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Updated: May 14, 2026
Repression of Multiple Myeloma Cell Growth In Vivo by Single-wall Carbon Nanotube (SWCNT)-delivered MALAT1 Antisense Oligos
Published on: December 13, 2018
An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma
Pradip De1, Nandini Dey, Breanne Terakedis
1Department of Hematology/Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA.
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.
Insights
SF1126, a pan-PI3K inhibitor, shows potent antitumor activity against multiple myeloma (MM) in preclinical studies. Combining SF1126 with bortezomib enhances its antimyeloma effects, supporting clinical trials.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- The phosphoinositide-3 kinase (PI3K)/AKT pathway is crucial for multiple myeloma (MM) cell survival and chemoresistance.
- Targeting this pathway presents a therapeutic strategy for MM treatment.
Purpose of the Study:
- To evaluate SF1126, a pan-PI3K inhibitor, for its preclinical efficacy in multiple myeloma (MM).
- To assess the potential of combining SF1126 with other agents for enhanced antitumor activity in MM.
Main Methods:
- In vitro cytotoxicity assays of SF1126 against 16 human MM cell lines.
- In vivo tumor growth suppression studies using human myeloma xenografts in mice.
- Pharmacodynamic assessment of SF1126 in MM patient-derived cells.
Main Results:
- SF1126 demonstrated cytotoxicity across all tested MM cell lines.
- Combination with bortezomib augmented SF1126's potency.
- SF1126 inhibited key signaling pathways (p-AKT, p-ERK, HIF1α) and reduced tumor growth by 94% in vivo.
- Pharmacodynamic knockdown of p-AKT was observed in patient-derived MM cells.
Conclusions:
- SF1126 exhibits potent in vitro and in vivo antitumor activity against MM.
- SF1126 combined with bortezomib shows augmented antimyeloma effects.
- SF1126 inhibits AKT activation in MM cells, supporting its clinical development and combination strategies.
