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Principal Investigator: Suzanne AW Fuqua
Organization: BAYLOR COLLEGE OF MEDICINE
Fiscal Year: 2024
Award: $324,901
Funding agency: National Cancer Institute
Our research focus is estrogen receptor (ER)-positive luminal breast cancer, representing 75% of primary breast
cancer patients, who are prescribed adjuvant endocrine therapy (ET) with hormonal agents. While recurrences
are delayed by the use of ET, resistance can evolve with the development of metastatic breast cancer (MBC) in
about one-fourth of ER-positive patients. MBC patients acquire ESR1 mutations in a significant percentage of
cases. Our overall goal is to identify new therapeutic vulnerabilities in ESR1m preclinical models that can
effectively block distant metastatic progression. Our proposal is highly translational. We hypothesize that
acquired ESR1m function as activated “oncogenes” inducing defective replication stress (RS) that suppresses
the DNA damage response (DDR), leading to a metastatic phenotype with actionable targets. Our innovation
includes a unique transplantable ER+ patient derived xenograft (PDX) frozen metastatic tumor bank to explore
the effects of selective cell cycle and DDR inhibitors. In Aim 1 we will study RS and DDR signaling in ex vivo
metastatic organoid cultures, focusing on ATR/Chk1, and PARP inhibitor effects on the DDR and its interactions
with ESR1m. In Aim 2, we will focus on cell cycle proteins AURKA/B and CDK1/2 to arrest the cell cycle in
ESR1m tumors. In Aim 3 we will evaluate mutant metastasis in vivo and the effects of novel therapeutics on
estrogen responses, EMT, and stem cell blockade. It is essential that the discovery of new therapeutic targets
and the preclinical testing of novel approaches be performed using metastatic models. Currently most preclinical
investigators only evaluate primary tumor proliferation, which may not reflect the ability of targeted inhibitors to
block the complex steps of metastasis. We predict that identifying the heterogeneity of driver mechanisms using
experimental modeling of ESR1 mutants will serve an important role in the development of therapeutic
combination interventions to overcome the clinical problem of resistance and rapid tumor progression. Our
project will fill a big gap in our clinical knowledge of how best to treat breast cancer patients who recur with
multiple and heterogeneous ER-positive metastases. With successful completion of our Aims we can impact
the effective ET maintenance of patients with ER-positive MBC and significantly delay time to progression.
Terms: <AIK gene><ARK1><AURKA><AURORA2><Adjuvant Therapy><Aik protein><Assay><Aurora-Related Kinase 1><Aurora/IPL1-Like Kinase><BTAK><Bioassay><Biological Assay><Breast Cancer><Breast Cancer Patient><Breast Cancer cell line><Breast Neoplasms><Breast Tumor Patient><Breast Tumors><Breast tumor cell line><CDC2><CDC2 Protein Kinase><CDC2 gene><CDK1><CDK4><CDK4 gene><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancer Genes><Cancer-Promoting Gene><Cas nuclease technology><Cell Communication and Signaling><Cell Cycle><Cell Cycle Arrest><Cell Cycle Checkpoint><Cell Cycle Controller CDC2 Gene><Cell Cycle Controller cdc2><Cell Cycle Proteins><Cell Division Control Protein 2 Homolog><Cell Division Cycle><Cell Division Cycle 2><Cell Division Cycle 2 Protein><Cell Division Cycle Proteins><Cell Division Kinase 4><Cell Signaling><Cell-Cycle Regulatory Proteins><ChIP Sequencing><ChIP-seq><ChIPseq><Checkpoint inhibitor><Clinical><Clinical Data><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Critical Paths><Critical Pathways><Cyclin-Dependent Kinase 1><Cyclin-Dependent Kinase 4><DNA Damage><DNA Injury><Development><Diagnosis><Distant><Distant Cancer><Distant Metastasis><ER Positive><ER+><ERalpha><ERα><ESR1><ESR1 gene><Endocrine Therapy><Engineering><Estradiol Receptor alpha><Estradiol Receptor α><Estrogen Receptor 1><Estrogen Receptor alpha><Estrogen Receptor α><Estrogen Receptors><Estrogen receptor positive><Estrogens><Evaluation><Evolution><Experimental Designs><Experimental Models><Freezing><Gene Expression><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Goals><Growth><Heterogeneity><Hormonal><Hormonal Therapy><Immune checkpoint inhibitor><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigators><Kinetics><Knowledge><Left><Ligands><Maintenance Therapy><Malignant Breast Neoplasm><Mammary Cancer><Mammary Neoplasms><Metastasis><Metastasis Induction><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Modeling><Mutation><NR3A1><Neoplasm Metastasis><Oncogenes><Oncology><Oncology Cancer><Organoids><Outcome><PARP Inhibitor><PARP-1 inhibitor><PARPi><PDX model><PSK-J3><Pathway interactions><Patient derived xenograft><Patients><Phenotype><Phosphorylation><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Pre-Clinical Model><Preclinical Models><Preclinical Testing><Primary Neoplasm><Primary Tumor><Progenitor Cells><Proliferating><Protein Phosphorylation><Proteins><RNA Seq><RNA sequencing><RNAseq><Recurrence><Recurrent><Reporter><Repression><Research><Research Personnel><Researchers><Resistance><Role><STK15><STK6><STK6 gene><STK6, Mouse, Homolog of><Secondary Neoplasm><Secondary Tumor><Serine/Threonine Protein Kinase 15><Short interfering RNA><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Testing><Therapeutic Estrogen><Time><Tissue Growth><Transforming Genes><Transplantation><Tumor Bank><Work><adjuvant endocrine therapy><adjuvant endocrine treatment><adjuvant treatment><aurora kinas><aurora kinase A><aurora-kinase A><biological signal transduction><cancer metastasis><cancer progression><cdc Proteins><cdc2 gene product><cdc2+ Protein><cdk1 Kinase><cell cycle check point><chromatin immunoprecipitation-sequencing><combat><developmental><experience><experiment><experimental research><experimental study><experiments><genome mutation><hormone therapy><immune check point inhibitor><in vivo><inhibitor><innovate><innovation><innovative><interventional strategy><knock-down><knockdown><malignant breast tumor><mammary tumor><mutant><neoplasm progression><neoplastic progression><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><p34 Protein Kinase><p34 Protein Kinase Gene><p34(CDC2) Gene><p34CDC2><pathway><patient derived xenograft model><pre-clinical><pre-clinical testing><preclinical><refractory cancer><replication stress><resistance mechanism><resistance to therapy><resistant><resistant cancer><resistant mechanism><resistant to therapy><response><siRNA><social role><stem cells><therapeutic agent development><therapeutic development><therapeutic resistance><therapeutically effective><therapy resistant><transcriptome sequencing><transcriptomic sequencing><transplant><treatment resistance><tumor><tumor cell metastasis><tumor progression>