This study is being conducted to determine the safety and biologic activity of PX-478, and to allow for observation of any preliminary evidence of antitumor activity in patients with advanced metastatic cancer.

Start Date01 Aug 2007

Sponsor / Collaborator

Cascadian Therapeutics LLC

100 Clinical Results associated with PX-478

100 Translational Medicine associated with PX-478

100 Patents (Medical) associated with PX-478

106

Literatures (Medical) associated with PX-478

31 Dec 2024·Journal of Obstetrics and Gynaecology

The therapeutic potential of PX-478 in a murine model of pelvic organ prolapse

Article

Author: Wu, Duan-Qing ; Yang, Ying ; Zhang, Li-Wen ; Yang, Yu-Qi ; Chen, Ru-Jun ; Ye, Jun ; Mei, Xiao-Hui ; Duan, Chun-Fang ; Fan, Wei-Min ; Sun, Ke

BACKGROUNDPelvic organ prolapse (POP), characterised by the downward displacement of pelvic organs, is a prevalent disorder that affects adult women. This study explored the therapeutic potential of PX-478, a selective hypoxia-inducible factor-1α (HIF-1α) inhibitor, in a murine POP model.METHODSA murine POP model was established through ovariectomy, mimicking oestrogen deprivation. Fifteen C57BL/6J mice were randomly assigned to control, POP, and PX-478 groups. PX-478, targeting HIF-1α, was administered intravaginally. The analysis of fibroblasts, macrophage and inflammation was performed through Masson staining, immunofluorescence, and ELISA. Collagen distribution was assessed using Sirius Red staining. Expression levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP-1) were determined through immunohistochemistry and western blot. Fibroblast proliferation and apoptosis were evaluated by CCK-8 assay and flow cytometry.RESULTSPX-478 treatment significantly reduced vaginal length, indicating a therapeutic effect on POP severity. Masson staining revealed reduced fibrotic changes and collagen disruption in PX-478-treated mice. Immunofluorescence showed increased fibroblast markers (Vimentin, α-SMA) and collagen fibres by PX-478. Sirius Red staining indicated PX-478 mitigated damage to Type I and Type III collagen fibres. PX-478 significantly reduced MMP-2 and MMP-9 expression while increased TIMP-1. In macrophages, PX-478 decreased M1 and M2 markers (CD80, CD206) and IL-18 secretion. Fibroblasts exhibited increased proliferation, reduced apoptosis, and altered MMP/TIMP expression under PX-478 influence.CONCLUSIONPX-478 demonstrates a therapeutic potential in the mice POP model. It reduces vaginal length, attenuates fibrosis, and modulates collagen synthesis. Its immunomodulation is evident through reduced M1 and M2 macrophages and suppressed IL-18 secretion.

12 Dec 2024·Biology of Reproduction

Fetal hypoxia exposure induces Hif1a activation and autophagy in adult ovarian granulosa cells

Article

Author: Zhang, Ke ; Jia, Gong-Xue ; Yang, Qi-En ; Zhao, Xi ; Fang, You-Gui ; Zhang, Lu-Yao ; Hou, Yun-Peng ; Tao, Hai-Ping

AbstractEnvironmental hypoxia adversely impacts the reproduction of humans and animals. Previously, we showed that fetal hypoxia exposure led to granulosa cell (GC) autophagic cell death via the Foxo1/Pi3k/Akt pathway. However, the upstream regulatory mechanisms underlying GC dysfunction remain largely unexplored. Here, we tested the hypothesis that fetal hypoxia exposure altered gene expression programs in adult GCs and impaired ovarian function. We established a fetal hypoxia model in which pregnant mice were maintained in a high-plateau hypoxic environment from gestation day (E) 0–16.5 to study the impact of hypoxia exposure on the ovarian development and subsequent fertility of offspring. Compared with the unexposed control, fetal hypoxia impaired fertility by disordering ovarian function. Specifically, fetal hypoxia caused mitochondrial dysfunction, oxidant stress, and autophagy in GCs in the adult ovary. RNA sequencing analysis revealed that 437 genes were differentially expressed in the adult GCs of exposed animals. Western blotting results also revealed that fetal exposure induced high levels of hypoxia-inducible factor 1-alpha (Hif1a) expression in adult GCs. We then treated granulosa cells isolated from exposed mice with PX-478, a specific pharmacological inhibitor of Hif1a, and found that autophagy and apoptosis were effectively alleviated. Finally, by using a human ovarian granulosa-like tumor cell line (KGN) to simulate hypoxia in vitro, we showed that Hif1a regulated autophagic cell death in GCs through the Pi3k/Akt pathway. Together, these findings suggest that fetal hypoxia exposure induced persistent Hif1a expression, which impaired mitochondrial function and led to autophagic cell death in the GCs of the adult ovary.

01 Dec 2024·International Immunopharmacology

The impact of X-rays on cardiac hydrometabolism and the regulatory role of AS-IV

Article

Author: Qiyang, Li ; Fuxian, Liu ; Yongqi, Liu ; Yan, Chen ; Sichao, Dai ; Gengqiang, Yang ; Shangzu, Zhang ; Liying, Zhang ; Zhiming, Miao ; Ting, Zhou ; Yutong, Wang ; Yangyang, Li

BACKGROUNDRadiation-induced cardiac injury has emerged as a significant pathological entity, with many studies focusing on the fibrotic changes in myocardial tissue. However, these do not offer solutions for the clinical prevention and treatment of radiation-induced heart disease. Regulating hydrometabolism presents a potential therapeutic target for the management of cardiovascular diseases. This research seeks to explore the impacts of irradiation on cardiac hydrometabolism and its regulatory mechanisms.METHODSThe impact of X-ray radiation on cardiac and cardiomyocyte hydrometabolism was studied through in vivo and in vitro experiments, examining the pharmacological effects and mechanisms of PX-478 and AS-IV interventions in cardiomyocytes.RESULTS28 days after direct chest irradiation with 20 Gy X-rays, C57BL/6 mice exhibited an increased heart wet-to-dry weight ratio, significant enlargement of cardiomyocyte cross-sectional area, and elevated protein expression of HIF-1α, AQP1, AQP4, Cx43, Caspase3, and Bax, with decreased expression of Bcl-2. Irradiation with 6 Gy X-rays induced edema and damage in AC16 and HL-1 cardiomyocytes at 24, 48, and 72 h, with increased expression of HIF-1α, AQP1, AQP4, and Cx43 proteins post-radiation. Inhibition of HIF-1α ameliorated edema and apoptosis in AC16 and HL-1 cardiomyocytes, reducing the expression of HIF-1α, AQP1, AQP4, and Cx43 proteins. AS-IV demonstrated strong binding affinity with HIF-1α, and successfully attenuated the expression levels of HIF-1α, AQP1, AQP4, and Cx43 proteins, alleviating edema, mitochondrial swelling, and apoptosis in AC16 and HL-1 cardiomyocytes. Furthermore, AS-IV improved cardiomyocyte edema by restoring the activity of Na/K-ATPase.CONCLUSIONAberrant activation of the HIF-1α/AQPs/Cx43 axis is a key mechanism in X-ray-induced cardiomyocyte edema and damage. AS-IV can ameliorate X-ray induced cardiac damage by regulating hydrometabolism.

100 Deals associated with PX-478

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Indication	Highest Phase	Country/Location	Organization	Date
Diffuse Large B-Cell Lymphoma	Preclinical	US	Feinberg School of Medicine	20 Nov 2009
Advanced Malignant Solid Neoplasm	Discovery	US	Cascadian Therapeutics LLC	01 Aug 2007
Lymphoma	Discovery	US	Cascadian Therapeutics LLC	01 Aug 2007

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