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Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-targeted combinations

Award Number: R01CA167291
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Pancreatic ductal adenocarcinoma or PDAC is a lethal disease with a 5 year mortality rate of ~93% and little improvement has been made despite the emergence of several targeted, selective agents. Therefore, a new approach is needed. We will pursue transcriptomic-guided combination therapy as well as targets that are upstream of several signaling pathways, thereby affecting multiple downstream cellular processes and potential resistance mechanisms. Redox factor-1 (Ref-1) is one such protein, as Ref-1 regulates multiple transcriptional factors (TFs) that are critical to pancreatic cancer survival and drug resistance. In the previous funding period, we have advanced APX3330, a Ref-1 inhibitor and the first drug targeting Ref-1 to cancer clinical trials (IND 125360) as a novel, oral, first-in-class drug in humans. We have shown that APX3330 reduces tumor growth in several models of PDAC as a single agent and potentiates gemcitabine-mediated inhibition of cell growth. The mechanism of action of APX3330 has been extensively investigated and characterized by our team. Through inhibition of Ref-1, the activity of STAT3, AP-1, NFkB, and HIF-1¿ can be blocked leading to a decrease in survival protein expression and response to hypoxia. Recognizing that combination therapy will be necessary in PDAC, we propose to utilize transcriptomic data to identify FDA-approved agents that are likely to synergize with APX3330. Drug synthetic lethality is defined as combination therapy of molecular targets whose dual inhibition leads to potentiation of cell death much more dramatically than when administered as single agents. Single cell RNA-seq data identified HIF-1 signaling pathways as significantly down-regulated following Ref-1 knockdown (p=0.0008). Therefore, we tested the combination of Ref-1 inhibition and HIF-1 target, carbonic anhydrase (CA9) in our 3-Dimensional (3D) tumor co-culture model. Dramatic enhancement of Ref-1-induced cell killing is observed upon dual-targeting of Ref-1 and CA9. Our hypothesis is that in order to extend the survival of PDAC patients multi-targeted, combination therapy is essential; therefore we will use original, pathway-driven screening approaches to discover appropriate FDA approved agents to partner with our Ref-1 inhibitor. AIM 1- Evaluate the mechanism and efficacy of simultaneous inhibition of the Ref-1 and HIF-1¿ pathways using in vivo models of PDAC. AIM 2- Investigate the role of Ref-1 in sensitizing PDAC to chemotherapy currently used in PDAC treatment. Gemcitabine (Gem), one of the agents that single cell RNA-seq expression profiling predicted should work with APX3330, will be used in combination with APX3330 in the phase 1B trial. AIM 3- Screen for drug synthetic lethal hits following Ref-1 inhibition in a validated 3D model system utilizing computational and transcriptomics pathway analysis. Selective disruption of individual molecular effectors has clear limitations; our approach focuses on multi-targeted combination treatments. Thus, this project has the potential to extend pancreatic cancer survival by using appropriate disease-relevant models such as 3D co-culture spheroids, orthotopic, and GEM models.


Issue Date FY	Funding FY	Recipient Name	DUNS Number	City	State	CFDA Number	CFDA Program Title	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $493,726 )
2021	2021	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	9	2/18/2021	NON-COMPETING CONTINUATION	$493,726


Issue Date FY: 2020 ( Subtotal = $493,726 )
2020	2020	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	8	2/11/2020	NON-COMPETING CONTINUATION	$493,726


Issue Date FY: 2019 ( Subtotal = $563,735 )
2019	2019	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	7	2/27/2019	NON-COMPETING CONTINUATION	$563,735


Issue Date FY: 2018 ( Subtotal = $721,280 )
2018	2018	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	6	3/9/2018	COMPETING CONTINUATION	$493,726
2018	2018	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	003	6	9/21/2018	SUPPLEMENT FOR EXPANSION	$227,554
2018	2017	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	5	3/6/2018	NON-COMPETING CONTINUATION	$0
2018	2017	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	002	5	6/14/2018	NON-COMPETING CONTINUATION	$0


Issue Date FY: 2017 ( Subtotal = $493,963 )
2017	2017	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	5	6/7/2017	NON-COMPETING CONTINUATION	$49,397
2017	2017	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	5	12/20/2016	NON-COMPETING CONTINUATION	$444,566


Issue Date FY: 2016 ( Subtotal = $493,963 )
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	4	3/4/2016	EXTENSION WITH OR WITHOUT FUNDS	$49,397
2016	2016	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	4	12/14/2015	EXTENSION WITH OR WITHOUT FUNDS	$444,566


Issue Date FY: 2015 ( Subtotal = $493,963 )
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	3	1/26/2015	NON-COMPETING CONTINUATION	$44,456
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	3	12/2/2014	NON-COMPETING CONTINUATION	$444,566
2015	2015	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	002	3	2/19/2015	NON-COMPETING CONTINUATION	$4,941


Issue Date FY: 2014 ( Subtotal = $479,144 )
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	2	4/17/2014	NON-COMPETING CONTINUATION	$34,577
2014	2014	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	2	12/17/2013	NON-COMPETING CONTINUATION	$444,567


Issue Date FY: 2013 ( Subtotal = $493,963 )
2013	2013	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	000	1	12/28/2012	NEW	$370,472
2013	2013	INDIANA UNIVERSITY, BLOOMINGTON	603007902	BLOOMINGTON	IN	93.395	Cancer Treatment Research	001	1	6/28/2013	NEW	$123,491


Grand Total All Awards = $4,727,463

Sum of Action Amount is $4,727,463;

Grand Total = $4,727,463

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Exploiting the Ref-1 node in pancreatic cancer: tailoring new pancreatic cancer therapy using multi-targeted combinations

Award Number: R01CA167291

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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