Shiaw-Yih Lin
University of Texas MD Anderson Cancer Center, TX·Medicine & Clinical Research
Triple-negative breast cancer (TNBC) is an aggressive breast cancer that lacks the three receptors most targeted drugs act on, so patients have few treatment options. TNBC cells divide rapidly and have unstable genomes.
- Fields
Medicine & Clinical Research
Pharmacology
Microbiology & Immunology
- Topics
triple-negative breast cancer
replication stress
RNase H2
- Grants
- 2 known grants, through Jun 2027
What they work on
- Test whether scarce DNA building blocks (dNTPs) cause RNA to be misinserted into TNBC genomes, and whether blocking RNase H2 leaves these errors in place, causing lethal replication stress. Also identify how tumors resist the inhibitor.
- Determine the tolerability and maximum tolerated dose of the RNase H2 inhibitor R14 in mice, then test its efficacy in 10 patient-derived xenograft models (human tumors grown in mice) spanning 5 TNBC subtypes.
- Evaluate R14 combined with anti-PD-1 immunotherapy in 5 syngeneic mouse TNBC models, which have intact immune systems, and assess how the treatment changes immune cells in the tumor.
- Map how replication stress response defects remodel the immune environment of TNBC using imaging mass cytometry, a method that measures many proteins at once in tissue, and manipulate this defect status to test links to immunotherapy response.
- Test whether single-stranded DNA in the cytoplasm drives checkpoint blockade response in TNBC models, and use an in vivo CRISPR screen to find which gene changes in the RSRD signature cause the response.
- Screen 6 candidate drugs for the ability to convert RSRD-low TNBC into RSRD-high tumors that respond to immune checkpoint blockade, and identify the best combination partner.
More about the research
This leaves them under heavy replication stress: their DNA-copying machinery keeps running into obstacles. Both projects ask how TNBC cells survive this stress, and how that weak point could be used to kill tumors or make them respond to immunotherapy.
Why it matters
Patients with triple-negative breast cancer lack targeted treatments, and many do not respond to chemotherapy or immunotherapy. This work could yield RNase H2 inhibitors such as R14 as a new treatment option, alone or with anti-PD-1 drugs. It could also deliver a biomarker that identifies which patients are likely to benefit from checkpoint immunotherapy, plus drug combinations that may widen the group of patients who respond.
Known grants
From NIH and NSF research grants. Labs often have other funding we can't see.
Closest labs
Yaguang Xi
University of Georgia, GA·Pharmacology
Determine how the oncogenic microRNA miR-10b and its target gene NR4A3 contribute to the experimental compound LG007's activity against triple-negative breast cancer.
Rebecca Aft
Washington University in St Louis, MO·Medicine & Clinical Research
Evaluate whether an 8-gene bone marrow test for disseminated tumor cells predicts distant metastasis in TNBC patients treated with carboplatin, paclitaxel and nivolumab, with or without cabiralizumab, in a phase II trial.
Ramesh Ganju
Ohio State University, OH·Microbiology & Immunology
Determine how S100A7 signaling controls genes that respond to interferon-gamma, especially PD-L1 and Fas, in African American TNBC cells and in engineered mice that overproduce mouse S100a7.
The school
University of Texas MD Anderson Cancer Center: 23 labs on PI Pages, $1.4B a year on research.
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