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Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma

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Abstract

Purpose

SF1126 is a vascular-targeted pan-PI-3K inhibitor prodrug with antitumor and antiangiogenic activity and has completed phase I clinical trial in solid tumors and B-cell malignancies. In this study, we investigated the effect of SF1126 on hypoxic HIF-1α/HIF-2α stability as well as on antitumor and/or antiangiogenic activity in renal cell carcinoma (RCC) models in vitro and in vivo.

Methods

The effect of SF1126 on hypoxic HIF-1α/HIF-2α protein stability, antitumor and antiangiogenic activity was studied on VHL-null (786-0) and VHL-WT (Caki) RCC cells.

Results

Our data demonstrate that SF1126 treatment abrogates the stabilization of HIF-2α in 786-0 (VHL-mutated) RCC cell line under normoxic and hypoxic conditions. Similarly, hypoxic stabilization of HIF-1α and its activity were also suppressed following SF1126 treatment in Caki cell line (VHL-WT). Herein, we provide mechanistic evidence that HIF-2α can be degraded in cytoplasm under hypoxic conditions via the 26S proteasome and that MDM2 is the E3 ligase which induces the hypoxic degradation of HIF-2α in PI-3K-dependent manner in VHL-deficient RCC cells. Moreover, SF1126 administered to RCC-xenografted mice at 25 mg/kg/dose subcutaneously three times per week for 3 weeks results in marked inhibition of tumor growth (>90 % inhibition) (P < 0.05). Consistent with SF1126 treatment’s effects on HIF-1α/HIF-2α, microvessel density analysis of Caki and 786-0 tumor tissues demonstrated that SF1126 has potent antiangiogenic activity in vivo. Finally, SF1126 caused a profound inhibition of integrin-mediated migration and blocked the integrin-induced conversion of GDP-Rac1 to its GTP-bound active state.

Conclusions

These results validate the in vivo efficacy of SF1126 as a clinically viable antiangiogenic, pan-PI-3K inhibitor prodrug for phase II clinical trials in the treatment of RCC.

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Acknowledgments

We acknowledge all of the dedicated people at SignalRx and the Durden laboratory for the commitment to bringing the first pan-PI-3K inhibitor into patient care. Funding for this work were from grants CA94233 and Georgia Cancer Coalition to DLD. This work was supported by the Aflac Cancer Center, St Balderick’s Foundation, Alex Lemonade Stand Foundation and Cricket Corporation.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Pediatric Hematology-Oncology, Moores Cancer Center, UC San Diego Health System, La Jolla, CA, 92093-0819, USA

    Shweta Joshi, Alok R. Singh & Donald L. Durden

  2. Division of Pediatric Hematology-Oncology, UCSD Rady Children’s Hospital, La Jolla, CA, USA

    Donald L. Durden

  3. Signal Rx Pharmaceuticals, San Diego, CA, USA

    Donald L. Durden

Authors
  1. Shweta Joshi
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  2. Alok R. Singh
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  3. Donald L. Durden
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Corresponding author

Correspondence to Donald L. Durden.

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Joshi, S., Singh, A.R. & Durden, D.L. Pan-PI-3 kinase inhibitor SF1126 shows antitumor and antiangiogenic activity in renal cell carcinoma. Cancer Chemother Pharmacol 75, 595–608 (2015). https://doi.org/10.1007/s00280-014-2639-x

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  • DOI: https://doi.org/10.1007/s00280-014-2639-x

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