title: Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer.
abstract: Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial.
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts. cespelin@merrimack.com.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Espelin
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Leonard
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Geretti
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.affiliation: Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
authors.forename: Bart S
authors.initials: BS
authors.lastname: Hendriks
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004357:Drug Synergism; D005260:Female; D006801:Humans; D011092:Polyethylene Glycols / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000068878:Trastuzumab / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D011092:Polyethylene Glycols; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D016159:Tumor Suppressor Protein p53; C506643:liposomal doxorubicin; C508053:ERBB2 protein, human