Abstract: Various embodiments relate to compounds, having structures according to Structure A or Structure B, as specified herein. The compounds according to various embodiments may inhibit NT5C2 nucleotidase. The compounds according to various embodiments may synergistically decrease cell viability of NT5C2 R367Q mutant lymphoblasts when used in combination with 6-mercaptopurine (6-MP) to treat a cancer. The cancer may be, but is not limited to, acute lymphoblastic leukemia. Various embodiments relate to a compositions that may include one or more compounds according to any embodiment described herein or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable carrier. Various embodiments relate to methods of treating cancer. The method may comprise administering a therapeutically effective amount of one or more compounds according to any embodiment described herein or a pharmaceutically acceptable salt or derivative thereof.

Abstract: The present invention relates to microRNAs (miRNAs) which are associated with cancer, particularly including hematologic malignancies, and particularly T-cell acute lymphoblastic leukemia (T-ALL), and to the assessment and modulation thereof in the treatment and management of cancer. The present invention is directed to methods and compositions for diagnosing and treating cancer, particularly T-ALL, by modulating miRNAs, and the use of miRNAs and antagonists thereof, particularly antagomirs, for predicting and assessing response to treatment, in assays for isolating and selecting antagonists, and as compositions for the treatment and management of cancer. Methods and compositions are provided for treatment or alleviation of cancer, particularly T-ALL, with antagonists/antagomirs of miRNAs, particularly one or more of miR-19b, miR-20a, miR26, miR92, miR148 and miR223.

Abstract: Whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing identified new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DN-MT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, new and recurrent, genetic defects are described including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.

Abstract: Whole exome sequencing of 12 tumor-normal DNA pairs, RNAseq analysis and targeted deep sequencing identified new genetic alterations in PTCL transformation. These analyses identified highly recurrent epigenetic factor mutations in TET2, DN-MT3A and IDH2 as well as a new highly prevalent RHOA p.Gly17Val (NM_001664) mutation present in 22/35 (67%) of angioimmunoblastic T-cell lymphomas (AITL) and in 8/44 (18%) not otherwise specified PTCL (PTCL NOS) samples. Mechanistically, the RHOA Gly17Val protein interferes with RHOA signaling in biochemical and cellular assays, an effect potentially mediated by the sequestration of activated Guanine Exchange Factor (GEF) proteins. In addition, new and recurrent, genetic defects are described including mutations in FYN, ATM, B2M and CD58 implicating SRC signaling, impaired DNA damage response and escape from immune surveillance mechanisms in the pathogenesis of PTCL.

Abstract: The invention is based on the discovery of certain new somatic single nucleotide substitution mutations of NT5C2 gene variants found in some Acute Lymphoblastic Leukemia (ALL) relapse subjects. Techniques include obtaining a biological sample taken from a subject having ALL, and detecting the presence or absence in the biological sample of a biomarker selected from the group consisting of an NT5C2 gene mutation, an mRNA transcribed from the NT5C2 gene mutation, or a protein encoded by the NT5C2 gene mutation. The method also includes determining that the subject has increased resistance to treatment with 6-mercaptopurine or 6-thioguanine, if the biomarker is detected. In some embodiments, the method still further includes treating the subject with a nucleoside analog other than 6-mercaptopurine or 6-thioguanine if the biomarker is detected.

Abstract: The present invention is based upon the identification of regions within the NOTCH-1 receptor that, when mutated, lead to increase receptor signaling. The mutations are associated with uncontrolled cellular growth and this growth may be arrested using agents that interfere with NOTCH-1 activity, such as inhibitors of gamma-secretase. Assays for the NOTCH-1 mutations may be used diagnostically or as part of a treatment regimen for cancer patients.

Abstract: The present invention relates to methods and compositions for preventing and/or treating various conditions in a patient, including for example, T-cell lymphoblastic leukemia and lymphoma as well as neurodegenerative diseases, such as for example, Alzheimer's disease. In one preferred embodiment of the invention, such methods include providing a patient with an effective amount of a combination of a NOTCH-1 inhibitor and glucocorticoid. The present invention further encompasses methods for increasing the efficacy of, and mitigating resistance to, glucocorticoids in the treatment of T-cell lymphoblastic leukemia and lymphoma, which generally include providing a patient with an effective amount of one or more NOTCH-1 inhibitors.

Abstract: The present invention relates to microRNAs (miRNAs) which are associated with cancer, particularly including hematologic malignancies, and particularly T-cell acute lymphoblastic leukemia (T-ALL), and to the assessment and modulation thereof in the treatment and management of cancer. The present invention is directed to methods and compositions for diagnosing and treating cancer, particularly T-ALL, by modulating miRNAs, and the use of miRNAs and antagonists thereof, particularly antagomirs, for predicting and assessing response to treatment, in assays for isolating and selecting antagists, and as compositions for the treatment and management of cancer. Methods and compositions are provided for treatment or alleviation of cancer, particularly T-ALL, with antagonists/antagomirs of miRNAs, particularly one or more of miR-19b, miR-20a, miR26, miR92, miR148 and miR223.

Abstract: The present invention relates to compositions and methods that may be used to diagnose and treat cancer, particularly T-cell leukemia. According to one preferred embodiment of the present invention, methods are provided for determining whether reducing or blocking NOTCH-1 activation will be effective to treat, prevent, or ameliorate the effects of a cancer in a patient, including T-cell leukemia, myeloleukemia, neuroblastoma, breast cancer, and ovarian cancer. The methods generally include determining if the patient harbors one or more mutations in a PTEN coding region. In particular, the methods may be used to determine whether reducing or blocking NOTCH-1 activation, with one or more ?-secretase inhibitors, will be effective to treat, prevent, or ameliorate the effects of a cancer in a patient.

Abstract: The present invention relates to methods and compositions for preventing and/or treating various conditions in a patient, including for example, T-cell lymphoblastic leukemia and lymphoma as well as neurodegenerative diseases, such as for example, Alzheimer's disease. In one preferred embodiment of the invention, such methods include providing a patient with an effective amount of a combination of a NOTCH-1 inhibitor and glucocorticoid. The present invention further encompasses methods for increasing the efficacy of, and mitigating resistance to, glucocorticoids in the treatment of T-cell lymphoblastic leukemia and lymphoma, which generally include providing a patient with an effective amount of one or more NOTCH-1 inhibitors.

Abstract: The present invention is based upon the identification of regions within the NOTCH-1 receptor that, when mutated, lead to increase receptor signaling. The mutations are associated with uncontrolled cellular growth and this growth may be arrested using agents that interfere with NOTCH-1 activity, such as inhibitors of gamma-secretase. Assays for the NOTCH-1 mutations may be used diagnostically or as part of a treatment regimen for cancer patients.

Abstract: The present invention is based upon the identification of regions within the NOTCH-1 receptor that, when mutated, lead to increased receptor signaling. The mutations are associated with uncontrolled cellular growth and this growth may be arrested using agents that interfere with NOTCH-1 activity, such as inhibitors of gamma-secretase. Assays for the NOTCH-1 mutations may be used diagnostically or as part of a treatment regimen for cancer patients.