Phase I study of the multikinase prodrug SF1126 in solid tumors and B-cell malignancies.

Mahadevan, Daruka; Chiorean, E. Gabriela; Harris, Wayne; Hoff, Daniel D. Von; Younger, Anne; Rensvold, D. M.; Cordova, Felina M.; Qi, Wenwen; Shelton, Candace; Becker, Martina; Garlich, Joseph R.; Ramanathan, R. K.

doi:10.1200/jco.2011.29.15_suppl.3015

Cited by 10 publications

(10 citation statements)

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“…94 SF1126 was well tolerated in 39 patients (toxicities were generally grade 1/2 with one DLT), and 19 of 33 (58%) patients experienced stable disease. 95 Prolonged stable disease >1 year was achieved in two patients, one of whom was a patient with RCC who had previously been treated with temsirolimus.…”

Section: Agents Being Investigated In Patients With Solid Tumorsmentioning

confidence: 96%

“…The PI3K/mTORC1/2 inhibitor SF1126, which has demonstrated antitumor activity in preclinical studies, is being tested in a Phase I trial in patients with advanced or metastatic solid tumors . SF1126 was well tolerated in 39 patients (toxicities were generally grade 1/2 with one DLT), and 19 of 33 (58%) patients experienced stable disease . Prolonged stable disease >1 year was achieved in two patients, one of whom was a patient with RCC who had previously been treated with temsirolimus.…”

Section: Novel Therapies Targeting Pi3k and Mtorc2: Progress In The Cmentioning

confidence: 96%

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Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Figlin

Kaufmann

Brechbiel

2013

Intl Journal of Cancer

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With the advent of molecularly targeted agents, treatment of metastatic renal cell carcinoma (mRCC) has improved significantly. Agents targeting the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin complex 1 (mTORC1) are more effective and less toxic than previous standards of care involving cytotoxic and cytokine therapies. Unfortunately, many patients relapse following treatment with VEGFR and mTORC1 inhibitors as a result of acquired resistance mechanisms, which are thought to lead to the reestablishment of tumor vasculature. Specifically, the loss of negative feedback loops caused by inhibition of mTORC1 leads to upregulation of downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and subsequent activation of hypoxia-inducible factor, an activator of angiogenesis. De novo resistance involving activated PI3K signaling has also been observed. These observations have led to the development of novel agents targeting PI3K, mTORC1/2 and PI3K/mTORC1/2, which have demonstrated antitumor activity in preclinical models of RCC. Several agents-BKM120, BEZ235 and GDC-0980-are being investigated in clinical trials in patients with metastatic/ advanced RCC, and similar agents are being tested in patients with solid tumors. The future success of mRCC treatment will likely involve a combination of agents targeting the multiple pathways involved in angiogenesis, including VEGFR, PI3K and mTORC1/2.Renal cell carcinoma (RCC) accounts for more than 2% of all human cancers, and its incidence is steadily rising by approximately 2% per year.

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Section: Agents Being Investigated In Patients With Solid Tumorsmentioning

confidence: 96%

Section: Novel Therapies Targeting Pi3k and Mtorc2: Progress In The Cmentioning

confidence: 96%

Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Figlin

Kaufmann

Brechbiel

2013

Intl Journal of Cancer

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“…Agents like BEZ235, GDC-0980, GSK458, SF1126, and XL765 have all shown evidence of tolerability and target inhibition although specific responses in breast tumors have yet to be seen (47)(48)(49)(50)(51). The side effects of the dual inhibitors overlap those seen with PI3K and mTOR-specific agents.…”

Section: Emergence Of Several Pi3k Pathway Inhibitorsmentioning

confidence: 86%

Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

Gordon

Banerji

2013

Clinical Cancer Research

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The triple-negative breast cancer (TNBC) subtype, defined clinically by the lack of estrogen, progesterone, and Her2 receptor expression, accounts for 10% to 15% of annual breast cancer diagnoses. Currently, limited therapeutic options have shown clinical benefit beyond cytotoxic chemotherapy. Defining this clinical cohort and identifying subtype-specific molecular targets remain critical for new therapeutic development. The current era of high-throughput molecular analysis has revealed new insights into these targets and confirmed the phosphoinositide 3-kinase (PI3K) as a key player in pathogenesis. The improved knowledge of the molecular basis of TNBC in parallel with efforts to develop new PI3K pathway-specific inhibitors may finally produce the therapeutic breakthrough that is desperately needed.

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“…SF1126 is a small molecule pro-drug, which can convert to LY294002 [ 100 ]. In a phase I study of 39 patients with B-cell malignancies and advanced solid tumors, one GIST patient resistant to temsirolimus was treated with SF1126, and his disease was stable for more than one year, which may indicate that SF1126 had an effect on mTORC1 [ 107 ]. In another phase I study, three GIST patients treated with GDC-980 showed greater than 25% reduction in FDG uptake as assessed by PET.…”

Section: Targeting the Pi3k/akt/mtor Pathway Via Gist Therapeuticsmentioning

confidence: 99%

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Duan

Haybaeck

Yang

2020

Cancers

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Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.

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Phase I study of the multikinase prodrug SF1126 in solid tumors and B-cell malignancies.

Cited by 10 publications

References 0 publications

Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Molecular Pathways: PI3K Pathway Targets in Triple-Negative Breast Cancers

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

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