80 research outputs found
CK2 as a Logical Target in Cancer Therapy: Potential for Combining CK2 Inhibitors with Various Classes of Cancer Therapeutic Agents
No full textAbstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textAbstract
Recent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.</jats:p
Abstract IA10: Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers
No full textRecent findings by our group have been instrumental in the development of the novel selective inhibitors of RNA Polymerase I (Pol I) (Drygin et al., Cancer Research, 2011; Bywater et al. Cancer Cell, 2012). This work has led to the fundamental discovery that ribosomal gene transcription by Pol I is not simply a “housekeeping” process in cancer cells but is highly regulated to maintain their viability (Bywater et al. Nature Reviews Cancer, 2013). Strikingly, inhibition of Pol I transcription shows a profound selectivity for malignant over normal cells in preclinical studies.
As with the majority of targeted therapies, despite initial favorable responses to approaches that target ribosome synthesis and/or function in MYC-driven lymphoma models, resistant disease emerges. It is increasingly clear that maximizing the inhibition of key signaling networks as a whole improves anti-tumor response. The well-established reliance of MYC-driven malignancies on elevated rates of ribosome biogenesis, mTORC1/eIF4E-driven protein synthesis, and cell growth makes them vulnerable to therapeutic strategies that target the ribosome. Thus we hypothesized that the simultaneous targeting of the ribosome at multiple points would antagonize the development of acquired resistance and consequently prolong survival in MYC-driven cancer models. We will present data to demonstrate that targeting both ribosome synthesis and function through the combination of novel inhibitors of RNA polymerase I transcription, and PI3K/AKT/mTOR signaling inhibitors or PIM Kinase inhibitors provides a significant increase in survival compared to treatment with single agents (Devlin et al., Cancer Discovery 2016; Rebello et al., Clinical Cancer Res. 2016). We will also discuss the molecular mechanism by which multipoint targeting of the ribosome synergizes to increase survival. Finally we will discuss our collaboration with Pimera, Inc. to develop highly selective second generation RNA Pol I inhibitors. The lead compound PMR-116 is showing exceptional activity in transgenic models of malignancy, including MLL-ENL AML and Vk*MYC driven multiple myeloma. We anticipate this compound will enter the clinic in 2017.
Citation Format: Ross D. Hannan, Nadine Hein, Katherine M. Hannan, Gretchen Poortinga, Elaine Sanij, Jirawas Sornkom, Kylee MacLachlan, Andrew Cuddihy, Carleen Cullinane, Luc Furic, Denis Drygin, Mustapha Haddach, Simon Harrison, Grant McArthur, Richard B. Pearson. Drugging the ribosome at the level of synthesis and translation to treat solid and hematologic cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA10.
©2017 American Association for Cancer Research
Sequence-dependent cytotoxicity of second-generation oligonucleotides
No full textIn this study, we have examined the potential of second-generation antisense chimeric 20-O-(2-methoxy)ethyl/DNA phosphorothioate oligonu-cleotides (ONs) to affect cell growth through non-antisense mechanisms. Evaluation of a series of ONs demonstrated that only a small number were cytotoxicatconcentrationsclose to thoserequiredfor antisense activity. Toxicity of the ONs appeared to be sequence dependent and could be affected by base and backbone modifications. Caspase-3 activa-tion occurs with some ONs and it is most likely secondary to necrosis rather than apoptosis, since cells treated with toxic ONs did not show chromatin condensation, but did exhibit high-extracellular lact-ate dehydrogenase activity. Caspase-3 activation does not correlate with and appears not to be required for the inhibition of cell proliferation. Toxicity was only observed when ONs were delivered intracellu-larly. The mechanism by which one of the most cytotoxic ON produces cytotoxicity was investigated in more detail. Treatment with the cytotoxic ON caused disruption of lysosomes and Pepstatin A, a specific inhibitor of aspartic proteases, reduced the cytotoxicity of the ON. Reduction of lysosomal aspartic protease cathepsin D by prior treatment with cathepsin D-specific antisense ON did not at-tenuate the cytotoxicity, suggesting that other aspar-tic proteases play a crucial role in the cellular proliferation inhibition by ONs
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