DELINEATING THE EVOLUTION AND ECOLOGY OF CHEMORESISTANCE IN BREAST CANCER WITH SINGLE CELL GENOMICS

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Principal Investigator: Nicholas  Navin
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $352,047
Funding agency: National Cancer Institute

PROJECT SUMMARY
Triple-negative breast cancer (TNBC) is an aggressive subtype in which patients display extensive intratumor
genomic heterogeneity and frequently (50%) develop resistance to neoadjuvant chemotherapy (NAC) which
leads to metastatic disease and death. Due to the absence of hormonal receptors and targeted therapies,
TNBC patients with refractory disease are often left with limited treatment options. Currently, our understanding
of the genomic evolution of tumor cells and the role of the tumor microenvironment in chemoresistant disease
at primary and metastatic organ sites represents a major gap in knowledge that this proposal aims to address.
Our group has developed cutting-edge single cell DNA and RNA sequencing technologies that can overcome
previous technical barriers and limitations with `bulk' genomic methods for studying the genomic and
phenotypic evolution of tumor cells in response to chemotherapy. Our preliminary data in a small number of
TNBC patients suggests that genomic evolution of chemoresistance occurs through the adaptive selection of
pre-existing mutations and copy number alterations, which is followed by transcriptional reprogramming, to
achieve a chemoresistant phenotype (Kim et al. 2018, Cell). We further hypothesize that transcriptional
reprogramming of cell types in the tumor microenvironment occurs in chemoresistant disease and that
resistance programs are clonally inherited at distant metastatic organ sites. To comprehensively investigate
these questions in matched longitudinal samples from TNBC patients in a large neoadjuvant chemotherapy
trial (ARTEMIS), we propose three synergistic aims: Aim 1 will determine if copy number aberrations (CNAs)
and subclonal mutations associated with chemoresistance are pre-existing and adaptively selected in response
to therapy. Aim 2 will investigate if tumor cells and cell types in the microenvironment undergo transcriptional
reprogramming in refractory disease. Aim 3 will determine if subpopulations of resistant cells in the primary
tumor seed the metastatic lesions and confer resistance programs at distant organ sites. Completion of these
aims will define the genomic and evolutionary basis of chemoresistance in TNBC patients and will provide new
diagnostic biomarkers and therapeutic targets for overcoming chemoresistant disease, which is a critical unmet
clinical need. Our long-term goal is to translate single cell sequencing technologies into the clinic, where they
are poised to have a major impact on the diagnosis and treatment of breast cancer patients. The proposed
aims are directly aligned with the mission of NIH to reduce morbidity and improve the quality of life for breast
cancer patients.

Terms: <Address><Adjuvant Chemotherapy><Adjuvant Drug Therapy><After Care><After-Treatment><Aftercare><Bionomics><Biopsy><Breast Cancer><Breast Cancer Patient><Breast Cancer Treatment><Breast Tumor Patient><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><Cas nuclease technology><Cell Body><Cell Line><Cell Reprogramming><CellLine><Cells><Cessation of life><Chemoresistance><Classification><Clinic><Clinical><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><DNA><DNA seq><DNA sequencing><DNAseq><Data><Data Set><Death><Deoxyribonucleic Acid><Diagnosis><Disease><Disease Resistance><Disorder><Distant><Ecology><Evolution><Expression Signature><Gene Expression><Gene Expression Profile><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Genotype><Goals><Grant><Hereditary><Heterogeneity><Hormonal><Human><In Vitro><Induction Therapy><Inherited><Knowledge><Left><Malignant Breast Neoplasm><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Mission><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Mutation><NEOADJ><NIH><National Institutes of Health><Neoadjuvant><Neoadjuvant Therapy><Neoadjuvant Treatment><Neoplasm Metastasis><Non-Polyadenylated RNA><Organ><Outcome><Patient Care><Patient Care Delivery><Patients><Phenotype><Primary Neoplasm><Primary Tumor><QOL><Quality of life><RNA><RNA Expression><RNA Gene Products><RNA Seq><RNA sequencing><RNAseq><Receptor Protein><Refractory Disease><Resistance><Resistance development><Resistant development><Ribonucleic Acid><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Single cell seq><Site><Strains Cell Lines><Stromal Cells><Systematics><TCGA><TNBC><Technology><The Cancer Genome Atlas><Therapeutic><Therapy trial><Time><Tissue Sample><Transcription><Translating><Tumor Cell><United States National Institutes of Health><cancer metastasis><cancer microenvironment><care for patients><care of patients><caring for patients><cell type><cellular reprogramming><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><clinical applicability><clinical application><cohort><cultured cell line><developing resistance><diagnostic biomarker><diagnostic marker><diagnostic technologies><gene expression pattern><gene expression signature><gene signatures><genetic signature><genome mutation><improved><induction therapies><knock-down><knockdown><malignant breast tumor><neoplastic cell><new diagnostics><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><next generation diagnostics><novel diagnostics><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><overexpress><overexpression><post treatment><programs><receptor><resistance to disease><resistant><resistant disease><resistant to disease><response><response to therapy><response to treatment><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell genomics><single cell next generation sequencing><single cell sequencing><single cell technology><single cell transcriptomic profiling><single-cell RNA sequencing><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic biomarker><therapeutic marker><therapeutic response><therapeutic target><therapy response><transcriptional profile><transcriptional reprogramming><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transcriptomics><treatment response><treatment responsiveness><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumor microenvironment>