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Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system

Award Number: R01CA265933
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system - Loss of NF1 plays a major role as an oncogenic driver in many cancer types and can be found in up to 33% of all breast cancers (BC). Loss of NF1 is also a prognostic indicator for increased cancer risk at an earlier age, poorer outcomes, and therapeutic resistance. In addition, certain NF1 genotypes may increase cancer risks, while others do not. NF1 is largely perceived as a classic Ras-opathy syndrome due to inactivating mutations in neurofibromin affecting Ras-MAPK signaling. However, recently it has been shown that NF1 binds estrogen receptor (ER) and acts as a transcriptional corepressor. This helps explain some of these BC findings specifically in ER+ BC patients. In this model, specific changes to NF1 that abrogate ER signaling lead to Ras driven tumor resistance to endocrine therapy in up to 20% of ER+ patients as cells are able to grow in low levels of E2 (and tamoxifen). We have generated novel rat models deficient for Nf1 that have a very robust ER+ BC phenotype, therefore more closely recapitulating clinical tumors compared to other preclinical models. Our models include a pathogenic patient missense allele c.3827G>A, p.R1276Q (knockin or KI), associated in humans with spinal NF1 and malignancy, as well as a 14 base pair deletion c.3661_3674del, p.P1220fs*1223 (knockout or KO) model. Phenotypic differences between our models indicate that the variant matters, and restriction of tumor development to pregnancy in the KI females indicates hormone induction plays a major role in tumor development. Rats also develop lung lesions positive for metastatic BC markers. Our overall goal is to characterize the phenotype of these rat models in terms of histopathology, Ras signaling, hormone signaling, immune components, and targeted drug response and compare/contrast them with what is known regarding patients with somatic or germline inactivation of NF1 and breast cancer. Ultimately, this will provide better prognostic predictions for patients and better therapeutics for treatment. Aim 1 will evaluate tumor onset, growth, histology, and molecular characterization of Ras and estrogen signaling over time and compare/contrast with human BC tumor samples. Aim 2 will characterize the Nf1 deficient tumor microenvironment (TME), identify immuno-targets, and evaluate immuno-targeting with and without Ras-targeting therapeutics. Aim 3 will evaluate the role of hormones in tumor initiation, maintenance and targeting therapeutics. We will better define which hormone(s) drive both initiation and maintenance of mammary tumors deficient for Nf1 and utilize this information to target them both with and without co-targeting Ras to show synergy. As HR+ BC accounts for ~80% of patient cases, and that appropriate mammalian models with intact immune systems are lacking, we believe that our proposed studies are highly significant and will substantially advance the development of new therapies to this disease.


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: 2025 ( Subtotal = $547,183 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	4	6/9/2025	NON-COMPETING CONTINUATION	$547,183
														Subtotal = $547,183

Issue Date FY: 2024 ( Subtotal = $519,825 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	3	6/11/2024	NON-COMPETING CONTINUATION	$519,825
														Subtotal = $519,825

Issue Date FY: 2023 ( Subtotal = $536,240 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	2	6/21/2023	NON-COMPETING CONTINUATION	$536,240
														Subtotal = $536,240

Issue Date FY: 2022 ( Subtotal = $547,183 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cancer Biology Research	000	1	6/10/2022	NEW	$547,183
														Subtotal = $547,183

Grand Total All Awards = $2,150,431

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Loss of NF1 drives hormone dependent mammary carcinogenesis in a rat model with intact immune system

Award Number: R01CA265933

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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