Abstract P6-13-10: Therapeutic efficacy of HER3-targeted nanobiologics on resistant tumors
Authors: Medina-Kauwe L , Sims J , Taguiam M , Hanson C , Alonso-Valenteen F , Cui X , Chung A , Gray H , Gross Z , Giuliano A 
Published: May 2016

Abstract
Elevated cell surface levels of the human epidermal growth factor receptor subunit 3 (HER3) are associated with resistance to a number of signal-blocking breast cancer treatments, including inhibitors of EGF-R (lapatinib), HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Additionally, HER3 elevation has been identified on "untarget-able" tumors such as triple-negative breast cancer (TNBC), including TNBC with acquired resistance to EGF-R inhibition. Patients with such refractory tumors currently have limited treatment options and a poor prognosis. Moreover, as up to 70% of cases resist or acquire resistance to signal-blocking therapies, an alternative approach addressing this important clinical problem has the potential for significant clinical impact.
We have developed a protein construct, HerPBK10, which self-assembles with a variety of payloads (including nucleic acids, chemotherapy agents, and imaging agents) and uses HER3 as a portal for targeted entry into cells. In contrast to receptor-targeted antibodies and tyrosine kinase inhibitors currently used in the clinic, HerPBK10 circumvents the need to modulate signaling by inducing rapid entry of toxic molecules into tumor cells through receptor-mediated endocytosis and membrane penetration.
We have previously shown that nanobiological particles formed between HerPBK10 and therapeutic payloads can elicit targeted toxicity to HER2+ tumors due to the prevalence of HER2-3 heterodimers on the tumor cell surface, while sparing heart and liver tissue. The particles that form (20-40 nm dia.) exhibit stability in serum and no detectable immunogenicity. Here we show that such particles resolve breast tumor cells with acquired resistance to HER2 and/or EGFR inhibitors in contrast to trastuzumab, pertuzumab, and combination treatment. Additionally, therapeutic efficacy is augmented on resistant over parental tumor cells, due in part to the elevated HER3 expression associated with resistance to these inhibitors. Our studies in preclinical models show that these nanoparticles ablate the growth of tumors with both acquired and pre-existing resistance to trastuzumab. Moreover, we have found that signal-inhibitors currently used in the clinic, such as trastuzumab, effectively augment the efficacy of our nanobiologic on both naïve and inherently-resistant breast tumor cells, in part through induced elevation of HER3. Thus, current targeted molecules such as trastuzumab or lapatinib may act as adjuvants to enhance tumor cell-sensitivity to HerPBK10-particles. Such an approach may address the tumor-heterogeneity associated with resistance, and corner tumors for attack by our particles.
Citation Format: Medina-Kauwe L, Sims J, Taguiam M, Hanson C, Alonso-Valenteen F, Cui X, Chung A, Gray H, Gross Z, Giuliano A. Therapeutic efficacy of HER3-targeted nanobiologics on resistant tumors. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-13-10.