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Principal Investigator: FARROKH DEHDASHTI
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $595,711
Funding agency: National Cancer Institute
ABSTRACT
Approximately 70% of breast cancers (BCs) are estrogen receptor (ER) positive (ER+) and human epidermal
growth factor receptor 2 negative (HER2-). Endocrine therapy (ET) reduces recurrence risk and improves
survival for many in this group. However, despite standard of care and adjuvant ET, over 20% of patients with
ER+/HER2- BC experience metastatic recurrence in the years to come, and virtually all patients with metastatic
disease eventually experience disease progression on ET due to intrinsic or acquired resistance mechanisms.
Progression on ET, however, does not preclude continued responsiveness to alternate forms of ET, including
those that combine therapies directed at ER and key signaling pathways that drive ET resistance. However,
there are currently no biomarkers that can reliably identify which patients will benefit from ET-based approaches
so that chemotherapy could be avoided or delayed. The PgR gene is highly regulated by ER at the RNA and
protein level, and thus expression of PgR in ER+ BC would be indicative of the functional status of ER and
associated predictive benefit from ET. We propose to evaluate the utility of positron emission tomography (PET)
imaging with the PgR radiotracer, [18F]fluoro-furanyl-norprogesterone (FFNP) to predict response to ET-based
therapies. In a recent phase II single-arm clinical trial, we demonstrated that FFNP-PET imaging, before and
after a one-day estradiol (E2) challenge (ΔFFNP-PET), predicted response to ET with 100% sensitivity and 100%
specificity in women with advanced ER+ BC. In this proposal, we will dissect the functional relationship between
PgR and ER and its implications for ΔFFNP-PET as a predictive imaging biomarker of ER function for the full
range of current and emerging ET-based approaches using patient-derived tumor xenografts (PDX) and
genetically engineered models, interfacing with a clinical trial. We propose three Aims. In Aim 1, we will examine
the impact of ESR1 gene mutations on ER-PgR crosstalk, PgR expression, and ΔFFNP-PET as an imaging
biomarker of ER function in preclinical models. In Aim 2, we will evaluate the utility of ΔFFNP-PET in predicting
response to single agent ET agents alone and in combination with targeted therapies in PDX models of
ER+/HER2- BC. In Aim 3, we will interface with a clinical trial to examine the impact of tumor genomics on
ΔFFNP-PET and its accuracy in predicting response to therapy in patients with metastatic ER+ HER2- breast
cancer enrolled in a phase II trial of endocrine therapy in combination with the CDK4/6 inhibitor abemaciclib.
Overall, this study aims to have a far-reaching and high impact on the implementation of precision medicine in
identifying, stratifying, and predicting response to clinically available and novel SERDs alone and in combination
with other targeted therapies in patients with advanced ER+/HER2- BC.
Terms: <1-Phosphatidylinositol 3-Kinase><Address><Agonist><Androstenedione Aromatase Inhibitor><Aquadiol><Aromatase Inhibitors><Biological Markers><Biopsy><Breast Cancer><Breast Cancer Patient><Breast Cancer cell line><Breast Tumor Patient><Breast tumor cell line><CDK4><CDK4 gene><Cell Division Kinase 4><Clinic><Clinical><Clinical Trials><Combined Modality Therapy><Cyclin-Dependent Kinase 4><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Dimenformon><Diogyn><Diogynets><Disease><Disease Progression><Disorder><Drugs><EGF Receptor><EGFR><ER Positive><ER Status><ER+><ERBB Protein><ERalpha><ERα><ESR1><ESR1 gene><Endocrine Therapy><Enrollment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Estrace><Estradiol><Estradiol Receptor alpha><Estradiol Receptor α><Estradiol-17 beta><Estradiol-17beta><Estraldine><Estrogen Receptor 1><Estrogen Receptor Status><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogen Synthase Inhibitor><Estrogen Synthetase Inhibitor><Estrogen decline><Estrogen receptor positive><Estrogens><Expression Signature><FES><FPS><FPS-FES Oncogene><Faslodex><Fujinami Sarcoma Virus and Feline Sarcoma Virus Transforming Gene><Fulvestrant><GEM model><GEMM model><GNRH><GNRH1><GNRH1 gene><Gene Alteration><Gene Expression Profile><Gene Mutation><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetic mutation><Genetically Engineered Mouse><Genomics><Goals><Gonadotropin Releasing Hormone 1><HER1><Hormonal Therapy><Human><ICI 182,780><ICI 182780><Image><LNRH><Luteinizing Hormone-Releasing Hormone><Malignant Breast Neoplasm><Medication><Metastatic breast cancer><Metastatic/Recurrent><Modeling><Modern Man><Multimodal Therapy><Multimodal Treatment><Mutate><Mutation><NR3A1><Non-Polyadenylated RNA><Oncogene FES><Ovocyclin><Ovocylin><PET><PET Scan><PET imaging><PETSCAN><PETT><PI-3 Kinase><PI3-Kinase><PI3CG><PI3K-Alpha><PI3KGamma><PI3k><PIK3><PIK3-Alpha><PIK3CA><PIK3CA gene><PIK3CG><PIK3CG gene><PSK-J3><Patients><Pharmaceutical Preparations><Phase><Phosphatidylinositol 3-Kinase><Phosphatidylinositol 3-Kinase, Catalytic, 110-kD, Alpha><Phosphatidylinositol 3-Kinase, Catalytic, Alpha><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Pre-Clinical Model><Preclinical Models><Prediction of Response to Therapy><Progesterone Receptors><Progestin Receptors><Progynon><Proteins><PtdIns 3-Kinase><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Rad.-PET><Receptor Cross-Talk><Receptor Gene><Receptor Signaling><Recombinant DNA Technology><Recurrence><Recurrent><Resistance><Ribonucleic Acid><Risk><SERMs><Selective Estrogen Receptor Modulators><Sequence Alteration><Signal Pathway><Specificity><TGF-alpha Receptor><Tamoxifen><Therapeutic Estradiol><Therapeutic Estrogen><Transforming Growth Factor alpha Receptor><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Urogastrone Receptor><Woman><Women's trial><Xenograft Model><adjuvant endocrine therapy><adjuvant endocrine treatment><advanced breast cancer><advanced stage breast cancer><arm><bio-markers><biologic marker><biomarker><c-erbB-1><c-erbB-1 Protein><chemotherapy><clinical development><combination therapy><combined modality treatment><combined treatment><decline in estrogen><decrease estrogen><decrease in estrogen><drug/agent><enroll><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><exome sequencing><exome-seq><experience><female trial><functional genomics><functional status><gene expression pattern><gene expression signature><gene signatures><genetic signature><genetically engineered><genetically engineered mouse model><genetically engineered murine model><genome mutation><genomic alteration><genomic classifier><genomic signature><hormone therapy><imaging><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><improved><indexing><inhibitor><mTOR Inhibitor><malignant breast tumor><multi-modal therapy><multi-modal treatment><novel><p110-Alpha><phase 2 trial><phase II trial><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><pre-clinical study><precision medicine><precision-based medicine><preclinical study><predict responsiveness><predict therapeutic response><predict therapy response><predicting response><predictive biomarkers><predictive marker><predictive molecular biomarker><proto-oncogene protein c-erbB-1><public health relevance><radiolabel><radiolabels><radiotracer><receptor expression><receptor function><reduced estrogen><resistance mechanism><resistant><resistant mechanism><response><response biomarker><response markers><response to therapy><response to treatment><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapy prediction><therapy response><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><treatment choice><treatment prediction><treatment response><treatment response prediction><treatment responsiveness><trial among women><trial in females><trial in women><tumor><tumor xenograft><virtual><xenograft transplant model><xenotransplant model>