Activation of prodrugs and protoxins. To evaluate FAP as a tumor-specific target, putative FAP-selective peptide protoxins were constructed through modification of the prodomain of melittin, a 26 amino acid amphipathic cytolytic peptide that is the main toxic component in the venom of the common European honeybee Apis milefera . Melittin is synthesized as promelittin, containing a 22 amino acid NH2-terminal prodomain rich in the amino acids proline and alanine. In this study, peptides containing truncated melittin prodomain sequences were tested on erythrocytes to determine the optimal prodomain length for inhibiting cytolytic activity. Once optimized, modified promelittin peptides were generated in which previously identified FAP substrate sequences were introduced into the prodomain. Peptide protoxins were identified that were efficiently activated by FAP and selectively toxic to FAP-expressing cell lines with an IC50 value in the low micromolar range that is similar to melittin. Intratumoral injection of an FAP-activated protoxin produced significant lysis and growth inhibition of human breast and prostate cancer xenografts with minimal toxicity to the host animal. [Mol Cancer Ther 2009;8(5):1378–86]
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targeting the cancer stroma with a Fibroblast Activation Protein activated promelittin protoxin
Molecular Cancer Therapeutics, 2009Co-Authors: Aaron M Lebeau, Nathaniel W Brennen, Saurabh Aggarwal, Samuel R DenmeadeAbstract:Fibroblast-Activation Protein-α (FAP) is a membrane-bound serine protease that is expressed on the surface of reactive stromal Fibroblasts present within the majority of human epithelial tumors but is not expressed by normal tissues. FAP is a postprolyl peptidase that differs from other dipeptidyl prolyl peptidases such as diprolylpeptidase 4 in that it also has gelatinase and collagenase endopeptidase activity. Therefore, FAP represents a potential pan-tumor target whose enzymatic activity can be exploited for the intratumoral Activation of prodrugs and protoxins. To evaluate FAP as a tumor-specific target, putative FAP-selective peptide protoxins were constructed through modification of the prodomain of melittin, a 26 amino acid amphipathic cytolytic peptide that is the main toxic component in the venom of the common European honeybee Apis milefera. Melittin is synthesized as promelittin, containing a 22 amino acid NH(2)-terminal prodomain rich in the amino acids proline and alanine. In this study, peptides containing truncated melittin prodomain sequences were tested on erythrocytes to determine the optimal prodomain length for inhibiting cytolytic activity. Once optimized, modified promelittin peptides were generated in which previously identified FAP substrate sequences were introduced into the prodomain. Peptide protoxins were identified that were efficiently activated by FAP and selectively toxic to FAP-expressing cell lines with an IC(50) value in the low micromolar range that is similar to melittin. Intratumoral injection of an FAP-activated protoxin produced significant lysis and growth inhibition of human breast and prostate cancer xenografts with minimal toxicity to the host animal.