ABSTRACT
Background: Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K inhibitor, and olaparib, a PARP inhibitor. Patients and methods: Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results: In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germline BRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions: BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-inhibitor combinations as compared with a PARP inhibitor alone.
Subject(s)
Aminopyridines/administration & dosage , BRCA1 Protein/genetics , BRCA2 Protein/genetics , Breast Neoplasms/drug therapy , Morpholines/administration & dosage , Ovarian Neoplasms/drug therapy , Phthalazines/administration & dosage , Piperazines/administration & dosage , Adult , Aged , Aminopyridines/pharmacokinetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Germ-Line Mutation , Humans , Middle Aged , Morpholines/pharmacokinetics , Neoplasm Grading , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Phosphoinositide-3 Kinase Inhibitors , Phthalazines/pharmacokinetics , Piperazines/pharmacokinetics , Poly(ADP-ribose) Polymerase Inhibitors/administration & dosage , Poly(ADP-ribose) Polymerases/geneticsABSTRACT
Phosphorylation on serines or threonines preceding proline (Ser/Thr-Pro) is a major signaling mechanism. The conformation of a subset of phosphorylated Ser/Thr-Pro motifs is regulated by the prolyl isomerase Pin1. Inhibition of Pin1 induces apoptosis and may also contribute to neuronal death in Alzheimer's disease. However, little is known about the role of Pin1 in cancer or in modulating transcription factor activity. Here we report that Pin1 is strikingly overexpressed in human breast cancers, and that its levels correlate with cyclin D1 levels in tumors. Overexpression of Pin1 increases cellular cyclin D1 protein and activates its promoter. Furthermore, Pin1 binds c-Jun that is phosphorylated on Ser63/73-Pro motifs by activated JNK or oncogenic Ras. Moreover, Pin1 cooperates with either activated Ras or JNK to increase transcriptional activity of c-Jun towards the cyclin D1 promoter. Thus, Pin1 is up-regulated in human tumors and cooperates with Ras signaling in increasing c-Jun transcriptional activity towards cyclin D1. Given the crucial roles of Ras signaling and cyclin D1 overexpression in oncogenesis, our results suggest that overexpression of Pin1 may promote tumor growth.
Subject(s)
Breast Neoplasms/metabolism , Breast/metabolism , Cyclin D1/genetics , Cyclin D1/metabolism , Gene Expression Regulation, Neoplastic/physiology , Peptidylprolyl Isomerase/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Signal Transduction/physiology , Transcription, Genetic , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Breast/cytology , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma in Situ/genetics , Carcinoma in Situ/metabolism , Carcinoma in Situ/pathology , Cells, Cultured , Female , Gene Expression Regulation/physiology , Humans , JNK Mitogen-Activated Protein Kinases , Middle Aged , Mitogen-Activated Protein Kinases/metabolism , NIMA-Interacting Peptidylprolyl Isomerase , Peptidylprolyl Isomerase/genetics , Phosphorylation , Promoter Regions, Genetic , Receptor, ErbB-2/analysis , Receptors, Estrogen/analysis , Tumor Cells, Cultured , ras Proteins/metabolismABSTRACT
The factor V Leiden mutation and a guanine-to-adenine mutation at nucleotide 20210 in the 3'-untranslated region of the prothrombin gene are the most prevalent genetic defects in patients with deep venous thrombosis. Heterozygosity for the factor V Leiden and the prothrombin gene mutations is found in approximately 20 and 6% of unselected patients with deep venous thrombosis, respectively, whereas the prevalences of the two mutations in the general Caucasian population are approximately 6 and 2%, respectively. We evaluated an 18-year-old man presenting with a spontaneous episode of superficial venous thrombosis for the presence of an inherited thrombotic disorder. After excluding deficiencies of antithrombin, protein C, and protein S, genomic DNA from the patient was tested for the presence of the factor V Leiden and prothrombin gene mutations. Consanguinity was not present in the family. Genotyping demonstrated that the patient was homozygous for the factor V Leiden and prothrombin gene mutations. The likelihood of identifying an individual in the general population who is homozygous for both mutations similar to our patient is estimated to be less than 1 in 10 million.
Subject(s)
3' Untranslated Regions/genetics , Factor V/genetics , Homozygote , Mutation/genetics , Prothrombin/genetics , Venous Thrombosis/genetics , Adolescent , Antithrombins/analysis , Blood Coagulation Factor Inhibitors/analysis , Blood Coagulation Tests , Female , Heterozygote , Homocysteine/blood , Humans , Male , Middle Aged , Nuclear Family , Prothrombin/analysis , Saphenous Vein/surgery , Venous Thrombosis/drug therapy , Venous Thrombosis/surgery , Warfarin/pharmacologyABSTRACT
The vav proto-oncogene is universally and specifically expressed in hematopoietic cells. vav contains a unique array of motifs allowing the protein to function as a signal transducer and possibly as a transcription factor. Under certain in vitro culture conditions murine embryonic stem cells develop into colonies containing multiple hematopoietic lineages. In embryonic stem cell lines, constitutively expressing high levels of antisense vav transcripts through a stably integrated transgene, differentiation into hematopoietic cells is disrupted. This observation presents the first evidence that vav has a critical role in the development of hematopoietic cells from totipotent cells.
Subject(s)
Cell Cycle Proteins , Hematopoiesis , Hematopoietic Stem Cells/cytology , Proto-Oncogene Proteins/genetics , Proto-Oncogenes , Animals , Base Sequence , Biomarkers , Cell Differentiation , DNA Primers/chemistry , Gene Expression , Mice , Molecular Sequence Data , Proto-Oncogene Proteins c-vav , RNA, Antisense , RNA, Messenger/geneticsABSTRACT
We have identified the mRNA for a human gene, denoted D4, which is expressed at very high levels in hematopoietic cell lines and in normal cells of lymphoid and myeloid origin. The 1.5-kb transcript is absent or detectable only at low levels in nonhematopoietic tissues. D4 encodes a 201-amino acid protein with homology to rhoGDI, an inhibitor of GDP dissociation for the ras-homologous protein rho. D4 might function also as a regulator of guanine nucleotide exchange for small GTP-binding proteins. A homologous transcript of similar size is also preferentially expressed in murine hematopoietic tissues. When totipotent murine embryonic stem cells develop in vitro into hematopoietic cells, the gene is activated with the onset of hematopoiesis. When hematopoietic cell lines are induced to differentiate, the expression of D4 is modulated. Thus, D4 appears to be a developmentally regulated gene. Its preferential expression in hematopoietic cells indicates that D4 likely plays some significant role in the growth and differentiation processes of hematopoietic cells. This significance is underscored by increasing evidence for the involvement of regulators of G proteins in clinical diseases.