The Fan Laboratory

Research Focus

My laboratory has two main research directions.

Dissect the mechanism of transcription-associated DNA repair within chromatin and evaluate the potential of targeting this repair pathway for advancing cancer therapy.

Oxidative stress is a mechanism underlying cancer development. Our recent studies demonstrate that the Cockayne syndrome protein B (CSB) chromatin remodeler couples Poly(ADP-ribose) polymerase 1 (PARP1)-dependent oxidative DNA damage repair to transcription, granting preferential access of single-strand breaks in transcribed regions, a process we term transcription-associated single-strand break repair (TA-SSBR). PARP1 is a valuable target in cancer therapy, as PARP inhibitors (PARPis) induce synthetic lethality in tumor cells defective for homologous recombination repair, such as BRCA1/2-mutated cancer. While PARPis show promise in progression-free survival, challenges remain as patients eventually develop resistance to PARPis. Moreover, one PARPi was FDA approved for use in ovarian cancer therapy irrespective of BRCA gene status, albeit with marginal effect. Therefore, methods to enhance PARPi efficacy will be of great value to cancer therapy, regardless of the homologous recombination repair status. We believe that TA-SSBR will be clinically relevant, but the mechanistic details are yet undefined. My lab is characterizing this novel DNA repair mechanism and determining if manipulation of TA-SSBR through CSB activity inhibition can be used as a novel approach to enhance the efficacy of PARPi-based therapy.

Improve cancer therapy by targeting the oncogenic NOTCH pathway.

The Notch pathway regulates cell proliferation, survival, apoptosis, and numerous developmental decisions.  Accordingly, aberrant Notch activation underlies tumor initiation, progression and chemoresistance of a variety of cancer types. The Notch pathway has, therefore, been a valuable target for cancer therapy; however, on-target toxicity and off-target effects have limited the use of current Notch inhibitors in the clinic. Using a quantitative, flow-cytometry-based screen with purified components we identified the FDA-approved drug auranofin as a novel and potent Notch pathway inhibitor. Auranofin blocks transcriptional activation of Notch target genes by inhibiting the binding of the sole transcriptional effector, RBPJ, to DNA. The wealth of pharmacological and clinical data that already exists indicates that auranofin will overcome the limitations associated with current Notch inhibition strategies. Using preclinical cell line-based mouse models, we have already found that auranofin synergizes with cisplatin, a standard chemotherapeutic agent, in killing ovarian and endometrial cancers with high Notch activity. We are now using patient-derived xenograft mouse models as well as patient-derived organoids to further test the efficacy of auranofin monotreatment and cisplatin cotreatment. The impact of our work will be significant as auranofin is FDA approved and can immediately advance to the clinic.

See Full List of Published Work