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Next generation strategies to intercept ErbB signaling

Award Number: R37CA072981
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/25/1997
PERIOD OF PERFORMANCE END DATE: 03/31/2015

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Next generation strategies to intercept ErbB signaling - The EGFR/HER2 signaling network emerges as an effective therapeutic target in lung, colon, pancreas, head/neck and breast tumors. Over the last five years our laboratory studied the HER2 subtype of breast cancer and highlighted functional features, which collectively confer robustness (outcome reproducibility) and plasticity (secondary resistance) to the HER2 network [Citri and Yarden (2006) Nature Reviews Molec. Cell Biol.]. Alongside, we demonstrated several novel strategies capable of intercepting the EGF-to-EGFR/HER2 pathway (e.g., antibody combinations, soluble chimeric receptors and anti-ligand antibodies). Our current working hypothesis assumes that the EGFR/HER2 network plays a driving role not only in the HER2 subtype of breast cancer, but also in the similarly aggressive basal-like subtype. Consistent with this proposition, EGFR is almost ubiquitously expressed in basal-like tumors, and according to a recent comprehensive study of expression profiles, almost all tumors of this class express EGFR-associated, poor prognostic signatures. If validated, the working model predicts that anti-EGFR/HER2 therapies may have broader than expected value in breast cancer therapy. Hence, over the next five years we will focus on both the HER2 and the basal-like subtypes and address collaborating biochemical mechanisms, as well as prospects for new targeted therapies. Our first task entails construction of relevant cellular model systems, expressing either an active form of EGFR, or an amplified HER2, on the genetic background of normal basal-like cells. In the next step, we will study the respective three-dimensional spheroids by extracting both genetic and proteomic signatures, as well as by introducing collaborative genetic events. For example, loss of expression of p53, PTEN, BRCA1 and Rb (basal-like models) and co-amplified, chromosome 17 genes (HER2 models). Our therapeutic task will extend the experimental armamentarium by developing EGFR/HER2-specific aptamers and testing them in tumor-bearing animals, either side by side or in combination with decoy receptors and other novel therapies we established over the last five years.


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 = $221,413 )
2014	2014	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	18	3/26/2014	NON-COMPETING CONTINUATION	$221,413
														Subtotal = $221,413

Issue Date FY: 2013 ( Subtotal = $216,389 )
2013	2013	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	17	3/11/2013	EXTENSION WITH OR WITHOUT FUNDS	$103,591
2013	2013	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	001	17	7/31/2013	EXTENSION WITH OR WITHOUT FUNDS	$112,798
														Subtotal = $216,389

Issue Date FY: 2012 ( Subtotal = $230,201 )
2012	2012	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	16	3/26/2012	NON-COMPETING CONTINUATION	$230,201
														Subtotal = $230,201

Issue Date FY: 2011 ( Subtotal = $230,202 )
2011	2011	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	15	3/23/2011	NON-COMPETING CONTINUATION	$219,998
2011	2011	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	001	15	5/13/2011	NON-COMPETING CONTINUATION	$10,204
														Subtotal = $230,202

Issue Date FY: 2010 ( Subtotal = $237,319 )
2010	2010	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	14	5/21/2010	EXTENSION WITH OR WITHOUT FUNDS	$237,319
														Subtotal = $237,319

Issue Date FY: 2009 ( Subtotal = $230,408 )
2009	2009	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH				ISL	Cancer Biology Research	000	13	3/26/2009	NON-COMPETING CONTINUATION	$230,408
														Subtotal = $230,408

Issue Date FY: 2008 ( Subtotal = $230,408 )
2008	2008	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	12	3/19/2008	NON-COMPETING CONTINUATION	$230,408
														Subtotal = $230,408

Issue Date FY: 2007 ( Subtotal = $230,408 )
2007	2007	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	11	4/4/2007	NON-COMPETING CONTINUATION	$230,408
														Subtotal = $230,408

Issue Date FY: 2006 ( Subtotal = $237,290 )
2006	2006	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	10	3/20/2006	NON-COMPETING CONTINUATION	$237,290
														Subtotal = $237,290

Issue Date FY: 2005 ( Subtotal = $243,000 )
2005	2005	WEIZMANN INSTITUTE OF SCIENCE	POST OFFICE BOX 26	REHOVOTH		00000		ISR	Cancer Biology Research	000	9	3/28/2005	COMPETING CONTINUATION	$243,000
														Subtotal = $243,000

Grand Total All Awards = $2,307,038

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Next generation strategies to intercept ErbB signaling

Award Number: R37CA072981

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/25/1997

PERIOD OF PERFORMANCE END DATE: 03/31/2015

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