A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination

Ramanathan, Ramesh K.; Abbruzzese, James L.; Dragovich, Tomislav; Kirkpatrick, Lynn; Guillen, Jose; Baker, Amanda F.; Pestano, Linda; Green, Sylvan; Hoff, Daniel D. Von

doi:10.1007/s00280-010-1343-8

Cited by 100 publications

(80 citation statements)

References 31 publications

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“…To the best of our knowledge, no combination studies with TrxR1 inhibitors and standard chemotherapy agents have been reported using PDAC cell lines. A randomised clinical study of PDAC patients with advanced disease treated with thioredoxin inhibitor monotherapy failed to demonstrate improved outcomes, however considerable methodological issues may have obscured potential benefits of inhibiting this antioxidant system (Ramanathan et al, 2011). Interestingly, TrxR1 may also regulate Nrf2 activation (Cebula et al, 2015).…”

Section: The Effects Of Suppressing Nrf2 Compared To Nrf2/are Effectomentioning

confidence: 99%

Keap1–Nrf2 signalling in pancreatic cancer

Hayes

Skouras

Haugk

et al. 2015

The International Journal of Biochemistry & Cell Biology

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a b s t r a c tTranscription factor NF-E2 p45-related factor 2 (Nrf2, also called Nfe2l2), a master regulator of redox homeostasis, and its dominant negative regulator, Kelch-like ECH-associated protein 1 (Keap1), together tightly control the expression of numerous detoxifying and antioxidant genes. Nrf2 and the 'antioxidant response element' (ARE)-driven genes it controls are frequently upregulated in pancreatic cancer and correlate with poor survival. Upregulation of Nrf2 is, at least in part, K-Ras oncogene-driven and contributes to pancreatic cancer proliferation and chemoresistance. In this review, we aim to provide an overview of Keap1-Nrf2 signalling as it relates to pancreatic cancer, discussing the effects of inhibiting Nrf2 or Nrf2/ARE effector proteins to increase chemosensitivity.

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Section: The Effects Of Suppressing Nrf2 Compared To Nrf2/are Effectomentioning

confidence: 99%

Keap1–Nrf2 signalling in pancreatic cancer

Hayes

Skouras

Haugk

et al. 2015

The International Journal of Biochemistry & Cell Biology

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“…Pharmacokinetic studies during a recent PX-12 phase I clinical trial revealed that PX-12 given at 400 mg/m 2 /d for 72 hours is safe to administer to patients (49). However, to determine whether PX-12 exhibits cytotoxicity to immune cells and cornea-specific…”

Section: Fungal Thioredoxin Mediates Resistance To Human Neutrophilsmentioning

confidence: 99%

Fungal antioxidant pathways promote survival against neutrophils during infection

Leal

Vareechon

Cowden³

et al. 2012

J. Clin. Invest.

126

156

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“…A patient with appendiceal adenocarcinoma had a minor response of 322 days (79). PX-12 was also investigated in a Phase II trial as a 3-h infusion at two dose levels in patients with previously treated advanced pancreatic cancer (78). Plasma Trx-1 levels were found elevated in only 3 of 28 (11%) patients screened for study.…”

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confidence: 99%

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

Kirkpatrick

Powis

2017

Antioxidants & Redox Signaling

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Significance: There are a number of redox-active anticancer agents currently in development based on the premise that altered redox homeostasis is necessary for cancer cell's survival. Recent Advances: This review focuses on the relatively few agents that target cellular redox homeostasis to have entered clinical trial as anticancer drugs. Critical Issues: The success rate of redox anticancer drugs has been disappointing compared to other classes of anticancer agents. This is due, in part, to our incomplete understanding of the functions of the redox targets in normal and cancer tissues, leading to off-target toxicities and low therapeutic indexes of the drugs. The field also lags behind in the use biomarkers and other means to select patients who are most likely to respond to redox-targeted therapy. Future Directions: If we wish to derive clinical benefit from agents that attack redox targets, then the future will require a more sophisticated understanding of the role of redox targets in cancer and the increased application of personalized medicine principles for their use. Antioxid. Redox Signal. 26, 262-273.

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A randomized phase II study of PX-12, an inhibitor of thioredoxin in patients with advanced cancer of the pancreas following progression after a gemcitabine-containing combination

Abstract: Due to the lack of significant antitumor activity and unexpectedly low baseline Trx-1 levels, the study was terminated early. PX-12 does not appear to be active in unselected patients with previously treated APC.

Cited by 100 publications

References 31 publications

Keap1–Nrf2 signalling in pancreatic cancer

Keap1–Nrf2 signalling in pancreatic cancer

Fungal antioxidant pathways promote survival against neutrophils during infection

Clinically Evaluated Cancer Drugs Inhibiting Redox Signaling

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