This research study will test OT-82, which is an investigational ("research" or "experimental" ) drug. The study has two stages (Stage 1 and Stage 2). The purpose of Stage 1 is to determine the safety and tolerability and the maximum tolerated dose (MTD) or the maximum tested dose of OT-82 administered orally to participants. The purpose of Stage 2 is to determine the preliminary efficacy of OT-82 in relapsed or refractory lymphoma at the MTD or the maximum tested dose. Both parts of the study will also evaluate the pharmacokinetics (absorption, distribution, metabolism, elimination) of OT-82.
OT-82 treatment slowed the growth, reduced the size, or in some cases cured certain cancers in animal studies. It is hoped that participants with relapsed or refractory lymphoma treated with OT - 82 in this study will experience slowing tumor growth and/or reduction of tumor size.

开始日期2019-07-29

申办/合作机构

Oncotartis, Inc.

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2020-07-01·Leukemia1区 · 医学

OT-82, a novel anticancer drug candidate that targets the strong dependence of hematological malignancies on NAD biosynthesis

1区 · 医学

Article

作者: Vujcic, Slavoljub ; Lock, Richard B ; Chernova, Olga B ; Joshi, Sangeeta ; Somers, Klaartje ; Polinsky, Alex ; Kononov, Eugene ; Veith, Jean ; Tian, Yuan ; Andrianova, Ekaterina L ; Toshkov, Ilia ; Chernov, Mikhail V ; Korotchkina, Lioubov ; Norris, Murray D ; Haber, Michelle ; Gudkov, Andrei V ; Komarov, Pavel G ; Henderson, Michelle J ; Antoch, Marina P ; Krasnov, Peter ; Middlemiss, Shiloh ; Kazyulkin, Denis ; Gupta, Mahima

AbstractEffective treatment of some types of cancer can be achieved by modulating cell lineage-specific rather than tumor-specific targets. We conducted a systematic search for novel agents selectively toxic to cells of hematopoietic origin. Chemical library screenings followed by hit-to-lead optimization identified OT-82, a small molecule with strong efficacy against hematopoietic malignancies including acute myeloblastic and lymphoblastic adult and pediatric leukemias, erythroleukemia, multiple myeloma, and Burkitt’s lymphoma in vitro and in mouse xenograft models. OT-82 was also more toxic towards patients-derived leukemic cells versus healthy bone marrow-derived hematopoietic precursors. OT-82 was shown to induce cell death by inhibiting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the salvage pathway of NAD synthesis. In mice, optimization of OT-82 dosing and dietary niacin further expanded the compound’s therapeutic index. In toxicological studies conducted in mice and nonhuman primates, OT-82 showed no cardiac, neurological or retinal toxicities observed with other NAMPT inhibitors and had no effect on mouse aging or longevity. Hematopoietic and lymphoid organs were identified as the primary targets for dose limiting toxicity of OT-82 in both species. These results reveal strong dependence of neoplastic cells of hematopoietic origin on NAMPT and introduce OT-82 as a promising candidate for the treatment of hematological malignancies.

2020-06-01·Leukemia1区 · 医学

Effective targeting of NAMPT in patient-derived xenograft models of high-risk pediatric acute lymphoblastic leukemia

1区 · 医学

Article

作者: Henderson, Michelle J ; Norris, Murray D ; Kees, Ursula R ; El-Ayoubi, Ali ; Somers, Klaartje ; Gupta, Mahima ; Lock, Richard B ; Middlemiss, Shiloh ; Gudkov, Andrei V ; Haber, Michelle ; Evans, Kathryn ; Kosciolek, Angelika ; Jones, Luke ; Erickson, Stephen W ; Teicher, Beverly ; Bongers, Angelika ; Smith, Malcolm A ; Mayoh, Chelsea ; Pritchard, Tara ; Chernova, Olga ; Cheung, Leanna ; Korotchkina, Lioubov ; Forgham, Helen ; Karsa, Mawar

The prognosis for children diagnosed with high-risk acute lymphoblastic leukemia (ALL) remains suboptimal, and more potent and less toxic treatments are urgently needed. We investigated the efficacy of a novel nicotinamide phosphoribosyltransferase inhibitor, OT-82, against a panel of patient-derived xenografts (PDXs) established from high-risk and poor outcome pediatric ALL cases. OT-82 was well-tolerated and demonstrated impressive single agent in vivo efficacy, achieving significant leukemia growth delay in 95% (20/21) and disease regression in 86% (18/21) of PDXs. In addition, OT-82 enhanced the efficacy of the established drugs cytarabine and dasatinib and, as a single agent, showed similar efficacy as an induction-type regimen combining three drugs used to treat pediatric ALL. OT-82 exerted its antileukemic action by depleting NAD⁺ and ATP, inhibiting the NAD⁺-requiring DNA damage repair enzyme PARP-1, increasing mitochondrial ROS levels and inducing DNA damage, culminating in apoptosis induction. OT-82 sensitivity was associated with the occurrence of mutations in major DNA damage response genes, while OT-82 resistance was characterized by high expression levels of CD38. In conclusion, our study provides evidence that OT-82, as a single agent, and in combination with established drugs, is a promising new therapeutic strategy for a broad spectrum of high-risk pediatric ALL for which improved therapies are urgently needed.

2019-05-01·Oncogene1区 · 医学

A novel small molecule that kills a subset of MLL-rearranged leukemia cells by inducing mitochondrial dysfunction

1区 · 医学

Article

作者: Angeli, Andrea ; Karsa, Mawar ; Raoufi-Rad, Newsha ; Osterman, Andrei L ; Gao, Jixuan ; Lim, James ; Imamura, Toshihiko ; Chudakova, Daria A ; Middlemiss, Shiloh M C ; Kwek, Alan ; Kavallaris, Maria ; Kees, Ursula R ; McCarroll, Joshua ; Norris, Murray D ; Kusnadi, Eric P ; Clifton, Molly ; Liu, Bing ; Jung, MoonSun ; Supuran, Claudiu T ; Bongers, Angelika ; Scott, David A ; Flemming, Claudia ; Henderson, Michelle J ; Somers, Klaartje ; Pandher, Ruby ; Davis, Thomas P ; Turner, Nigel ; Hannan, Ross D ; Wen, Victoria W ; Failes, Tim W ; Haber, Michelle ; Hannan, Kate M ; Forgham, Helen ; Gudkov, Andrei V ; Mayoh, Chelsea ; Pearson, Richard B ; Osborne, Brenna

Survival rates for pediatric patients suffering from mixed lineage leukemia (MLL)-rearranged leukemia remain below 50% and more targeted, less toxic therapies are urgently needed. A screening method optimized to discover cytotoxic compounds selective for MLL-rearranged leukemia identified CCI-006 as a novel inhibitor of MLL-rearranged and CALM-AF10 translocated leukemias that share common leukemogenic pathways. CCI-006 inhibited mitochondrial respiration and induced mitochondrial membrane depolarization and apoptosis in a subset (7/11, 64%) of MLL-rearranged leukemia cell lines within a few hours of treatment. The unresponsive MLL-rearranged leukemia cells did not undergo mitochondrial membrane depolarization or apoptosis despite a similar attenuation of mitochondrial respiration by the compound. In comparison to the sensitive cells, the unresponsive MLL-rearranged leukemia cells were characterized by a more glycolytic metabolic phenotype, exemplified by a more pronounced sensitivity to glycolysis inhibitors and elevated HIF1α expression. Silencing of HIF1α expression sensitized an intrinsically unresponsive MLL-rearranged leukemia cell to CCI-006, indicating that this pathway plays a role in determining sensitivity to the compound. In addition, unresponsive MLL-rearranged leukemia cells expressed increased levels of MEIS1, an important leukemogenic MLL target gene that plays a role in regulating metabolic phenotype through HIF1α. MEIS1 expression was also variable in a pediatric MLL-rearranged ALL patient dataset, highlighting the existence of a previously undescribed metabolic variability in MLL-rearranged leukemia that may contribute to the heterogeneity of the disease. This study thus identified a novel small molecule that rapidly kills MLL-rearranged leukemia cells by targeting a metabolic vulnerability in a subset of low HIF1α/low MEIS1-expressing MLL-rearranged leukemia cells.

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