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

Sims, Jessica D. and Taguiam, Jan Michael and Alonso-Valenteen, Felix and Markman, Janet and Agadjanian, Hasmik and Chu, David and Lubow, Jay and Abrol, Ravinder and Srinivas, Dustin and Jain, Anjali and Han, Bingchen and Qu, Ying and Mirzadehgan, Parisa and Hwang, Jae-Youn and Rentsendorj, Altan and Chung, Alice and Lester, Jenny and Karlan, Beth Y. and Gray, Harry B. and Gross, Zeev and Giuliano, Armando and Cui, Xiaojiang and Medina-Kauwe, Lali K. (2018) Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics. Journal of Controlled Release, 271 . pp. 127-138. ISSN 0168-3659. http://resolver.caltech.edu/CaltechAUTHORS:20180108-103844165

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.jconrel.2017.12.024DOIArticle
http://www.sciencedirect.com/science/article/pii/S0168365917310945PublisherArticle
ORCID:
AuthorORCID
Abrol, Ravinder0000-0001-7333-6793
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.
Funders:
Funding AgencyGrant Number
NIHR01 CA129822
NIHR01 CA140995
Department of DefenseW81XWH-15-1-0604
Avon Foundation02–2015-060
Margie and Robert E. Petersen FoundationUNSPECIFIED
Clinical and Translational Science InstituteCTSI V087
Eos BiosciencesUNSPECIFIED
Subject Keywords:HER3; Neuregulin; Target; Tumor; Therapeutic; Nanobiologic; Resistance
Record Number:CaltechAUTHORS:20180108-103844165
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180108-103844165
Official Citation:Jessica D. Sims, Jan Michael Taguiam, Felix Alonso-Valenteen, Janet Markman, Hasmik Agadjanian, David Chu, Jay Lubow, Ravinder Abrol, Dustin Srinivas, Anjali Jain, Bingchen Han, Ying Qu, Parisa Mirzadehgan, Jae-Youn Hwang, Altan Rentsendorj, Alice Chung, Jenny Lester, Beth Y. Karlan, Harry B. Gray, Zeev Gross, Armando Giuliano, Xiaojiang Cui, Lali K. Medina-Kauwe, Resistance to receptor-blocking therapies primes tumors as targets for HER3-homing nanobiologics, Journal of Controlled Release, Volume 271, 10 February 2018, Pages 127-138, ISSN 0168-3659, https://doi.org/10.1016/j.jconrel.2017.12.024.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84163
Collection:CaltechAUTHORS
Deposited By: Melissa Ray
Deposited On:08 Jan 2018 20:53
Last Modified:08 Jan 2018 20:53

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