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Published February 10, 2018 | Supplemental Material + Published
Journal Article Open

Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics

Abstract

Resistance to anti-tumor therapeutics is an important clinical problem. Tumor-targeted therapies currently used in the clinic are derived from antibodies or small molecules that mitigate growth factor activity. These have improved therapeutic efficacy and safety compared to traditional treatment modalities but resistance arises in the majority of clinical cases. Targeting such resistance could improve tumor abatement and patient survival. A growing number of such tumors are characterized by prominent expression of the human epidermal growth factor receptor 3 (HER3) on the cell surface. This study presents a "Trojan-Horse" approach to combating these tumors by using a receptor-targeted biocarrier that exploits the HER3 cell surface protein as a portal to sneak therapeutics into tumor cells by mimicking an essential ligand. The biocarrier used here combines several functions within a single fusion protein for mediating targeted cell penetration and non-covalent self-assembly with therapeutic cargo, forming HER3-homing nanobiologics. Importantly, we demonstrate here that these nanobiologics are therapeutically effective in several scenarios of resistance to clinically approved targeted inhibitors of the human EGF receptor family. We also show that such inhibitors heighten efficacy of our nanobiologics on naïve tumors by augmenting HER3 expression. This approach takes advantage of a current clinical problem (i.e. resistance to growth factor inhibition) and uses it to make tumors more susceptible to HER3 nanobiologic treatment. Moreover, we demonstrate a novel approach in addressing drug resistance by taking inhibitors against which resistance arises and re-introducing these as adjuvants, sensitizing tumors to the HER3 nanobiologics described here.

Additional Information

© 2018 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). Received 12 August 2017; revised 9 December 2017; accepted 21 December 2017; available online 27 December 2017. The authors thank Josie Bergeron, Catherine Bresee, and Xiao Zhang for assistance with biostatistics; and Accixx Biomedical Consulting (www.Accixx.com) for editorial assistance. LKMK thanks C Rey, A and M Medina-Kauwe, and D Revetto for ongoing support. This work was supported in part by grants to LKMK from the NIH/NCI (R01 CA129822, R01 CA140995), the DoD (W81XWH-15-1-0604), the Avon Foundation (02–2015-060), Margie and Robert E. Petersen Foundation, and the Clinical and Translational Science Institute (CTSI V087). The studies shown in Fig. S1, D-I were supported by Eos Biosciences through a contractual research agreement. Dr. Medina-Kauwe and Cedars-Sinai Medical Center hold significant financial interest in Eos Biosciences, Inc., of which Dr. Medina-Kauwe is co-founder and scientific advisor. A patent describing the H3-D (HerDox) nanobiotherapeutic (US Patent No. 9,078,927) has been awarded, and another describing the application of this particle for treating resistant tumors (No. 62/342,829) has recently been filed.

Attached Files

Published - 1-s2.0-S0168365917310945-main.pdf

Supplemental Material - ec0025.docx

Supplemental Material - ec0030.docx

Supplemental Material - supp-fig-s1.docx

Supplemental Material - supp-fig-s2.docx

Supplemental Material - supp-fig-s3.docx

Supplemental Material - supp-fig-s4.docx

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Additional details

Created:
August 21, 2023
Modified:
October 18, 2023