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

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 multiple myeloma, and (2) to begin combining pan PI-3 kinase 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 with16 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 PI-3 kinase inhibitor has potent antitumor activity against multiple myeloma 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.

Systemic modeling myeloma-osteoclast interactions under normoxic/hypoxic condition using a novel computational approach

“…Our drug simulation indicated that combination of PI3K and integrin inhibitors potentially reduced the myeloma cell proliferation in normoxia and inhibited cell migration in hypoxia. These predicted results were consistent with the previously reported results 40 41 .…”

“…The combination of these two therapeutic agents has improved outcomes for MM patients 41 . SF1126 , an integrin-targeted PI3K inhibitor, has potent antitumor activity against multiple myeloma in vitro and in vivo 40 . Treatment with SF1126 on MM appeared to affect the tumor microenvironment by inhibiting angiogenesis 40 .…”

Differential Activation of Wnt-β-Catenin Pathway in Triple Negative Breast Cancer Increases MMP7 in a PTEN Dependent Manner

“…Cells were harvested at 72 hours. Beta-catenin, PTEN, pGSK3β, GSK-3β and MMP7 protein levels were determination of by Western blot [32]. …”

PI3K‐dependent multiple myeloma cell survival is mediated by the PIK3CA isoform

“…However, genetic lesions that directly affect genes for PI3K isoforms do not occur in MM (Müller et al , ; Ismail et al , ; Chapman et al , ; Leich et al , ), although oncogenic signalling via the PI3K/Akt axis is a prominent feature in MM cells (Hsu et al , ; Zöllinger et al , ; Baumann et al , ; Steinbrunn et al , ; Ramakrishnan et al , ; Munugalavadla et al , ). Inhibition of PI3K activity may therefore represent a promising therapeutic strategy to target the disease in a large subgroup of MM patients, and we and others have previously demonstrated that abrogation of PI3K‐dependent signalling impairs MM cell survival (Hsu et al , ; Pene et al , ; Zöllinger et al , ; Steinbrunn et al , , ; Stengel et al , ; De et al , ; Azab et al , ; Munugalavadla et al , ). With the development of novel isoform‐specific PI3K inhibitors, more selective targeting of the relevant isoforms has become possible, potentially permitting enhanced anti‐tumour activity and a reduction of off‐target effects.…”