Long-term Survival and Biomarker Correlates of Tasquinimod Efficacy in a Multicenter Randomized Study of Men with Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer

Armstrong, Andrew J.; Häggman, Michael; Stadler, Walter M.; Gingrich, Jeffrey R.; Assikis, Vasily J.; Polikoff, Jonathan; Damber, Jan Erik; Belkoff, Laurence; Nordle, Örjan; Forsberg, G.; Carducci, Michael A.; Пили, Роберто

doi:10.1158/1078-0432.ccr-13-1581

Cited by 52 publications

(43 citation statements)

References 38 publications

(60 reference statements)

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“…43,44 The S100A9 inhibitor, tasquinimod, is a quinolone-3-carboxamide derivative, capable of suppressing the growth and metastasis of tumor cells, and its clinical efficacy for controlling metastatic castrationresistant prostate cancer has been positively evaluated in a phase 2 randomized controlled trial. 45 Because of the pleiotropic functions exerted by S100A9, the precise mechanisms by which tumors are controlled by tasquinimod remain to be determined; however, growing evidence has underscored that tasquinimod suppresses the local recruitment and function of myeloid-derived suppressor cells (MDSCs), thereby disrupting the immunosuppressive tumor microenvironment. 46 Given that human and mouse MDSCs express high levels of S100A9, 47,48 it is intriguing to predict that the granulomaresident S100A9 1 neutrophils may be equipped with MDSC functions that are sensitive to tasquinimod.…”

Section: Discussionmentioning

confidence: 99%

Neutrophils and the S100A9 protein critically regulate granuloma formation

et al. 2016

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Key Points• S100A91 neutrophils accumulated prominently in the central area of granulomas in humans and guinea pigs.• Granuloma formation was markedly impaired by a treatment with the S100A9 inhibitor, tasquinimod. antigen as S100A9, a calcium-binding protein of the S100 family, which was expressed abundantly in neutrophils. Consistent with the multifaceted functions attributed to S100A9, including its role in neutrophil extravasation and macrophage activation, the blockade of S100A9 functions with the specific inhibitor, tasquinimod, impaired the formation of organized granulomas with neutrophil cores. These results demonstrate the critical role of neutrophils and the S100A9 protein in granuloma formation. Because intragranuloma S100A9 1 neutrophils were also detected in humans, these results indicate the potential of tasquinimod, a new anticancer drug candidate, for manipulating human granulomatous diseases.

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Section: Discussionmentioning

confidence: 99%

Neutrophils and the S100A9 protein critically regulate granuloma formation

et al. 2016

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“…Chronic once daily oral dosing with tasquinimod doubles the median progression-free survival and prolongs survival of patients with metastatic, castrate resistant prostate cancer in randomized prospective clinical trials [15, 16]. These positive clinical results are produced using an oral dose of tasquinimod of only 0.5-1 mg/day.…”

Section: Discussionmentioning

confidence: 99%

“…Tasquinimod is currently in clinical development for the treatment of prostate cancer and other solid malignancies [13, 14]. In a placebo-controlled, phase II randomized trial, tasquinimod doubled median progression-free survival and prolonged survival of patients with metastatic, castrate resistant prostate cancer [15, 16]. A registration phase III clinical trial of tasquinimod as monotherapy in the same patient population is ongoing (NCT01234311).…”

Section: Introductionmentioning

confidence: 99%

Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment

et al. 2014

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Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial “sprouting” in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo.Tasquinimod's potency is facilitated by its reversible binding (Kd < 35 μM) to the IIA subdomain of albumin (Sudlow's site I). As blood vessels within the compromised cancer microenvironment are characterized by a higher degree of leakiness than those in normal tissues, this results in an enhanced uptake of tasquinimod bound to albumin in cancer tissue via a tumor specific process known as the “enhanced permeability and retention” (i.e., EPR) effect. Thus, despite plasma levels of < 1 μM, the EPR effect results in intracellular drug concentrations of 2-3 μM, levels several-fold higher than needed for inhibition of endothelial sprouting (IC50 ~ 0.5 μM) or for inhibition of HDAC4 and S100A9 mediated tumor growth.

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“…The use of anti-VEGF therapies in preclinical and clinical studies has been associated with increased side effects, including hypertension, gastrointestinal bleeding, intestinal perforation, and pulmonary embolism (Mangoni et al 2012, Ogita et al 2012. Although bevacizumab has shown some promise with improved progression-free survival, no significant improvement in overall survival has been achieved even in combination therapies (reviewed by Small & Oh (2012) and Armstrong et al (2013)). A newer anti-angiogenesis agent derived from the extracellular domains of the VEGFR (aflibercept) in combination with docetaxel and prednisone also offered no improvement in overall survival (Tannock et al 2013).…”

Section: Anti-vegf Signaling Therapies In the Clinical Management Of Pcamentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

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Long-term Survival and Biomarker Correlates of Tasquinimod Efficacy in a Multicenter Randomized Study of Men with Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer

Cited by 52 publications

References 38 publications

Neutrophils and the S100A9 protein critically regulate granuloma formation

Neutrophils and the S100A9 protein critically regulate granuloma formation

Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment

Regulation of vascular endothelial growth factor in prostate cancer

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