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Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody–liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer. Mol Cancer Ther; 14(9); 2060–71. ©2015 AACR.

Heregulin-driven ERBB3 signaling has been implicated as a mechanism of resistance to cytotoxic and antiendocrine therapies in preclinical breast cancer models. In this study, we evaluated the effects of seribantumab (MM-121), a heregulin-blocking anti-ERBB3 monoclonal antibody, alone and in combination with the aromatase inhibitor letrozole, on cell signaling and tumor growth in a preclinical model of postmenopausal estrogen receptor–positive (ER+) breast cancer. In vitro, heregulin treatment induced estrogen receptor phosphorylation in MCF-7Ca cells, and long-term letrozole-treated (LTLT-Ca) cells had increased expression and activation levels of EGFR, HER2, and ERBB3. Treatment with seribantumab, but not letrozole, inhibited basal and heregulin-mediated ERBB receptor phosphorylation and downstream effector activation in letrozole-sensitive (MCF-7Ca) and -refractory (LTLT-Ca) cells. Notably, in MCF-7Ca–derived xenograft tumors, cotreatment with seribantumab and letrozole had increased antitumor activity compared with letrozole alone, which was accompanied by downregulated PI3K/MTOR signaling both prior to and after the development of resistance to letrozole. Moreover, the addition of an MTOR inhibitor to this treatment regimen did not improve antitumor activity and was not well tolerated. Our results demonstrate that heregulin-driven ERBB3 signaling mediates resistance to letrozole in a preclinical model of ER+ breast cancer, suggesting that heregulin-expressing ER+ breast cancer patients may benefit from the addition of seribantumab to antiendocrine therapy. Mol Cancer Ther; 14(11); 2642–52. ©2015 AACR.

Background: The benefit of EGFR tyrosine kinase inhibitors (TKIs) is largely restricted to EGFR mutation-positive cancers and resistance invariably develops. A central theme of acquired resistance is persistent ErbB3 signaling, resulting in activation of the PI3K/AKT survival pathway. MM-121 is a fully human IgG1 monoclonal antibody (mAb) to ErbB3 with pre-clinical activity as a single agent and in combination with erlotinib in NSCLC, particularly in cancers with ligand-dependent activation of EGFR. This phase 1 study evaluated the safety and tolerability of MM-121 and erlotinib in NSCLC, as well as PK, immunogenicity, efficacy endpoints and exploratory biomarker evaluation. Methods: Patients with advanced NSCLC, good performance status and adequate organ function were enrolled. Patients were EGFR TKI-naïve, unless they were EGFR mutant, in which case acquired resistance was allowed. MM-121 was administered weekly and erlotinib was administered daily. Seven cohorts were enrolled, evaluating varying dose levels of the combination, as well as alternate MM-121 infusion schedules. Dose levels were determined by safety and pharmacokinetic (PK) data. Results: Between February 2010 and July 2011, 33 patients were enrolled. Median age was 64 years and there were 19 (57.5%) women. Twenty-four patients were erlotinib-naïve and 1 patient was an EGFR mutant. The most frequent adverse events were rash, diarrhea, nausea and fatigue. As of 31 July 2001, 16 patients remain on study. Full results will be presented at the meeting. Conclusions: In this phase 1 dose escalation study, MM-121 plus erlotinib was well tolerated by the majority of patients. A phase 2 study is planned. Reference: NCT00994123 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C27.

MM-398 (aka PEP02) is a stable, nanotherapeutic encapsulation of the pro-drug CPT-11 (irinotecan) that is currently in clinical development. In preclinical experiments, treatment with MM-398 resulted in significantly higher intratumoral concentrations of both irinotecan (142-fold) and its major metabolite, SN-38 (9-fold) and exhibited superior anti-tumor activity compared to free irinotecan in multiple tumor xenografts. Subsequently, multiple phase 1 and 2 studies have established a pharmacokinetic and safety profile that supports continued clinical development, including in pancreatic, gastric, colorectal and potentially other cancers. Because current evidence suggests that resistance to pancreatic cancer is driven largely by inadequate drug penetration into these often poorly vascularized, stromally dense and hypoxic tumors, we sought to better understand how this relatively large (100nm) liposomal nanotherapeutic could potentially result in increased efficacy in very advanced gemcitabine-resistant pancreatic cancer and other cancer types. We developed a mechanism-based PK model of MM-398 and free irinotecan designed to predict intratumor SN-38 levels. Sensitivity analysis revealed that for MM-398 local activation of irinotecan to SN-38 was a far more important parameter than systemic activation. Through cellular uptake studies, we demonstrated in vitro that MM-398 was preferentially internalized by phagocytic macrophage/monocyte cell lines and, to a far lesser extent, by tumor cell lines. Furthermore, tumor microdistribution studies by flow cytometry and IHC showed uptake of MM-398 liposomes in both tumor cells and tumor-associated macrophages with more liposomal material being present in the macrophages. This distribution also suggests that macrophages may contribute to the postulated rate limiting process of irinotecan activation. The sensitivity analysis also suggested that tumor permeability and vascularization are important determinants of tumor-associated SN-38 levels for both free irinotecan and MM-398. To determine the effect of MM-398 on these parameters we treated mice bearing HT29 (colorectal cancer) xenografts with a single dose of MM-398 and measured hypoxic markers (CAIX) and microvessel density (CD31) by IHC. Tumors treated with MM-398 showed a greater degree of CD31 staining and lower CAIX staining, indicating that MM-398 may be able to affect tumor characteristics that traditionally have contributed to therapy resistance and limited the delivery of cancer therapeutics and resistance. In summary, encapsulation of irinotecan alters rate-limiting processes that determine tumoral SN-38 levels. Delivery of MM-398 is believed to alter tumor microvessel density and decrease hypoxia. These intriguing mechanisms of action findings support the continued clinical development of MM-398 as a differentiated therapeutic for several cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C207.