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EPIGENETIC POTENTIATION OF INTERFERON USING DECITABINE

Award Number: R21CA122270
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2007
PERIOD OF PERFORMANCE END DATE: 10/05/2010

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EPIGENETIC POTENTIATION OF INTERFERON USING DECITABINE - DESCRIPTION (provided by applicant): Aberrant hypermethylation of CpG islands within promoter regions of DNA modifies expression of genes involved in diverse cellular processes that impact tumor cell growth and behavior. Recent studies have shown that promoter methylation is important in silencing DNA repair enzymes, and inducing expression of drug sensitivity or resistance phenotypes. For example, cancer cell sensitivity to interferon-a is believed to be regulated by promoter methylation of key genes. The nucleoside analogue 5-aza-2'- deoxycytidine (decitabine) is a potent pharmacological inhibitor of DNA methylation in vitro. Decitabine-induced DNA hypomethylation, gene reactivation, and effects on cell function require incorporation into DNA followed by several cellular division cycles in vitro. We previously performed a phase I trial of decitabine, which established that 2mg/m2/day, given as a 168h continuous i.v. infusion resulted in significantly decreased MAGE-1promoter-specific and total genomic DNA methylation with minimal toxicity. Further preclinical studies suggested that the interferon-signaling pathway is reactivated following decitabine exposure of cancer cells. We propose to build on our previous preclinical experiments to perform a phase I clinical trial to test whether a decitabine infusion can sensitize cancer cells to interferon-a in vivo. In Specific Aim1 we plan to perform a phase I clinical trial to assess the toxicities of a continuous intravenous infusion of decitabine with escalating doses of subcutaneous PEG-IFN in patients with refractory metastatic cancer. The clinical protocol is designed to identify the dose limiting toxicity and the maximum tolerated dose of PEG-IFN in this combination. In Specific Aim 2 we will perform molecular correlation studies to evaluate pretreatment and post treatment samples of blood, skin and tumor from patients to identify changes in global (genomic) DNA methylation, as well as evaluating promoter-specific methylation . Additional experiments will evaluate interferon signaling and DNA damage response pathways in normal and neoplastic cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $0 )
2011	2008	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Treatment Research	000	2	2/4/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $0 )
2010	2008	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Treatment Research	000	2	6/16/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2008 ( Subtotal = $226,328 )
2008	2008	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Treatment Research	000	2	8/12/2008	NON-COMPETING CONTINUATION	$226,328
														Subtotal = $226,328

Issue Date FY: 2007 ( Subtotal = $243,677 )
2007	2007	NEVADA CANCER INSTITUTE	1000 WEST CHARLESTON BOULEVARD	LAS VEGAS	NV	89135	CLARK	USA	Cancer Treatment Research	000	1	9/7/2007	NEW	$243,677
														Subtotal = $243,677

Grand Total All Awards = $470,005

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EPIGENETIC POTENTIATION OF INTERFERON USING DECITABINE

Award Number: R21CA122270

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2007

PERIOD OF PERFORMANCE END DATE: 10/05/2010

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