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Our Research

Genetics Ribbon

Genomic technology has revolutionized our ability to study the molecular defects that occur in cancer. We use next-generation sequencing assays and computational analysis to study the gene expression, transcription factor binding and DNA methylation patterns in breast cancer. Our goals are to answer fundamental questions about how epigenetic gene regulation is disrupted in cancer cells as well as to discover pathways and biomarkers that may have a more immediate impact on breast cancer treatment. Our projects involve the development of new molecular methods and bioinformatics approaches to explore the cancer genome and translate our discoveries into clinical tools that improve patient care. 


  


KT VArley 1

Epigenome Engineering

Fusion Transcript 1


Fusion Transcripts as Drug Targets

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Transcription Factors Driving Metastasis

Fusion Transcript2
Detecting Circulating Tumor DNA

Clinical Trial Thumb

Clinical Trial Genomics

Long Non-Coding RNA

LncRNAs Associated with Therapy Response

 

Epigenome Engineering


Epigenome EngineeringAberrant DNA methylation across the genome is a hallmark of cancer. New therapeutics are being developed to inhibit general epigenetic pathways but unfortunately many have cytotoxic side effects.  We have identified genomic loci that are aberrantly methylated across different types of cancer, and we are now developing methods that utilize genome-editing techniques to modify the methylation state of these cancer-associated loci. This will allow us to distinguish which methylation defects across the genome are driving tumor development and which methylation defects are consequences of unregulated tumor growth.  Once we identify the specific epigenetic defects that are crucial for tumor growth, we can begin to determine why they occur and what downstream pathways are mis-regulated due to this epigenetic event.  These discoveries will enable the development of therapies that target the specific epigenetic events or mis-regulated pathways that are crucial for tumor proliferation and spare the general epigenetic pathways utilized by most cells.

KT Varley Lab

 

Fusion Transcripts as Drug Targets


Aberrant transcripts composed of a fusion between two genes can be a driving defect in tumor growth. We have identified fusion transcripts that occur specifically in breast cancer.

Fusion Transcript 1
Whey Chemical Structure

Unlike previously identified fusion genes, which are formed through chromosomal translocations, the breast cancer associated fusion transcripts we identified are formed during transcription from apparently normal DNA. Many questions remain about these newly discovered molecular defects:  Why do the mRNA transcripts from the two genes become spliced together in breast cancer? Does expression of the novel fusion transcripts contribute to tumor cell proliferation, migration and invasion? Are the fusion proteins expressed on the surface of breast cancer cells?  Can antibody-drug conjugates be used to deliver chemotherapy drugs specifically to cancer cells expressing these aberrant fusions?

drug targets

 

Transcription Factors Driving Metastasis


Transcription Factors 1

Estrogen receptor (ER) is a transcription factor that drives the expression of a suite of genes involved in the proliferation of the most common type of breast cancer (ER+ breast cancer). Inhibiting this transcription factor in ER+ breast cancer is one of the most effective cancer treatments developed to date. In light of the success of this paradigm, we are working to identify transcription factors responsible for the proliferation of other types of breast cancer.  We use an integrated genomic approach that includes measuring genome-wide gene expression, DNA methylation and transcription factor binding to predict which transcription factors could be driving gene expression signatures specific to metastatic breast cancer. We then use tissue culture experiments to determine how perturbing these candidate transcription factors influences gene expression and whether inhibiting these factors inhibits proliferation, migration or invasion.

Transcription Factors

 

Detecting Circulating Tumor DNA



circulating tumor dna

Imaging and repeated biopsies are currently used to monitor a tumor’s response to treatment and detect tumor mutations associated with acquired resistance to therapy.  These approaches pose health risks to patients and are expensive and therefore performed less frequently.  They also have limited sensitivity to detect small tumors, intra-tumor heterogeneity, tumors in locations that are difficult to image or biopsy, and micro-metastases. Recent studies have demonstrated that tumor cells release fragmented genomic DNA into the blood, which is stable in circulation.  The ability to detect this cell-free circulating tumor DNA in blood provides the opportunity to develop non-invasive tests to measure tumor burden and detect molecular signatures in tumors that are associated with resistance to therapy. We are developing targeted next-generation sequencing assays to quantify tumor-specific DNA methylation and somatic mutations in blood plasma samples from breast cancer patients that can be used to monitor patients’ responses to therapy.

 

Clinical Trial Genomics


We collaborate with clinical investigators conducting clinical trials of new therapeutics in breast cancer. In each clinical trial there is a subset of patients that respond to the treatment, and unfortunately, a fraction of patients that do not respond. Drug development programs are often canceled in early phase trials if the fraction Clinical Trials Diagram of patients that receive benefit is not sufficient, even if the drug is extremely effective for a small subset of patients. If a biomarker test could be developed to identify the subset of patients that receive the greatest benefit from each therapy, more drugs would be approved for specific indications and more of the diverse subtypes of breast cancer would have effective therapies. We perform genomic analyses (including RNA-seq, DNA methylation analysis, and whole genome sequencing) on tumor biopsies collected from patients enrolled in clinical drug trials. Our goal is to identify genomic signatures that distinguish patients that respond, and rapidly develop clinical-scale tests that can be used to selectively enroll similar patients in subsequent trials. We hope that developing companion diagnostic biomarker tests early in clinical drug trials will lead to the approval of more therapeutics for use in the specific patient populations that receive the most benefit.

     

   

Long Non-coding RNAs Associated with Therapy Response


Long Non-Coding RNA

Recent studies have shown that expression of specific long non-coding RNAs (LncRNAs), such as HOTAIR, are associated with breast cancer treatment response and prognosis and may serve as important drug targets and biomarkers in the treatment of breast cancer.  New technologies are revealing that there are thousands of lncRNAs in the genome and many lncRNAs, including HOTAIR, appear to be chromatin-associated and involved in gene regulation.  We have identified several lncRNAs whose expression is associated with breast cancer, and we are developing methods to determine which lncRNAs are chromatin-associated.  We are exploring which lncRNAs are involved in regulating specific gene expression signatures, and whether knocking down expression of the lncRNAs influences breast cancer cell proliferation, migration or invasion.

RNA