My lab studies the molecular mechanisms of action and resistance to standard and novel therapeutics for the treatment of malignancy; primarily lung and breast cancer. Our translational studies have contributed to the development of novel tubulin ligands, conceptualizing combinatorial therapies that target molecular dependencies in cancer, and investigating drug tolerance that manifests as senescence.

AS A SENESCENCE-CENTRIC LAB, OUR BROAD GOAL IS TO UNDERSTAND AND EXPLOIT THE SENESCENCE THAT OCCURS IN RESPONSE TO CANCER THERAPY

Our interests in senescence date back to studies with the tubulin ligand discodermolide (DDM) and the discovery that it is a potent inducer of senescence. We were one of the first groups to propose that therapy-induced senescence (TIS) is an underappreciated mechanism of drug resistance and tumor dormancy. Using drug-resistant cancer cells that escaped TIS, we challenged the dogma that senescence was a ‘permanent state,’ at least in cancer. Subsequent and ongoing studies indicate that senescent cells emerge from dormancy with aggressive biological phenotypes, culminating in metastasis.

Emerging data from our lab indicate that the proteomic signature of TIS reflects patterns of genomic instability, selected for via senescence.  We hypothesize that these genomic alterations confer molecular vulnerabilities that can be therapeutically targeted.

Active laboratory projects include:

(i) detecting and quantifying TIS in human malignancy to compute a senescence burden metric that can be used to inform future therapy (biomarker development)

(ii) investigating senescence-mediated genomic alterations/enrichments and their impact on cancer etiology (cancer etiology)

and pre-clinical pharmacology directed at:

(iii) defining molecular dependencies of senescent cells for therapeutic eradication (senolytics), and

(iv) improving the pharmacologic efficacy of tubulin ligands to attenuate TIS (chemical-biology) in collaboration with Dr. Amos B. Smith III (UPenn). 

Chao SK, Lin J, Brouwer-Visser J, Smith AB 3rd, Horwitz SB, McDaid HM (2010). Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1-dependent. Proc Natl Acad Sci U S A.;108(1):391-6. PMCID: PMC3017154

Samaraweera L, Adomako A, Rodriguez-Gabin A and McDaid HM. (2017) A Novel Indication for Panobinostat as a Senolytic in NSCLC and HNSCC. Sci Rep;7(1):1900. PMID: 28507307

Prota AE, Bargsten K, Redondo M, Smith III AB, Yang C-PH, McDaid HM, Paterson I, Horwitz SB, Díaz JF and Steinmetz MO (2017). Structural Basis of Microtubule Stabilization by Discodermolide. Chembiochem. Chembiochem. 18(10):905-909. PMID: 28207984

Krausz AE, Adler BL, Makdisi J, Schairer D, Rosen J, Landriscina A, Navati M, Alfieri A, Friedman JM, Nosanchuk JD, Rodriguez-Gabin A, Ye KQ, McDaid HM*, Friedman AJ* (2018). Nanoparticle-Encapsulated Doxorubicin Demonstrates Superior Tumor Cell Kill in Triple Negative Breast Cancer Subtypes Intrinsically Resistant to Doxorubicin. Precis Nanomed. 1(3):173-182. *senior

Mathew D, Wang Y, VanArsdale A, Horwitz SB and McDaid HM (2018). Expression of βV-tubulin in secretory cells of the fallopian tube epithelium as a biomarker for cellular atypia. Int J Gynecol Cancer Feb 28(2):363-370. PMID: 29298171.

Nadaradjane C, Yang CH, Rodriguez-Gabin A, Ye K, Sugasawa K, Atasoylu O, Smith AB 3rd, Horwitz SB, McDaid HM (2018). Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners. Journal of natural products; 81(3):607-615. PMID:29522336

Guo B, Rodriguez-Gabin A, Zhang N, Ye K, Atsaoylu O, Horwitz SB, Smith AB III, and McDaid HM (2020). Structural Refinement of the Tubulin Ligand Discodermolide to Attenuate Chemotherapy-Mediated Senescence. Molecular Pharmacology, 98 (2) 156-167.

Yang CH, Horwitz SB and McDaid HM (2022). Utilization of Photoaffinity Labeling to Investigate Binding of Microtubule Stabilizing Agents to P-glycoprotein and -Tubulin. Journal of natural products. Nat Prod. 2022 Mar 25;85(3):720-728. PMID: 35240035