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

JOURNAL OF CONTROLLED RELEASE

卷:271

Article

Sims, Jessica D.¹  Taguiam, Jan Michael¹  Alonso-Valenteen, Felix¹  Markman, Janet¹  Agadjanian, Hasmik¹  Chu, David¹  Lubow, Jay¹  Abrol, Ravinder¹  Srinivas, Dustin¹  Jain, Anjali¹  Han, Bingchen¹  Qu, Ying¹  Mirzadehgan, Parisa¹  Hwang, Jae-Youn¹  Rentsendorj, Altan¹  Chung, Alice¹  Lester, Jenny¹  Karlan, Beth Y.¹  Gray, Harry B.²  Gross, Zeev³  Giuliano, Armando¹  Cui, Xiaojiang¹  Medina-Kauwe, Lali K.^1,4 

[1] Cedars Sinai Med Ctr, 8700 Beverly Blvd, Los Angeles, CA 90048 USA

[2] CALTECH, Pasadena, CA USA

[3] Technion Israel Inst, Haifa, Israel

[4] Univ Calif Los Angeles, Los Angeles, CA USA

关键词: HER3;    Neuregulin;    Target;    Tumor;    Therapeutic;    Nanobiologic;    Resistance;   

DOI  :  10.1016/j.jconrel.2017.12.024

来源: Elsevier

【 摘 要 】

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 naive 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.

【 授权许可】

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