Abstract P6-17-05: A corrole nanobiologic crosses the blood-brain-barrier and recognizes triple negative breast cancer: Implications for targeting brain metastases

Patients with breast cancer metastases to the brain on average survive less than one year. These tumors tend to be resistant to current therapies, and the majority of targeted therapeutics are unable to breach the blood brain barrier (BBB) to reach these tumors, thus improved alternatives are urgently needed. Elevated cell surface levels of the human epidermal growth factor receptor subunit 3 (HER3) is associated with metastatic breast tumors, including those that spread to the brain. Elevated HER3 is also associated with resistance to a number of targeted therapies currently used in the clinic, including inhibitors of EGFR (lapatinib), HER2 (lapatinib, trastuzumab, T-DM1), HER2-3 (pertuzumab), and combination therapy. Whereas a number of targeted therapies are currently used to combat peripheral breast tumors, the delivery of these molecules to brain metastases is limited by the blood brain barrier (BBB). This is exemplified by HER2+ breast tumors that metastasize to the brain: these tumors, while targetable outside of the central nervous system (CNS) by HER2 antibodies such as trastuzumab, are unreachable by these same antibodies because the HER2 subunit, though present on the brain endothelium, does not mediate antibody transcytosis across the blood vessel wall. HER3, on the other hand, undergoes rapid transcytosis across the brain endothelium upon ligand binding, which normally occurs to mediate the delivery of neuregulin growth factors for neural growth and maintenance. We have developed a self-assembling nanobiological particle, HerMn, which uses HER3 as a portal for targeted entry of toxic molecules into tumor cells. HerMn is a 10-20 nm diameter serum-stable particle comprised of a HER3-targeted cell penetration protein non-covalently assembled with a sulfonated manganese(III) corrole (S2Mn or Mn-corrole). Tumor-targeted toxicity by HerMn occurs by mitochondria membrane disruption and superoxide-mediated damage to the cytoskeleton. HerMn can also elicit tumor-selective detection by magnetic resonance imaging (MRI) due to the paramagnetic property of the corrole. HerMn distributes to the brain after systemic injection in mice, in addition to showing preferential homing and toxicity to subcutaneous tumors expressing the HER2-3 dimer. Interestingly, the Mn corrole is known to exhibit neuroprotective effects due to its antioxidant activity on normal tissue. Consistent with this, we have found that HerMn supports human cardiac cell survival ex vivo. Our studies interrogating the therapeutic potential of HerMn suggest that this nanobiologic bears the capacity for targeting toxicity to brain-metastatic breast tumors while sparing off-target tissue due to both its targeting capacity and ability to provide beneficial protective effects to normal tissue such as the brain and heart. Citation Format: Medina-Kauwe L, Sims J, Taguiam M, Hanson C, Alonso-Valenteen F, Cui X, Wagner S, Sorasaenee K, Moats R, Marban E, Chung A, Gray H, Gross Z, Giuliano A. A corrole nanobiologic crosses the blood-brain-barrier and recognizes triple negative breast cancer: Implications for targeting brain metastases. [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 P6-17-05.