Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies Volume 1

Novel Sensitizing Agents for Therapeutic Anti-EGFR Antibodies presents a description of the sensitizers used to overcome resistance to anti-EGFR targeted antibody therapies in cancer, including novel engineered antibody drugs and other sensitizers. The book gives insights into the landscape of anti-EGFR based cancer treatments, the challenges of targeted therapy, and a glimpse into the future of antibody therapy. It offers pertinent science information on strategies used for the rational design and discovery of novel sensitizing agents, and in addition, translational studies involving pre-clinical and clinical design. This book is an indispensable resource for cancer researchers, medicinal chemists and other biomedical scientists.

Finally, the book covers basic science strategies used in drug discovery and preclinical evaluation focused on EGFR blockage resistance, as well as clinical trial methodology, including clinical pharmacokinetics and imaging to address issues of efficacy evaluation of the new anticancer sensitizers for anti-EGFR drug resistance.

1. Introduction: Overview of anti-EGFR antibody therapy in cancer 2. Molecular Mechanisms of Resistance to therapeutic antibodies to the Epidermal Growth Factor Receptor

Part I: 1?ERBB inhibitors as sensitizers for anti-EGFR antibodies 3. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations 4. Sym004 Anti-EGFR Antibody Mixture overcomes resistance to anti-EGFR antibodies in Metastatic Colorectal Cancer 5. HER3 Targeting with MM-121 Sensitizes HNSCC to Cetuximab by Reducing HER3 Activity and HER2/HER3 Dimerization 6. Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes resistance to anti-EGFR antibodies. 7. Pan-HER targeting with Four-in-one antibodies disrupting the HER/MET crosstalk 8. Overcoming acquired resistance to cetuximab by combined EGFR and HER3 neutralizing monoclonal antibodies 9. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors 10. Inhibition of ERBB2 signaling overcome resistance to the EGFR-directed therapeutic antibody cetuximab 11. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR models

Part II: Alternative receptor tyrosine kinase inhibitors as sensitizers for anti-EGFR antibodies 12. BET Inhibition Overcomes Receptor Tyrosine Kinase-Mediated Cetuximab Resistance in HNSCC 13. Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Patients with Metastatic Colorectal Cancer 14. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors 15. Use MET kinase inhibitor to overcome cetuximab resistance in CRC 16. EGFR- and VEGF(R)-targeted small molecules show synergistic activity in colorectal cancer models refractory to combinations of monoclonal antibodies 17. Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to anti epidermal growth factor receptor therapy

Part III: Downstream kinase inhibitors as sensitizers for anti-EGFR antibodies 18. Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in colon cancer 19. Primary and acquired resistance of colorectal cancer cells to anti-EGFR antibodies converge on MEK/ERK pathway activation and can be overcome by combined MEK/EGFR inhibition 20. MEK1/2 inhibitors may be potential therapies for colorectal cancer that is resistant to EGFR monoclonal antibody therapy 21. EGFR/JIP-4/JNK2 signaling attenuates cetuximab-mediated radiosensitization of squamous cell carcinoma cells 22. Efficient blockade of Akt signaling is a determinant factor to overcome resistance to matuzumab.

Part IV: Other sensitizers for anti-EGFR antibodies 23. Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab 24. Targeting of PYK2 Synergizes with EGFR Antagonists in Basal-like TNBC and Circumvents HER3-Associated Resistance via the NEDD4-NDRG1 Axis 25. Targeting EGFR/Notch to overcome resistance to anti-EGFR antibodies 26. Hedgehog signaling alters reliance on EGF receptor signaling and mediates anti-EGFR therapeutic resistance in head and neck cancer 27. Novel toll-like receptor 9 agonist induces epidermal growth factor receptor (EGFR) inhibition and synergistic antitumor activity with EGFR inhibitors 28. Rationale for combination of therapeutic antibodies targeting tumor cells and immune checkpoint receptors

Dr. Shi Hu received an MD and a PhD in tumor immunology from Second Military Medical University, Shanghai, China. Since 2015, Dr. Hu leads a research laboratory in the Department of Biophysics, at second military medical university with a faculty position. His laboratory is interested in synthetic immunology based cancer therapeutics and antibody engineering, primarily development of novel sensitizers for antibody-based therapies (e.g., Anti-ERBB antibodies). Dr. Hu's research is currently supported by the National Natural Science Foundation of China.