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Mechanism of action and clinical activity of tasquinimod in castrate-resistant prostate cancer.

Gupta N, Al Ustwani O, Shen L, Pili R - Onco Targets Ther (2014)

Bottom Line: Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC.Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC.The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

ABSTRACT
Castrate-resistant prostate cancer (CRPC) is a disease where survival is poor and treatment is challenging. Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC. However, despite the presence of new approved drugs such as enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and alpharadin, there is still an unmet need for novel agents with different mechanisms of action to target CRPC. Based on earlier studies demonstrating therapeutic potential of a quinoline-3-carboxamide agent roquinimex as an anticancer drug, efforts were directed to identify other useful members in this class. Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC. The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease. Tasquinimod is an orally available agent that has shown efficacy and favorable safety profile as deduced by the results of Phase I and II clinical trials of this drug in prostate cancer. The place of tasquinimod in the treatment of CRPC patients is currently under examination in an ongoing Phase III clinical trial. In this review, we will discuss tasquinimod, starting from its discovery and current knowledge on potential mechanisms of action to its clinical potential in CRPC.

No MeSH data available.


Related in: MedlinePlus

Mechanism of action of tasquinimod.Abbreviations: HIF α, hypoxia inducing factor α; HDAC, histone deacetylase; VEGF, vascular endothelial growth factor; SDF-1, stromal derived factor-1; CXCR 4, C-X-C chemokine receptor 4; LOX, lysyl oxidase; TSP, thrombospondin; TAM, tumor associated macrophages; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin motifs 1; MDSC, myeloid derived suppressor cells; TLR, Toll-like receptor; RAGE, receptor for advanced glycation end products; NCOR, nuclear receptor co-repressor; BMDVMC, bone marrow derived vascular modulatory cells.
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f3-ott-7-223: Mechanism of action of tasquinimod.Abbreviations: HIF α, hypoxia inducing factor α; HDAC, histone deacetylase; VEGF, vascular endothelial growth factor; SDF-1, stromal derived factor-1; CXCR 4, C-X-C chemokine receptor 4; LOX, lysyl oxidase; TSP, thrombospondin; TAM, tumor associated macrophages; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin motifs 1; MDSC, myeloid derived suppressor cells; TLR, Toll-like receptor; RAGE, receptor for advanced glycation end products; NCOR, nuclear receptor co-repressor; BMDVMC, bone marrow derived vascular modulatory cells.

Mentions: The mode of action of quinoline-3-carboxamide compounds is not fully understood. Several studies have demonstrated that this group of agents interferes with tumor angiogenesis, macrophage infiltration, cytokine production, and autoimmune/inflammatory diseases.21,24–26 Although further studies are needed to elucidate all the pathways by which quinoline-3-carboxamide agents function, recent preclinical studies have led to significant improvement in our understanding of actions of this class. Most of these studies involve tasquinimod, which is the lead second-generation quinoline-3-carboxamide employed for clinical development. Tasquinimod has unique pharmacotherapeutic properties and acts through multi-targeted mechanisms to treat prostate cancer. Figure 3 shows a representation of potential mechanisms of activity of tasquinimod. In preclinical human prostate cancer models, it has been demonstrated that tasquinimod has both antitumor and anti-metastatic activities, which are affected mainly through its anti-angiogenic and immunomodulatory effects.27 The anti-metastatic action likely occurs through interference with the tumor establishment process. In a preclinical study by Jennbacken et al, it was observed that tasquinimod seems to mainly inhibit the initial establishment of metastatic deposits and had lesser effect on inhibition of growth of already metastasized deposits.27


Mechanism of action and clinical activity of tasquinimod in castrate-resistant prostate cancer.

Gupta N, Al Ustwani O, Shen L, Pili R - Onco Targets Ther (2014)

Mechanism of action of tasquinimod.Abbreviations: HIF α, hypoxia inducing factor α; HDAC, histone deacetylase; VEGF, vascular endothelial growth factor; SDF-1, stromal derived factor-1; CXCR 4, C-X-C chemokine receptor 4; LOX, lysyl oxidase; TSP, thrombospondin; TAM, tumor associated macrophages; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin motifs 1; MDSC, myeloid derived suppressor cells; TLR, Toll-like receptor; RAGE, receptor for advanced glycation end products; NCOR, nuclear receptor co-repressor; BMDVMC, bone marrow derived vascular modulatory cells.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928061&req=5

f3-ott-7-223: Mechanism of action of tasquinimod.Abbreviations: HIF α, hypoxia inducing factor α; HDAC, histone deacetylase; VEGF, vascular endothelial growth factor; SDF-1, stromal derived factor-1; CXCR 4, C-X-C chemokine receptor 4; LOX, lysyl oxidase; TSP, thrombospondin; TAM, tumor associated macrophages; ADAMTS 1, a disintegrin and metalloproteinase with thrombospondin motifs 1; MDSC, myeloid derived suppressor cells; TLR, Toll-like receptor; RAGE, receptor for advanced glycation end products; NCOR, nuclear receptor co-repressor; BMDVMC, bone marrow derived vascular modulatory cells.
Mentions: The mode of action of quinoline-3-carboxamide compounds is not fully understood. Several studies have demonstrated that this group of agents interferes with tumor angiogenesis, macrophage infiltration, cytokine production, and autoimmune/inflammatory diseases.21,24–26 Although further studies are needed to elucidate all the pathways by which quinoline-3-carboxamide agents function, recent preclinical studies have led to significant improvement in our understanding of actions of this class. Most of these studies involve tasquinimod, which is the lead second-generation quinoline-3-carboxamide employed for clinical development. Tasquinimod has unique pharmacotherapeutic properties and acts through multi-targeted mechanisms to treat prostate cancer. Figure 3 shows a representation of potential mechanisms of activity of tasquinimod. In preclinical human prostate cancer models, it has been demonstrated that tasquinimod has both antitumor and anti-metastatic activities, which are affected mainly through its anti-angiogenic and immunomodulatory effects.27 The anti-metastatic action likely occurs through interference with the tumor establishment process. In a preclinical study by Jennbacken et al, it was observed that tasquinimod seems to mainly inhibit the initial establishment of metastatic deposits and had lesser effect on inhibition of growth of already metastasized deposits.27

Bottom Line: Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC.Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC.The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.

ABSTRACT
Castrate-resistant prostate cancer (CRPC) is a disease where survival is poor and treatment is challenging. Over the past 3 years, significant advances in the field have been made with US Food and Drug Administration approval of new drugs for patients with CRPC. However, despite the presence of new approved drugs such as enzalutamide, abiraterone, sipuleucel-T, cabazitaxel, and alpharadin, there is still an unmet need for novel agents with different mechanisms of action to target CRPC. Based on earlier studies demonstrating therapeutic potential of a quinoline-3-carboxamide agent roquinimex as an anticancer drug, efforts were directed to identify other useful members in this class. Tasquinimod is a second-generation quinoline-3-carboxamide agent that is currently in final stages of clinical development as a treatment for CRPC. The preclinical studies of tasquinimod have formed the basis for its success as an antiangiogenic and immunomodulatory agent in this disease. Tasquinimod is an orally available agent that has shown efficacy and favorable safety profile as deduced by the results of Phase I and II clinical trials of this drug in prostate cancer. The place of tasquinimod in the treatment of CRPC patients is currently under examination in an ongoing Phase III clinical trial. In this review, we will discuss tasquinimod, starting from its discovery and current knowledge on potential mechanisms of action to its clinical potential in CRPC.

No MeSH data available.


Related in: MedlinePlus