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Donald L. Durden - One of the best experts on this subject based on the ideXlab platform.
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An integrin-targeted, pan-isoform, Phosphoinositide-3 kinase Inhibitor, SF1126, has activity against multiple myeloma in vivo
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Pradip De, Joseph R. Garlich, Breanne Terakedis, P. Leif Bergsagel, Zhi Hua Li, Daruka Mahadevan, Suzanne Trudel, Milan T. Makale, Donald L. DurdenAbstract: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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An integrin-targeted, pan-isoform, Phosphoinositide-3 kinase Inhibitor, SF1126, has activity against multiple myeloma in vivo.
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Nandini Dey, Joseph R. Garlich, Breanne Terakedis, P. Leif Bergsagel, Daruka Mahadevan, Suzanne Trudel, Milan T. Makale, Donald L. DurdenAbstract: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.
Joseph R. Garlich - One of the best experts on this subject based on the ideXlab platform.
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An integrin-targeted, pan-isoform, Phosphoinositide-3 kinase Inhibitor, SF1126, has activity against multiple myeloma in vivo
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Pradip De, Joseph R. Garlich, Breanne Terakedis, P. Leif Bergsagel, Zhi Hua Li, Daruka Mahadevan, Suzanne Trudel, Milan T. Makale, Donald L. DurdenAbstract: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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An integrin-targeted, pan-isoform, Phosphoinositide-3 kinase Inhibitor, SF1126, has activity against multiple myeloma in vivo.
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Nandini Dey, Joseph R. Garlich, Breanne Terakedis, P. Leif Bergsagel, Daruka Mahadevan, Suzanne Trudel, Milan T. Makale, Donald L. DurdenAbstract: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.
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A vascular targeted pan Phosphoinositide 3-Kinase Inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity
Cancer Research, 2008Co-Authors: Joseph R. Garlich, Nandini Dey, Xiaodong Peng, Antoinette Miller, R. Murali, Gordon B. Mills, Vikas KundraAbstract:PTEN and the pan Phosphoinositide 3-Kinase (PI3K) Inhibitor 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one (LY294002) exert significant control over tumor-induced angiogenesis and tumor growth in vivo. The LY294002 compound is not a viable drug candidate due to poor pharmacologic variables of insolubility and short half-life. Herein, we describe the development and antitumor activity of a novel RGDS-conjugated LY294002 prodrug, termed SF1126, which is designed to exhibit increased solubility and bind to specific integrins within the tumor compartment, resulting in enhanced delivery of the active compound to the tumor vasculature and tumor. SF1126 is water soluble, has favorable pharmacokinetics, and is well tolerated in murine systems. The capacity of SF1126 to inhibit U87MG and PC3 tumor growth was enhanced by the RGDS integrin (alpha v beta 3/alpha 5 beta 1) binding component, exhibiting increased activity compared with a false RADS-targeted prodrug, SF1326. Antitumor activity of SF1126 was associated with the pharmacokinetic accumulation of SF1126 in tumor tissue and the pharmacodynamic knockdown of phosphorylated AKT in vivo. Furthermore, SF1126 seems to exhibit both antitumor and antiangiogenic activity. The results support SF1126 as a viable pan PI3K Inhibitor for phase I clinical trials in cancer and provide support for a new paradigm, the application of pan PI3K Inhibitory prodrugs for the treatment of cancer.
Lewis C Cantley - One of the best experts on this subject based on the ideXlab platform.
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stand up to cancer phase ib study of pan Phosphoinositide 3 kinase Inhibitor buparlisib with letrozole in estrogen receptor positive human epidermal growth factor receptor 2 negative metastatic breast cancer
Journal of Clinical Oncology, 2014Co-Authors: Ingrid A Mayer, Vandana G. Abramson, Steven J Isakoff, Andres Forero, Justin M Balko, Maria G Kuba, Melinda E Sanders, Annick D Van Den Abbeele, Yisheng Li, Lewis C CantleyAbstract:Purpose Buparlisib, an oral reversible Inhibitor of all class I Phosphoinositide-3-Kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients and Methods Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [18F]fluorodeoxyglucose–positron emission tomography/computed tomography ([18F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for Phosphoinositide-3-Kinase pathway mutation analysis. Results Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's...
Pradip De - One of the best experts on this subject based on the ideXlab platform.
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An integrin-targeted, pan-isoform, Phosphoinositide-3 kinase Inhibitor, SF1126, has activity against multiple myeloma in vivo
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Pradip De, Joseph R. Garlich, Breanne Terakedis, P. Leif Bergsagel, Zhi Hua Li, Daruka Mahadevan, Suzanne Trudel, Milan T. Makale, Donald L. DurdenAbstract: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.
Patrick Hwang - One of the best experts on this subject based on the ideXlab platform.
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The reno-protective effect of a Phosphoinositide 3-Kinase Inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats
Experimental & Molecular Medicine, 2012Co-Authors: Young-woo Jang, Patrick HwangAbstract:Diabetic nephropathy (DN) is a progressive kidney disease that is caused by injury to kidney glomeruli. Podocytes are glomerular epithelial cells and play critical roles in the glomerular filtration barrier. Recent studies have shown the importance of regulating the podocyte actin cytoskeleton in early DN. The Phosphoinositide 3-Kinase (PI3K) Inhibitor, wortmannin, simultaneously regulates Rac1 and Cdc42, which destabilize the podocyte actin cytoskeleton during early DN. In this study, in order to evaluate the reno-protective effects of wortmannin in early DN by regulating Rac1 and Cdc42, streptozotocin (STZ)-induced proteinuric renal disease (SPRD) rats were treated with wortmannin. The albuminuria value of the SPRD group was 3.55 ± 0.56 mg/day, whereas wortmannin group was 1.77 ± 0.48 mg/day. Also, the albumin to creatinine ratio (ACR) value of the SPRD group was 53.08 ± 10.82 mg/g, whereas wortmannin group was 20.27 ± 6.41 mg/g. Changes in the expression level of nephrin, podocin and Rac1/Cdc42, which is related to actin cytoskeleton in podocytes, by wortmannin administration were confirmed by Western blotting. The expression levels of nephrin (79.66 ± 0.02), podocin (87.81 ± 0.03) and Rac1/Cdc42 (86.12 ± 0.02) in the wortmannin group were higher than the expression levels of nephrin (55.32 ± 0.03), podocin (53.40 ± 0.06) and Rac1/Cdc42 (54.05 ± 0.04) in the SPRD group. In addition, expression and localization of nephrin, podocin and desmin were confirmed by immunofluorescence. In summary, we found for the first time that wortmannin has a reno-protective effect on SPRD rats during the early DN. The beneficial effects of wortmannin in SPRD rats indicate that this compound could be used to delay the progression of the disease during the early DN stage.