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Targeted epigenetic silencing of oncogenic Transcription Factors (PQ18)

Award Number: R01CA170370
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2012
PERIOD OF PERFORMANCE END DATE: 05/31/2016

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Targeted epigenetic silencing of oncogenic Transcription Factors (PQ18) - DESCRIPTION (provided by applicant): Epigenetic modifications play a key role in tumor origin and progression. Oncogenic transcription factors (TFs) are frequently over-expressed in breast cancers, while being silenced in normal epithelial cells. TFs can switch entire transcriptional gene cascades, resulting in tumor initiation and progression. Since most TFs do not have intrinsic enzymatic activities and they lack small-molecule-binding pockets, these targets have been refractory to drug design. The oncogenic TFs Sox2 is over-expressed in breast cancers of advanced stage, while the gene is silenced and hyper-methylated in normal epithelial cells. As a stable repressive mark, DNAme catalyzed by DNA-methyltransferases, is regarded as a key player in epigenetic silencing. DNAme orchestrate other epigenetic modifications, shaping the architecture of the promoter and driving chromatin condensation and gene silencing. A hallmark of DNAme is that it is hereditary and thereby transmitted over cell generations. In many developmentally regulated TFs, such as Sox2, DNAme constitute an epigenetic switch, which changes cells from an active mitogenic state towards a G0/G1 arrest and differentiation. In this application, our objective is to target DNAme into the promoter of Sox2, which is highly expressed in breast cancer cell lines, with levels comparable or superior to embryonic stem cells. To direct specific DNAme, we will fuse engineered DNA-binding proteins made of sequence-specific Zinc Finger (ZF) domains with a catalytically active DNA-methyltransferase domain (Dnmt3a). Our objective is to restore the hereditable epigenetic silencing in the Sox2 promoter of the tumor cell in a pattern that is similar to breast epithelial cells. We hypothesize that ZFs-Dnmt3a fusions are able to target DNAme marks into the Sox2 oncogenic promoter, resulting in transmission of these marks over cell generations. This epigenetic memory will be accompanied by the maintenance of the transcriptional silencing and tumor cell growth inhibition. In Aim1 we propose the construction of 6ZF proteins linked to the Dnmt3a and inactive mutants, to assess whether these engineered proteins deposit specific silencing marks into the Sox2 promoter, resulting in oncogenic silencing. In Aim2 we monitor the longevity of the silencing implemented by the 6ZF- silencers. We will express the 6ZF constructs using inducible vectors to "pulse" and "chase" DNAme in cell culture and breast tumor models. Next, to move the technology towards a pre-clinical phase, we will deliver ATF mRNAs using nanoparticles that will be injected in mouse models of breast cancer (Aim 3). While RNAi technology can be used to knock-down oncogenes, its therapeutic effect is transient because of the short-lived time of the small RNA. The significance of this application is the potential of the ZF agent to induce an endogenous epigenetic reprogramming of the target TF, which is expected to maintain the longevity of the therapeutic effect. Thus, this work will be of vital importance to develop stable, inherited, oncogenic silencing methods, to suppress oncogenic expression in tumor 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: 2018 ( Subtotal = $0 )
2018	2015	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY		6009		AUS	Cancer Cause and Prevention Research	000	4	11/29/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2015	UNIVERSITY OF WESTERN AUSTRALIA	**	NEDLANDS		00000		AUS	Cancer Cause and Prevention Research	000	4	8/25/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $247,767 )
2015	2015	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	000	4	6/8/2015	NON-COMPETING CONTINUATION	$247,767
														Subtotal = $247,767

Issue Date FY: 2014 ( Subtotal = $134,377 )
2014	2014	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	002	3	5/20/2014	NON-COMPETING CONTINUATION	$134,377
2014	2013	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	000	2	2/27/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$210,655
2014	2013	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	001	2	3/5/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,655
														Subtotal = $134,377

Issue Date FY: 2013 ( Subtotal = $210,655 )
2013	2013	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	001	2	6/28/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,655
2013	2013	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	002	2	2/27/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$210,655
2013	2013	UNIVERSITY OF WESTERN AUSTRALIA	35 STIRLING HWY	CRAWLEY				AUS	Cancer Cause and Prevention Research	003	2	3/5/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$210,655
2013	2012	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	1	6/28/2013	NEW	$0
														Subtotal = $210,655

Issue Date FY: 2012 ( Subtotal = $307,100 )
2012	2012	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Cancer Cause and Prevention Research	000	1	7/25/2012	NEW	$307,100
														Subtotal = $307,100

Grand Total All Awards = $899,899

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Targeted epigenetic silencing of oncogenic Transcription Factors (PQ18)

Award Number: R01CA170370

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2012

PERIOD OF PERFORMANCE END DATE: 05/31/2016

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