Current Research and Major Achievements
Our laboratory continues to bridge fundamental discoveries with clinical applications, focusing on understanding and exploiting DNA repair deficiencies to enhance cancer therapy effectiveness. Our four areas of focus are:
1. Fundamental DNA Damage Response Mechanisms
Landmark BRIT1 discoveries
- Characterized BRIT1's master regulatory role in DNA damage response through chromatin remodeling:
- Regulates SWI/SNF chromatin remodeling complex recruitment
- Facilitates chromatin relaxation at damage sites
- Enables access of repair and checkpoint proteins
- Demonstrated tumor suppressor functions:
- Controls DNA damage checkpoint activation
- Maintains chromosomal stability
- Prevents genomic instability
2. Development of Precision Medicine Signatures
Homologous recombination deficiency (HRD)
- Created transcriptomic signature to identify HRD cancers
- Developed PARP inhibitor sensitivity predictor
- Demonstrated clinical utility across multiple cancer types
Mismatch repair deficiency (MMRD)
- Established MMRD transcriptome signature
- Discovered that MMRD induces protein-destabilizing mutations leading to proteome instability
- Identified MLN4924 (pevonedistat) as effective therapy for MSI cancers
- Initiated Phase II trial combining MLN4924 with pembrolizumab
Replication stress response (RSR) defects
- Developed first reliable predictor for immunotherapy response in non-hypermutated cancers
- Validated across 12 independent patient cohorts from 7 tumor types
- Demonstrated superiority over traditional biomarkers like tumor mutation burden
3. Enhancing Tumor Immunogenicity
Multiple approaches to convert "cold" tumors to "hot"
- Targeting replication stress:
- Demonstrated that RSR defects predict immunotherapy response in non-hypermutated cancers
- Showed RSR deficiency leads to aberrant origin firing and RPA exhaustion
- Revealed mechanism of immunostimulatory cytosolic DNA accumulation
- Validated increased dendritic cell infiltration in tumors
- Confirmed RSR modulation controls ICB response
- RNase H2 inhibition strategy:
- Identified RNase H2 as essential for TNBC survival under replication stress
- Demonstrated selective killing of TNBC cells while sparing normal cells
- Showed increased DNA damage through pRPA32 and γH2AX elevation
- Characterized immune activation through T cell-attracting chemokines
- Validated synergy with DNA damage inhibitors and immunotherapy
- TREX1 targeting:
- Discovered correlation between cytosolic ssDNA and tumor-infiltrating lymphocytes
- Characterized STING-independent immune activation via DDX3X
- Demonstrated enhanced ICB efficacy through ssDNA accumulation
- Identified CEP-701 as novel ssDNA inducer with minimal toxicity and will be testing a novel TREX1 enzymatic inhibitor in TNBC
4. Clinical Translation
Clinical application
- Phase II trial of MLN4924/pembrolizumab combination in MMRD cancers
- Biomarker-guided patient selection studies
Drug development
- Testing novel immune sensitizers
- Developing combination strategies
- Validating biomarker-guided approaches
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Research Areas
Find out about the four types of research taking place at MD Anderson.
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