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

Pradip De, Nandini Dey, Breanne Terakedis, Peter Leif Bergsagel, Zhi Hua Li, Daruka Mahadevan, Joseph R. Garlich, Suzanne Trudel, Milan T. Makale, Donald L. Durden

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)867-881
Number of pages15
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number4
DOIs
StatePublished - Apr 2013

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1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Multiple Myeloma
Integrins
Protein Isoforms
Phosphotransferases
Tumors
Cells
Pharmacodynamics
Neoplasms
Clinical Trials, Phase I
Hematologic Neoplasms
SF 1126
Cell Line
Proteasome Inhibitors
Proliferating Cell Nuclear Antigen
Growth
Microvessels
Insulin-Like Growth Factor I
Heterografts

Keywords

  • IGF-1
  • IL-6
  • Multiple myeloma
  • Pan-PI-3 kinase inhibitor
  • SF1126

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. / De, Pradip; Dey, Nandini; Terakedis, Breanne; Bergsagel, Peter Leif; Li, Zhi Hua; Mahadevan, Daruka; Garlich, Joseph R.; Trudel, Suzanne; Makale, Milan T.; Durden, Donald L.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 4, 04.2013, p. 867-881.

Research output: Contribution to journalArticle

De, Pradip ; Dey, Nandini ; Terakedis, Breanne ; Bergsagel, Peter Leif ; Li, Zhi Hua ; Mahadevan, Daruka ; Garlich, Joseph R. ; Trudel, Suzanne ; Makale, Milan T. ; Durden, Donald L. / An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo. In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 4. pp. 867-881.
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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{\circledR}, 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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T1 - An integrin-targeted, pan-isoform, phosphoinositide-3 kinase inhibitor, SF1126, has activity against multiple myeloma in vivo

AU - De, Pradip

AU - Dey, Nandini

AU - Terakedis, Breanne

AU - Bergsagel, Peter Leif

AU - Li, Zhi Hua

AU - Mahadevan, Daruka

AU - Garlich, Joseph R.

AU - Trudel, Suzanne

AU - Makale, Milan T.

AU - Durden, Donald L.

PY - 2013/4

Y1 - 2013/4

N2 - 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.

AB - 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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