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Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy

Award Number: K22CA160725
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2011
PERIOD OF PERFORMANCE END DATE: 07/02/2013

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Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy - Abstract Epidermal growth factor receptor (EGFR) has been heavily exploited as a target for blockade in cancer therapy. In normal epithelial cells, ligand-induced internalization of activated receptors and their sorting for degradation in lysosomes is the limiting mechanism for EGFR signaling. This desensitization process is commonly circumvented by cancer cells to promote their growth and survival even in the presence of EGFR signaling inhibitors. We have identified a novel role for the sterol biosynthesis pathway to influence this recycling process which could significantly improve the efficacy of EGFR-targeting inhibitors. Silencing of SC4MOL (sterol C4-methyl oxidase-like) significantly sensitizes tumor cells to EGFR inhibitors using a network-guided siRNA-based screen (Astsaturov, 2010). We have determined that SC4MOL and a functionally linked partner protein, NSDHL (NADP-dependent steroid dehydrogenase-like), are negative regulators of trafficking of EGFR and its family members ErbB2 and ErbB3 from the plasma membrane to the lysosome for destruction. Our central hypothesis is that metabolic blockade of the sterol biosynthesis pathway will accelerate receptor degradation and thus suppress EGFR signaling in vitro; in NSDHL conditional knockout mice, this will limit epithelial carcinogenesis. Our immediate objective is to validate a new metabolic target for cancer therapy involving these previously unexplored genes in the distal sterol biosynthesis pathway. With the strong team of collaborators assembled, we propose the following 3 specific Aims: Aim 1. Investigate the mechanism of EGFR signaling regulation by genes in the sterol biosynthesis pathway. On the basis of preliminary data and complementary bioinformatic analysis, we hypothesize that blockade of SC4MOL and NSDHL causes altered EGFR trafficking that accelerates EGFR degradation in lysosomes. Aim 2. Determine the value of combined targeting of SC4MOL and EGFR in tumor xenografts. Based on our preliminary in vitro data, we propose that shRNA silencing of SC4MOL will increase the response of tumor xenografts to EGFR blockade. Aim 3. Investigate in vivo effects of sterol pathway on EGFR signaling and susceptibility to carcinogens. We hypothesize that the EGFR-antagonistic effects of the epithelial NSDHL deficiency will limit the H-Ras-dependent or -independent carcinogenesis. This proposal is significant because it will provide fundamentally new knowledge on how the metabolism of sterols regulates signaling activity of essential cancer receptors such as EGFR. We believe that pharmacological inhibition of sterol pathway targets such as SC4MOL and NSDHL has the potential for cancer chemotherapy and chemoprevention as an entirely novel class of agents.


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: 2014 ( Subtotal = -$195,961 )
2014	2013	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	001	3	1/2/2014	NON-COMPETING CONTINUATION	-$195,961
2014	2013	INSTITUTE FOR CANCER RESEARCH	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	000	4	1/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = -$195,961

Issue Date FY: 2013 ( Subtotal = $195,961 )
2013	2013	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	002	3	8/12/2013	NON-COMPETING CONTINUATION	$195,961
2013	2013	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	005	3	9/5/2013	NON-COMPETING CONTINUATION	$0
2013	2013	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	001	3	7/24/2013	NON-COMPETING CONTINUATION	-$195,961
2013	2013	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	000	3	6/11/2013	NON-COMPETING CONTINUATION	$195,961
2013	2013	INSTITUTE FOR CANCER RESEARCH	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	007	4	1/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2013	2013	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	004	4	9/5/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,961
2013	2013	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	006	3	1/2/2014	NON-COMPETING CONTINUATION	-$195,961
2013	2013	FOX CHASE CANCER CENTER	7701 BURHOLME AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	003	3	8/15/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $195,961

Issue Date FY: 2012 ( Subtotal = $197,098 )
2012	2012	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	000	2	6/21/2012	NON-COMPETING CONTINUATION	$197,098
														Subtotal = $197,098

Issue Date FY: 2011 ( Subtotal = $199,245 )
2011	2011	FOX CHASE CANCER CENTER	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Cancer Research Manpower	000	1	6/30/2011	NEW	$199,245
														Subtotal = $199,245

Grand Total All Awards = $396,343

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Targeting Sterol Gene SC4MOL and EGFR as Synergistic Anti-Cancer Strategy

Award Number: K22CA160725

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2011

PERIOD OF PERFORMANCE END DATE: 07/02/2013

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