NU 2023-110

INVENTORS

• Huiping Liu*
• Nurmaa Dashzeveg

SHORT DESCRIPTION

This technology introduces methods of use for an anti-PODXL antibody that effectively prevents and treats metastasis in breast cancer by inhibiting circulating tumor cell (CTC) cluster formation.

BACKGROUND

Cancer metastasis is mediated by circulating tumor cells (CTC) and accounts for 90% of cancer deaths. CTCs are predominantly found as single cells in the bloodstream, but a subset form multicellular clusters with significantly higher metastatic potential. These clusters can evade chemotherapy and contribute to cancer progression. Current treatments struggle to target these clusters effectively, posing a challenge in managing metastatic breast cancer.

ABSTRACT

New research from Northwestern shows that chemo-evasive CTC clusters are relatively quiescent with a specific loss of ST6GAL1-catalyzed α2,6-sialylation in glycoproteins. Recently identified protein substrates of ST6GAL1, such as adhesion and stemness marker, PODXL, contributes to CTC clustering (aggregation) and metastatic seeding. Inhibition or neutralization of PODXL disrupts cluster formation, thereby reducing metastatic spread. In preclinical models, administration of an antibody against PODXL significantly curtailed metastatic seeding, showcasing the potential of a PODXL antibody as a therapeutic strategy in combination with other treatments.

APPLICATIONS

• Metastasis Prevention:
  • Anti-PODXL prevents and treats cancer metastasis.
• Chemotherapy-Induced Metastasis:
  • Anti-PODXL prevents and treats chemotherapy-induced metastasis.
• Combination therapy:
  • Anti-PODXL treats metastasis alongside other anti-cancer or immunotherapy agents.

ADVANTAGES

• Targeted Action:
  • Anti-PODXL specifically targets tumor cell surface proteins with predicted minimal off-target effects.
• Reduced Metastatic Potential:
  • Inhibits hyposialylation-associated metastasis post-chemotherapy.
• Minimal Toxicities:
  • Potential for lower toxicity in comparison to other metastatic treatments.

PUBLICATIONS

• Dashzeveg, Liu et al, "Dynamic Glycoprotein Hyposialylation Promotes Chemotherapy Evasion and Metastatic Seeding of Quiescent Circulating Tumor Cell Clusters in Breast Cancer," Cancer Discovery, September 06, 2023.

IP STATUS

• US Patent Pending

J, Experimental design of cotreatment of mice bearing orthotropic (OI) PDX-M1 tumors. First, ST6KO M1-PDX cells were injected into a mammary fat pad. Mice were cotreated with PAX-NAB (13.5 mg/kg) or PBS and αP or IgG control (20 μg/mouse) once every 3 days. After 11 times treatments, mice were sacrificed for further analysis. M, Lung bioluminescence imaging with normalized quantification of lung total flux with tumor weight. N, Count of CTC clusters.