PhD Public Seminar: SHRADDHA SUBRAMANIAN, MS
When & Where
November 9
1:00 PM - 2:00 PM
UTHealth Houston, Institute of Molecular Medicine, IMM Auditorium, SRB 104 and via Zoom (View in Google Map)
Contact
- Joy A. Lademora
- 713-500-5072
- [email protected]
Event Description
Co-Targeting MET and LGR5 with Antibody-Drug Conjugates to Combat Therapy Resistance in Colorectal Cancer
Shraddha Subramanian, MS (Advisor: Kendra S. Carmon, PhD)
Colorectal cancer (CRC) is a lethal malignancy, with relapse often mediated by drug resistance, necessitating improved therapies to prevent recurrence. Antibody-drug conjugates (ADCs) exhibit enhanced efficacy by combining antibody specificity with cytotoxic payloads while minimizing systemic toxicity. We previously developed ADCs targeting Leucine-rich repeat-containing G protein-coupled Receptor 5 (LGR5), a cancer stem-like cell marker frequently upregulated in CRC. LGR5-targeting ADCs incorporating different payloads demonstrated tumor inhibition initially, yet tumors eventually recur in part due to antigen downregulation. In this study, we demonstrate that treatment with chemotherapies or topoisomerase I inhibitor-conjugated LGR5-targeting ADC (8E11-CPT2) reduces LGR5 levels and drives increased MET receptor expression and/or activation in CRC cells, supporting the rationale to co-target LGR5 and MET simultaneously. Consequently, we engineered a MET-targeting ADC (ABT-700–SG3199) via site-specific conjugation of the anti-MET antibody telisotuzumab with the DNA-crosslinking pyrrolobenzodiazepine (PBD) dimer SG3199. ABT-700–SG3199 exhibited improved potency in CRC models compared to clinical-stage anti-MET ADCs ABBV-399 and ABBV-400. ABT-700–SG3199 also demonstrated robust anti-tumor activity and favorable tolerability. ABT-700–SG3199 monotherapy increased LGR5 levels, suggesting reciprocal regulation of LGR5 and MET. Combining ABT-700–SG3199 and 8E11-CPT2 enhanced CRC cell-killing efficacy. In patient-derived xenografts, treatment with the ADC combination markedly delayed tumor relapse and enhanced survival relative to ADC monotherapy. Collectively, these findings delineate a novel feedback mechanism underlying therapy resistance and supports MET/LGR5 ADC-based combination therapies as a strategy to overcome resistance and more effectively treat CRC.
Advisory Committee:
- Kendra S. Carmon, PhD, Chair
- Ali Azhdarinia, PhD
- Sunil Krishnan, MD
- Vihang Narkar, PhD
- Eduardo Vilar-Sanchez, MD, PhD
Join via Zoom (Please contact Ms. Subramanian for her Zoom meeting info)
Co-Targeting MET and LGR5 with Antibody-Drug Conjugates to Combat Therapy Resistance in Colorectal Cancer
Shraddha Subramanian, MS (Advisor: Kendra S. Carmon, PhD)
Colorectal cancer (CRC) is a lethal malignancy, with relapse often mediated by drug resistance, necessitating improved therapies to prevent recurrence. Antibody-drug conjugates (ADCs) exhibit enhanced efficacy by combining antibody specificity with cytotoxic payloads while minimizing systemic toxicity. We previously developed ADCs targeting Leucine-rich repeat-containing G protein-coupled Receptor 5 (LGR5), a cancer stem-like cell marker frequently upregulated in CRC. LGR5-targeting ADCs incorporating different payloads demonstrated tumor inhibition initially, yet tumors eventually recur in part due to antigen downregulation. In this study, we demonstrate that treatment with chemotherapies or topoisomerase I inhibitor-conjugated LGR5-targeting ADC (8E11-CPT2) reduces LGR5 levels and drives increased MET receptor expression and/or activation in CRC cells, supporting the rationale to co-target LGR5 and MET simultaneously. Consequently, we engineered a MET-targeting ADC (ABT-700–SG3199) via site-specific conjugation of the anti-MET antibody telisotuzumab with the DNA-crosslinking pyrrolobenzodiazepine (PBD) dimer SG3199. ABT-700–SG3199 exhibited improved potency in CRC models compared to clinical-stage anti-MET ADCs ABBV-399 and ABBV-400. ABT-700–SG3199 also demonstrated robust anti-tumor activity and favorable tolerability. ABT-700–SG3199 monotherapy increased LGR5 levels, suggesting reciprocal regulation of LGR5 and MET. Combining ABT-700–SG3199 and 8E11-CPT2 enhanced CRC cell-killing efficacy. In patient-derived xenografts, treatment with the ADC combination markedly delayed tumor relapse and enhanced survival relative to ADC monotherapy. Collectively, these findings delineate a novel feedback mechanism underlying therapy resistance and supports MET/LGR5 ADC-based combination therapies as a strategy to overcome resistance and more effectively treat CRC.
Advisory Committee:
- Kendra S. Carmon, PhD, Chair
- Ali Azhdarinia, PhD
- Sunil Krishnan, MD
- Vihang Narkar, PhD
- Eduardo Vilar-Sanchez, MD, PhD
Join via Zoom (Please contact Ms. Subramanian for her Zoom meeting info)
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