New phosphatidylinositol 3-kinase inhibitors for cancer

Bowles, Daniel W.; Jimeno, Antonio

doi:10.1517/13543784.2011.562192

Cited by 54 publications

(35 citation statements)

References 104 publications

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“…Nausea, vomiting, and diarrhea are common side effects seen with other PI3K inhibitors and were also tolerable with antiemetics and antidiarrheals. Interestingly, PX-866 was not associated with the significant hyperglycemia or skin toxicity reported with many other compounds targeting PI3K (19,31). This is not entirely unique as GDC-0941 in a phase Ib combination with chemotherapy with or without bevacizumab showed no hyperglycemia and only a mild rash (32).…”

Section: Discussionmentioning

confidence: 85%

“…The PTEN (phosphatase and tensin homologue) tumor suppressor gene, which negatively regulates PI3K signaling, may be lost via deletion (25% of melanoma, breast, and prostate cancers), mutation, or epigenetic suppression (14)(15)(16)(17)(18). Finally, upstream growth factor receptors with increased activity in some cancers, such as EGF receptor (EGFR), activate downstream PI3K signaling (19).…”

Section: Introductionmentioning

confidence: 99%

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A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

Hong

Bowles

Falchook

et al. 2012

Clinical Cancer Research

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Purpose: The objectives of the study were to evaluate the maximum tolerated dose (MTD), safety, pharmacodynamics, pharmacokinetics, and antitumor activity of PX-866 in patients with incurable cancers.Experimental Design: This was a phase I, open-label, dose-escalation study. Drug was administered orally once per day either on an intermittent (arm 1; days 1-5 and 8-12 of a 28-day cycle) or continuous (arm 2; days 1-28 of a 28-day cycle) schedule. Additional patients were treated at the arm 2 MTD in a food effects substudy.Results: Eighty-four patients were treated in the arm 1 (n ¼ 51), arm 2 (n ¼ 20), and food effects (n ¼ 13) cohorts. The most frequent study drug-related adverse events were gastrointestinal disorders (69.0%), with diarrhea being the most common (48.8%). The MTD was 12 and 8 mg for arm 1 and 2, respectively. The dose-limiting toxicities (DLT) consisted of grade III diarrhea (n ¼ 3) and grade III elevated aspartate aminotransferase (AST; n ¼ 1). The pharmacokinetics profile was dose proportional, with no evidence of drug accumulation. PX-866-associated inhibition of platelet pAKTSER473 was observed at the arm 2 MTD. The best response per Response Evaluation Criteria in Solid Tumors (RECIST) was stable disease in 22% of evaluable patients in arm 1, 53% in arm 2, and 11% in the food effects cohort. Eight patients were on study for 4 or more months.Conclusions: This first-in-human study shows that PX-866, an irreversible small-molecule inhibitor of phosphatidylinositol 3-kinase (PI3K), was well tolerated and was associated with prolonged stable disease, particularly when using a continuous dosing schedule. Clin Cancer Res; 18(15); 4173-82. Ó2012 AACR.

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Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

Hong

Bowles

Falchook

et al. 2012

Clinical Cancer Research

Self Cite

154

103

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“…The PI3K signaling axis has a well-established role in treatment resistance to EGF inhibitors (20) and is likely to be involved in escape mechanisms to other therapies (10). Although PI3K is not frequently mutated in pancreatic cancer (15), it is downstream of KRAS that is frequently altered in PDA.…”

Section: Discussionmentioning

confidence: 99%

“…PI3K alone has generally resulted only in stable disease, not disease regression, with the exception of dual PI3K-mTOR inhibitors where isolated responses have been communicated (10). Thus, it is likely that PI3K inhibitors will need to be combined with other therapies, and rigosertib dual activity may be a significant benefit.…”

Section: Discussionmentioning

confidence: 99%

“…Since that discovery, an elaborate signaling cascade has been described in which PI3K plays an important role in cellular processes critical to both normal tissue growth and metabolism, as well as oncogenesis and tumor survival (9). There are multiple PI3K inhibitors undergoing clinical development with diverse selectivity both within PI3K subunits and with other targets such as mTOR or Akt (10), but rigosertib is the sole dual PI3K and Plk1 pathway inhibitor undergoing development.…”

Section: Introductionmentioning

confidence: 99%

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Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer

Wee

Messersmith

et al. 2012

Clinical Cancer Research

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Purpose: Rigosertib, a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase pathways (PI3K), and gemcitabine have synergistic antitumor activity when combined in preclinical studies. This phase I study aimed to determine the recommended phase II dose (RPTD) of the combination of rigosertib and gemcitabine in patients with cancer.Experimental Design: Patients with solid tumors who failed standard therapy or were candidates for gemcitabine-based therapy were eligible. Gemcitabine was administered on days 1, 8, and 15 on a 28-day cycle and rigosertib on days 1, 4, 8, 11, 15, and 18. Pharmacokinetic studies were conducted during an expansion cohort of patients with advanced pancreatic ductal adenocarcinoma (PDA).Results: Forty patients were treated, 19 in the dose-escalation phase and 21 in the expansion cohort. Dose levels evaluated were (gemcitabine/rigosertib mg/m 2

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Loss of p^Ser2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers

Müller

Ehlers

Burkhardt

et al. 2012

Intl Journal of Cancer

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Prevalence and clinical significance of mammalian target of rapamycin (mTOR) phosphorylation at the serine 2448 is disputed in prostate cancer. A tissue microarray containing 3,261 prostate cancers and 49 normal prostate samples with clinical followup data was analyzed for p Ser2448 -mTOR expression by immunohistochemistry. Moderate to strong p Ser2448 -mTOR staining was found in all (n 5 49) normal prostate tissues, but was lost in 24% or weak in 29% cancers. Moderate and strong staining was found in 36 and 11% of tumors. Loss of p Ser2448 -mTOR staining was significantly linked to advanced stage (p 5 0.0027), high-grade (p 5 0.0045), nodal positive cancers (p 5 0.0483), early tumor recurrence (p < 0.0001, independently from stage and grade, p 5 0.0016), lack of Ets-related gene (ERG) fusion (p < 0.0001), reduced androgen receptor expression (p < 0.0001 each) and increased cell proliferation (p 5 0.0092) in all cancers and in the subset of ERG-fusion-positive cancers. Loss of p Ser2448 -mTOR expression was linked to tumor metastasis (p 5 0.0275) in ERG-fusion-positive cancers only. Molecular subset analysis using pre-existing phosphatase and tensin homolog (PTEN) deletion data revealed that loss of p Ser2448 -mTOR expression is of prognostic relevance and defines a subpopulation of PTEN-deleted and ERG-fusion-positive cancers with a particular poor outcome. The results of our study strongly suggest that loss of p Ser2448 -mTOR expression is a marker for activated AKT/mTOR signaling. Tumors with concomitant PTEN deletion and activated mTOR signaling indicated by loss of p Ser2448 -mTOR expression characterize a small (4%) but clinically significant subset of prostate cancers that might optimally benefit from anti-mTOR therapies.

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New phosphatidylinositol 3-kinase inhibitors for cancer

Cited by 54 publications

References 104 publications

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer

Loss of p^Ser2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers

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New phosphatidylinositol 3-kinase inhibitors for cancer

Cited by 54 publications

References 104 publications

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

A Multicenter Phase I Trial of PX-866, an Oral Irreversible Phosphatidylinositol 3-Kinase Inhibitor, in Patients with Advanced Solid Tumors

Phase I Study of Rigosertib, an Inhibitor of the Phosphatidylinositol 3-Kinase and Polo-like Kinase 1 Pathways, Combined with Gemcitabine in Patients with Solid Tumors and Pancreatic Cancer

Loss of pSer2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers

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Loss of p^Ser2448‐mTOR expression is linked to adverse prognosis and tumor progression in ERG‐fusion‐positive cancers