Shapiro Lab
Principal Investigator: Geoffrey I. Shapiro
Institution: Dana-Farber Cancer Institute (Boston, MA)
Primary Subfield: Genetics/Genomics
Recruitment Status: ✅ Hiring Postdocs
Research Focus
PROJECT SUMMARY/ABSTRACT Homologous recombination (HR) repair-deficient cancers are dependent on polymerase theta (POLq)-mediated DNA end joining, so that POLq is a candidate target for these cancers. This reliance extends to the PARP inhibitor-resistant state, where POLq limits excessive DNA end resection and RAD51 loading, preventing the accumulation of toxic intermediates. POLq deficiency has also been linked to micronucleation, a process associated with activation of innate immunity. Through high-throughput small molecule screens, we have recently identified the antibiotic novobiocin (NVB) as a specific POLq inhibitor that selectively kills HR-deficient cells in vitro and in vivo, including those with acquired PARP inhibitor resistance, suggesting that NVB may be useful alone or in combination with PARP inhibition in treating cancers with HR alterations. NVB also induces micronucleation and consequent cGAS/STING pathway activation in HR-deficient cells. In the first Specific Aim, multiple cell line and patient-derived xenograft models of BRCA-mutant breast, ovarian and pancreatic cancer, including those that are PARP inhibitor-sensitive and those with acquired PARP inhibitor re…
Active NIH Awards
- 5P01CA269021-03: Pathology Core (2026)
- 5P50CA168504-12: Project 4: Combined targeting of DNA repair and macrophage-mediated immunosuppression in BRCA1/2-associated breast cancer (2026)
- 5P30CA006516-61: Program 12: Developmental Therapeutics (2026)
- 3UM1CA186709-09S2: Extension of the Dana Farber Harvard Cancer Center Consortium for the ETCTN (2026)
- 4R01CA272982-04: Novobiocin-mediated polymerase theta inhibition in homologous recombination repair-deficient cancers (2025)
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