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Novel pharmacologic approach to enhance the epigenetic and immune priming effect of decitabine in patients with advanced non-small cell lung cancer

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DNA methyl transferase 1 (DNMT-1) is a key epigenetic enzyme in cancer cells which inactivates proliferation terminating genes and downregulates the expression of cancer related proteins and neoantigens by hypermethylation... Clinical use of decitabine to target DNMT-1 is restricted by its short in vivo half-life (about 10 minutes) due to rapid inactivation by the enzyme cytidine deaminase (CDA) present in tissues... Tetrahydrouridne(THU), an oral inhibitor of CDA can overcome the pharmacokinetic (PK) limitation... Novel pharmacologic combination of THU with micro-doses of DAC can significantly increase half-life of DAC allowing sufficient interaction between DNMT-1 and decitabine to overcome epigenetic repression by DNMT-1... Increased lymphocytic infiltrate in the tumor post the immune priming by decitabine can augment response to immune checkpoint inhibitor MPDL3280A, an anti PD-L1 antibody... The first stage will be an assessment of the immunologic effect of the combination... The second stage, which will occur only if THU-DAC is shown to have a significant priming effect, will assess the ability of the immunologic response to translate to clinical efficacy... Based on our previous studies we anticipate in advanced stage NSCLC approximately 25% patients will have high TILs and hypothesize that THU-DAC will increase that proportion to >50%... With 24 patients there will be at least 90% power to detect such a difference... Assuming the combination does indeed prime the immune system, stage 2 will be implemented and a two-stage accrual design will be used to assess clinical efficacy, with the 24 patients already accrued.

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Mentions: This is a proof-of-concept Phase II single arm open label prospective clinical trial in patients with advanced non-small cell lung cancer (NSCLC) with at least one prior chemotherapy (Figure 1).


Novel pharmacologic approach to enhance the epigenetic and immune priming effect of decitabine in patients with advanced non-small cell lung cancer
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4645121&req=5

Mentions: This is a proof-of-concept Phase II single arm open label prospective clinical trial in patients with advanced non-small cell lung cancer (NSCLC) with at least one prior chemotherapy (Figure 1).

View Article: PubMed Central - HTML

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

DNA methyl transferase 1 (DNMT-1) is a key epigenetic enzyme in cancer cells which inactivates proliferation terminating genes and downregulates the expression of cancer related proteins and neoantigens by hypermethylation... Clinical use of decitabine to target DNMT-1 is restricted by its short in vivo half-life (about 10 minutes) due to rapid inactivation by the enzyme cytidine deaminase (CDA) present in tissues... Tetrahydrouridne(THU), an oral inhibitor of CDA can overcome the pharmacokinetic (PK) limitation... Novel pharmacologic combination of THU with micro-doses of DAC can significantly increase half-life of DAC allowing sufficient interaction between DNMT-1 and decitabine to overcome epigenetic repression by DNMT-1... Increased lymphocytic infiltrate in the tumor post the immune priming by decitabine can augment response to immune checkpoint inhibitor MPDL3280A, an anti PD-L1 antibody... The first stage will be an assessment of the immunologic effect of the combination... The second stage, which will occur only if THU-DAC is shown to have a significant priming effect, will assess the ability of the immunologic response to translate to clinical efficacy... Based on our previous studies we anticipate in advanced stage NSCLC approximately 25% patients will have high TILs and hypothesize that THU-DAC will increase that proportion to >50%... With 24 patients there will be at least 90% power to detect such a difference... Assuming the combination does indeed prime the immune system, stage 2 will be implemented and a two-stage accrual design will be used to assess clinical efficacy, with the 24 patients already accrued.

No MeSH data available.