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Principal Investigator: Aimee Marie Crago
Organization: SLOAN-KETTERING INST CAN RESEARCH
Fiscal Year: 2024
Award: $530,202
Funding agency: National Cancer Institute
Desmoid-type fibromatosis is a mesenchymal tumor that does not progress to high-grade disease or
metastasize. Surgery was the standard treatment for desmoids, but in patients with extensive disease, surgery
can lead to complications as morbid as the tumors themselves, and ~30% of patients have local recurrence.
For these and other reasons, active observation is prescribed to an increasingly large subset of patients with
asymptomatic disease. Desmoid outcomes, however, are highly variable; under observation half of desmoids
do not progress over two years and a subset will regress spontaneously, while other desmoids grow
relentlessly. Locally aggressive tumors can cause severe symptoms: pain and contracture from desmoids in
the extremities and intestinal fistulization and death from abdominal desmoids. Once present, symptoms can
be difficult to reverse. Therefore, there is need for tools to predict outcome prior to recommending active
observation. Nearly all desmoids contain CTNNB1 mutations that constitutively activate the gene product, β-
catenin, but extensive genetic analyses have failed to identify any additional genetic alterations that may
underlie variations in patient prognosis. This proposal builds upon preliminary results suggesting that β-catenin
promotes desmoid oncogenesis through non-canonical downstream targets, including hypoxia-inducible factor
α (HIF1α). Both HIF1α protein levels and desmoid cell proliferation are also increased by activated PDGFRβ,
which may explain the fact that sorafenib, an inhibitor of PDGFRβ among other receptor tyrosine kinases, has
activity in desmoids. Based on these and other preliminary data, we hypothesize that HIF1α mediates
mitogenic signals from PDGFRβ in a manner dependent on activated β-catenin. We propose to investigate the
role of this and other pathways in desmoid biology and to use the insight gained to identify and test potential
biomarkers of desmoid tumor growth. In Aim 1, we seek to determine the roles of HIF1α and β-catenin in
mediating PDGFRβ signaling and proliferation in desmoid cells. In Aim 2, we perform highly focused screens to
identify additional genes and druggable pathways that are necessary for desmoid cell proliferation. We will
then test whether they act upstream of a PDGFRβ/β-catenin/HIF1α axis or act independently of this axis.
Finally, in Aim 3, we propose to use biopsy specimens, collected as part of a phase II trial, to examine whether
desmoid progression during active observation can be predicted by markers from the PDGFRβ/β-
catenin/HIF1α pathway or other pathways defined in Aims 1 and 2. We expect the proposed studies to identify
biomarkers that will help clinicians to identify optimal therapeutic pathways for individual desmoid patients. In
addition, by elucidating the molecular basis of oncogenesis in desmoids, this work may identify novel
therapeutic targets for the disease. Because aberrant β-catenin activity can be observed in a wide range of
neoplasms, our results may provide insight that affects our approach to other cancers as well.
Terms: <21+ years old><Abdomen><Adriablastin><Adriablastine><Adriacin><Adriamycin PFS><Adriamycin RDS><Adriblastin><Adriblastina><Adriblastine><Adrimedac><Adult><Adult Human><Affect><Aggressive Fibromatosis><BAY 54-9085><BCL1><Benefits and Risks><Beta Cadherin-Associated Protein><Beta-1 Catenin><Binding><Biological Markers><Biology><Biopsy Sample><Biopsy Specimen><Body Tissues><CAP102 protein><CCND1><CCND1 gene><CTNNB><CTNNB1><CTNNB1 gene><CUL-2><Cancers><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cells><Cellular Proliferation><Cessation of life><Characteristics><Clinical><Contracture><Counseling><Cyclin D1 Gene><D11S287E><DNA Alteration><DNA Sequence Alteration><DNA mutation><DOXO-CELL><Data><Death><Deep Fibromatosis><Deep Fibromatosis/Desmoid Tumor><Desmoid><Desmoid Fibromatosis><Desmoid Tumor><Desmoid-Type Fibromatosis><Disease><Disease Progression><Disorder><Doxolem><Doxorubin><Extensive Disease><Extremities><Farmiblastina><Generalized Disease><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic analyses><Genetic defect><Genetic mutation><Growth><HIF 1 alpha><HIF-1alpha><HIF1-Alpha><HIF1A><HIF1A gene><HIF1α><Hypoxia Inducible Factor><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><In Vitro><Individual><Intestinal><Intestines><Intracellular Communication and Signaling><Ligands><Limb structure><Limbs><Link><Liposomal Adriamycin><MOP1><Malignant Neoplasms><Malignant Tumor><Mediating><Mesenchymal Cell Neoplasm><Mesenchymal Cell Tumor><Mesenchymal Neoplasm><Mesenchymal Tumor><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mutation><Neoplasm Metastasis><Neoplasms><Non-Trunk><Oncogenesis><Oncogenic><Operative Procedures><Operative Surgical Procedures><Outcome><PDGF><PDGF-BB><PRAD1><PRO2286><PTK Receptors><Pain><Painful><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Physicians><Platelet-Derived Growth Factor><Progression-Free Survivals><Proliferating><Proteins><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Recommendation><Recurrence><Recurrent><Regimen><Reproducibility><Research><Role><Rubex><SYS-TX><Secondary Neoplasm><Secondary Tumor><Sequence Alteration><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sorafenib><Surgical><Surgical Interventions><Surgical Procedure><Symptoms><Systemic Therapy><Testing><Therapeutic><Therapeutic Intervention><Tissue Growth><Tissues><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transmembrane Receptor Protein Tyrosine Kinase><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><U21B31><Variant><Variation><Widespread Disease><Work><adriamycin><adulthood><adverse event risk><alpha E-catenin><alpha catenin><alpha-1 catenin><alphaE catenin><beta catenin><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker identification><bowel><cadherin-associated protein 102 kDa><cancer metastasis><druggable target><gene product><genetic analysis><genome mutation><genomic alteration><identification of biomarkers><identification of new biomarkers><individual patient><inhibitor><insight><intervention therapy><knock-down><knockdown><malignancy><marker identification><mid life><mid-life><middle age><middle aged><midlife><neoplasia><neoplasm/cancer><neoplastic growth><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><ontogeny><outcome prediction><overexpress><overexpression><pathway><patient oriented outcomes><patient prognosis><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><phase 2 trial><phase II trial><platelet-derived growth factor BB><potential biological marker><potential biomarker><predictive biomarkers><predictive marker><predictive molecular biomarker><social role><standard care><standard treatment><surgery><therapeutic target><tool><tumor><tumor cell metastasis><tumor growth><tumorigenesis><α-catenin><αE-catenin><β-catenin>