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Targeting ADAM17 inhibits human colorectal adenocarcinoma progression and tumor-initiating cell frequency
Joseph Dosch1, Elizabeth Ziemke1, Shanshan Wan2
1Department of Radiology, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) has emerged as a potential therapeutic target in colorectal cancer (CRC) and other cancers, due in part to its role in regulating various tumor cell surface proteins and growth factors and cytokines in the tumor microenvironment. The emergence of MEDI3622, a highly potent and specific antibody-based ADAM17 inhibitor, has allowed testing of the concept that targeting ADAM17 may be an important new therapeutic approach for CRC patients. We demonstrate that MEDI3622 is highly efficacious on tumor growth in multiple human CRC PDX models, resulting in improved survival of animals bearing tumor xenografts. MEDI3622 was further found to impact Notch pathway activity and tumor-initiating cells. The promising preclinical activity seen here supports further clinical investigation of this treatment approach to improve therapeutic outcome for patients diagnosed with metastatic CRC, including patients with KRAS-mutant tumors for whom other therapeutic options are currently limited.
Insights
A new antibody, MEDI3622, effectively targets ADAM17 (a disintegrin and metalloproteinase 17) to inhibit colorectal cancer (CRC) growth and improve survival in preclinical models. This approach shows promise for treating metastatic CRC, including KRAS-mutant tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- ADAM17 (a disintegrin and metalloproteinase 17)/TACE (TNFα converting enzyme) is implicated in cancer progression by regulating tumor microenvironment factors.
- Targeting ADAM17 presents a potential therapeutic strategy for various cancers, including colorectal cancer (CRC).
Purpose of the Study:
- To evaluate the efficacy of MEDI3622, a novel antibody-based ADAM17 inhibitor, as a therapeutic approach for colorectal cancer.
- To assess the impact of MEDI3622 on tumor growth, survival, and key cellular pathways in preclinical CRC models.
Main Methods:
- Testing MEDI3622 in multiple human colorectal cancer patient-derived xenograft (PDX) models.
- Assessing tumor growth, animal survival, Notch pathway activity, and tumor-initiating cell populations.
Main Results:
- MEDI3622 demonstrated significant efficacy in reducing tumor growth across various CRC PDX models.
- Treatment with MEDI3622 led to improved survival rates in animals with tumor xenografts.
- MEDI3622 was observed to modulate Notch pathway activity and affect tumor-initiating cells.
Conclusions:
- The potent and specific ADAM17 inhibitor MEDI3622 shows promising preclinical efficacy for colorectal cancer treatment.
- These findings support further clinical investigation of MEDI3622 for metastatic CRC, particularly for patients with limited therapeutic options like KRAS-mutant tumors.