Oncotarget

Research Papers:

Phosphatase inhibitor, sodium stibogluconate, in combination with interferon (IFN) alpha 2b: phase I trials to identify pharmacodynamic and clinical effects

Taolin Yi _, Paul Elson, Masato Mitsuhashi, Barbara Jacobs, Emese Hollovary, G. Thomas Budd, Timothy Spiro, Pierre Triozzi and Ernest Borden

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2011; 2:1155-1164. https://doi.org/10.18632/oncotarget.563

Metrics: PDF 1214 views  |   HTML 1511 views  |   ?  


Abstract

Taolin Yi1,2, Paul Elson1, Masato Mitsuhashi3, Barbara Jacobs1, Emese Hollovary1, G. Thomas Budd1, Timothy Spiro1, Pierre Triozzi1 and Ernest C. Borden1

1 Taussig Cancer Institute, The Cleveland Clinic, Cleveland, OH, USA

2 Department of Immunology of Lerner Research Institute, The Cleveland Clinic, Cleveland, OH, USA

3 Hitachi Chemical Research Center, Inc., Irvine, CA, USA

Received: December 19, 2011; Accepted: December 21, 2011; Published: December 22, 2011;

Keywords: Cancer, phase-I-trial, phosphatase-inhibitor, IFN-alpha2β, SSG

Correspondence:

Taolin Yi, email:

Abstract

Since sodium stibogluconate (SSG) inhibited phosphatases including SHP-1 and augmented anti-tumor actions of IFN-α2b in vitro and in mice, two Phase I trials of SSG/IFN-α2b combination were undertaken to evaluate safety and target inhibition. Escalating doses of SSG (200-1200 mg/m2) and fixed doses of IFN-α2b (3x106 units/m2) with or without chemotherapy (dacarbazine, vinblastine, cisplatin) were evaluated for side effects and impact on SHP-1 phospho-substrates and IFNα-stimulated-genes (ISGs) in peripheral blood in 40 patients with metastatic melanoma, soft tissue sarcomas, gastrointestinal stromal tumors, and breast or colorectal carcinomas who did not have other established treatment options. Common adverse events were bone marrow suppression, fatigue, gastrointestinal upset, and asymptomatic lipase elevation (n=13); the latter was dose related and mostly after 10d of SSG/IFN-α2b in combination. Levels of SHP-1 substrates (pSTAT1, pSTAT3, pLck and pSlp76) were increased (up to 3x) in peripheral blood cells following SSG with no potentiation by combination with IFN-α2b. Representative ISGs in peripheral blood were induced after IFN-α2b at 4 and 24 hrs with selective modulations by combination. The median time on trials was 2.3 months (10-281d) with no objective regression of disease. Alive at 1y were 17/40 (43%) patients and after 2y were 8/40 (20%) following treatment initiation. These data demonstrate that SSG impacted signal molecules consistent with PTP inhibition and was tolerated in combination with IFN-α2b. Phase II investigations of SSG could safely utilize doses of up to 1200 mg/m2 of SSG for up to 10d alone or in combination with IFN-α2b with or without chemotherapy.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 563