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Ref Type Journal Article
PMID (23355037)
Authors De P, Dey N, Terakedis B, Bergsagel PL, Li ZH, Mahadevan D, Garlich JR, Trudel S, Makale MT, Durden DL
Title An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo.
Journal Cancer chemotherapy and pharmacology
Vol 71
Issue 4
Date 2013 Apr
Abstract Text 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.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.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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
SF1126 SF1126 4 3
Drug Name Trade Name Synonyms Drug Classes Drug Description
SF1126 BRD4 Inhibitor 7 PI3K Inhibitor (Pan) 38 SF1126 is a prodrug of LY294002, a pan PI3K inhibitor with additional activity against BRD4, which potentially results in reduced tumor immunosuppression and inhibits tumor growth (PMID: 23355037, PMID: 27496136, PMID: 31018997).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown hepatocellular carcinoma not applicable SF1126 + Sorafenib Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of SF1126 and Nexavar (sorafenib) was synergistic or additive in inhibiting proliferation of hepatocellular carcinoma cell lines in culture, and demonstrated increased efficacy in hepatocellular carcinoma cell line xenograft models compared to SF1126 alone (PMID: 23355037). 23355037