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An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

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Abstract

Purpose

Multiple reports point to an important role for the phosphoinositide-3 kinase (PI3K) and AKT signaling pathways in tumor survival and chemoresistance in multiple myeloma (MM). The goals of our study were: (1) to generate the preclinical results necessary to justify a Phase I clinical trial of SF1126 in hematopoietic malignancies including MM and (2) to begin combining pan-PI3K inhibitors with other agents to augment antitumor activity of this class of agent in preparation for combination therapy in Phase I/II trials.

Methods

We determined the in vitro activity of SF1126 with 16 human MM cell lines. In vivo tumor growth suppression was determined with human myeloma (MM.1R) xenografts in athymic mice. In addition, we provide evidence that SF1126 has pharmacodynamic activity in the treatment of patients with MM.

Results

SF1126 was cytotoxic to all tested MM lines, and potency was augmented by the addition of bortezomib. SF1126 affected MM.1R cell line signaling in vitro, inhibiting phospho-AKT, phospho-ERK, and the hypoxic stabilization of HIF1α. Tumor growth was 94 % inhibited, with a marked decrease in both cellular proliferation (PCNA immunostaining) and angiogenesis (tumor microvessel density via CD31 immunostaining). Our clinical results demonstrate pharmacodynamic knockdown of p-AKT in primary patient-derived MM tumor cells in vivo.

Conclusions

Our results establish three important points: (1) SF1126, a pan-PI3K inhibitor has potent antitumor activity against MM in vitro and in vivo, (2) SF1126 displays augmented antimyeloma activity when combined with proteasome inhibitor, bortezomib/Velcade®, and (3) SF1126 blocks the IGF-1-induced activation of AKT in primary MM tumor cells isolated from SF1126-treated patients The results support the ongoing early Phase I clinical trial in MM and suggest a future Phase I trial in combination with bortezomib in hematopoietic malignancies.

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Acknowledgments

We acknowledge the excellent technical assistance of Chenghu Prince. We acknowledge all of the dedicated people at Semafore Pharmaceuticals, SignalRx pharmaceuticals and the Durden laboratory for their commitment to bringing the first pan-isoform PI3K inhibitor into myeloma care. Funding for this work was by The Multiple Myeloma Research Committee to Donald L. Durden and grant CA94233 to D. L. Durden from the National Institutes of Health, the Georgia Cancer Coalition and the Aflac Cancer Center.

Conflict of interest

Dr. Durden discloses financial conflict of interest in Semafore and SignalRx Pharmaceuticals and in the SF1126 drug. The relationship between Dr. Durden and SignalRx has been internally reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.

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Authors and Affiliations

  1. Department of Pediatrics, Moores UCSD Cancer Center, UCSD School of Medicine, Rady Children’s Hospital, University of California, 3855 Health Sciences Drive #0819, San Diego, La Jolla, CA, 92093-0819, USA

    Donald L. Durden

  2. Department of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA

    Pradip De, Nandini Dey & Breanne Terakedis

  3. Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA

    P. Leif Bergsagel

  4. Department of Medical Oncology and Hematology, Princess Margaret Hospital, Toronto, ON, Canada

    Zhi Hua Li & Suzanne Trudel

  5. West Clinic, University of Tennessee Health Sciences, Memphis, TN, USA

    Daruka Mahadevan

  6. SignalRx Pharmaceuticals, San Diego, CA, USA

    Joseph R. Garlich

  7. Division of Neuro-oncology, UCSD Moores Cancer Center, La Jolla, CA, USA

    Milan T. Makale

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  1. Pradip De
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  2. Nandini Dey
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  10. Donald L. Durden
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Correspondence to Donald L. Durden.

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De, P., Dey, N., Terakedis, B. et al. An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. Cancer Chemother Pharmacol 71, 867–881 (2013). https://doi.org/10.1007/s00280-013-2078-0

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