Breast tumors that express p95HER2 are resistant to trastuzumab and may require alternative or additional anti-HER2-targeting strategies.

Glioma-initiating cells (GICs), also called glioma stem cells, are responsible for tumor initiation, relapse, and therapeutic resistance. Here, we show that TGF-β inhibitors, currently under clinical development, target the GIC compartment in human glioblastoma (GBM) patients. Using patient-derived specimens, we have determined the gene responses to TGF-β inhibition, which include inhibitors of DNA-binding protein (Id)-1 and -3 transcription factors. We have identified a cell population enriched for GICs that expresses high levels of CD44 and Id1 and tend to be located in a perivascular niche. The inhibition of the TGF-β pathway decreases the CD44(high)/Id1(high) GIC population through the repression of Id1 and Id3 levels, therefore inhibiting the capacity of cells to initiate tumors. High CD44 and Id1 levels confer poor prognosis in GBM patients.

Glioma-initiating cells (GICs) are responsible for the initiation and recurrence of gliomas. Here, we identify a molecular mechanism that regulates the self-renewal capacity of patient-derived GICs. We show that TGF-beta and LIF induce the self-renewal capacity and prevent the differentiation of GICs. TGF-beta induces the self-renewal capacity of GICs, but not of normal human neuroprogenitors, through the Smad-dependent induction of LIF and the subsequent activation of the JAK-STAT pathway. The effect of TGF-beta and LIF on GICs promotes oncogenesis in vivo. Some human gliomas express high levels of LIF that correlate with high expression of TGF-beta2 and neuroprogenitor cell markers. Our results show that TGF-beta and LIF have an essential role in the regulation of GICs in human glioblastoma.

The overactivation of the HERs, a family of tyrosine kinase receptors, leads to the development of cancer. Although the canonical view contemplates HER receptors restricted to the secretory and endocytic pathways, full-length HER1, HER2 and HER3 have been detected in the nucleoplasm. Furthermore, limited proteolysis of HER4 generates nuclear C-terminal fragments (CTFs). Using cells expressing a panel of deletion and point mutants, here we show that HER2 CTFs are generated by alternative initiation of translation from methionines located near the transmembrane domain of the full-length molecule. In vitro and in vivo, HER2 CTFs are found in the cytoplasm and nucleus. Expression of HER2 CTFs to levels similar to those found in human tumors induces the growth of breast cancer xenografts in nude mice. Tumors dependent on CTFs are sensitive to inhibitors of the kinase activity but do not respond to therapeutic antibodies against HER2. Thus, the kinase domain seems necessary for the activity of HER2 CTFs and the presence of these HER2 fragments could account for the resistance to treatment with antibodies.

The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the meso form 1(S,R)) and their corresponding tetrahydrochlorides 11 were prepared from (S)- and (R)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC(50) values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower K(B) for AMD3100, with the 1(R,R) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice.

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Leukemia Inhibitory Factor (LIF) is a pleiotropic cytokine, which is highly expressed in a subset of tumors and correlates with poor prognosis. LIF is hypothesized to contribute to tumor microenvironment immunosuppression and regulation of cancer stem cells. MSC-1 is a first-in-class humanized IgG1 monoclonal antibody that potently and selectively inhibits LIF. In pre-clinical models, MSC-1 decreases tumor growth through inhibition of STAT3 signaling, promoting immune stimulatory macrophages and increasing tumor infiltration of CD8 T and NK cells. The Phase Ia clinical study employed an accelerated 3 + 3 escalation design to explore safety and tolerability, dose-limiting toxicities (DLTs), preliminary efficacy, define a recommended phase II dose (RP2D), and evaluate exploratory tumor biomarkers. Eligible patients had advanced relapsed/refractory solid tumors and received treatment with MSC-1 intravenously (75mg-1500 mg) once every 3-weeks as a single agent until disease progression. The three highest dose cohorts were expanded to further assess safety, PK, engagement of LIF in the periphery, and assess immuno-regulatory tumor activity in matched pre- and on-treatment tumor biopsies. Forty-one patients (pts) were enrolled (14 in dose escalation; 27 in expanded cohorts) with the last pt completing the study on September 23, 2019. The most common tumor types were pancreatic (13), colorectal (5), head & neck (4) and ovarian (4). Pts had received a median of 3 prior lines of therapy. All pts experienced at least one adverse event (AE). The most common considered drug-related AEs were fatigue (N=8, 20%) and gastrointestinal disorder (N=8, 20%), and there was 1 considered drug-related SAE (Gr 2 osteonecrosis of jaw in a head and neck cancer patient who previously received radiation to the area and denosumab). There were no Dose Limiting Toxicities observed during the first cycle of treatment and 2 pts discontinued treatment due to AEs. The PK profile of MSC-1 was linear with an estimated terminal half-life of ∼13 days and benign anti-drug antibody profile. There was evidence of durable peripheral saturation of LIF binding demonstrating high level of target engagement. Results supported the selection of a RP2D of 1500 mg Q3W. Prolonged stable disease (≥ 16 weeks) was observed in 9 pts. Analysis of paired biopsies collected from matched metastatic lesions supported MSC-1 mediated STAT3 signaling inhibition, stimulatory (M1) to suppressive (M2) macrophage skewing in the majority of paired biopsies evaluated and increased CD8 T-cell infiltration in a subset of samples. Single agent MSC-1 was well tolerated in doses ranged from 75 mg to 1500 mg IV OD in patients with advanced solid tumors, showed promising activity as an anti-cancer therapy, and is Phase 1b/2 ready for combination with other agents. The updated final safety, efficacy, PK, LIF stabilization analyses, and tumor biopsy data will be presented. Citation Format: Alison Schram, Erkut Borazanci, Irene Brana, Maria Vieito Villar, Elena Garralda, Anna Spreafico, Marc Oliva, Nehal Lakhani, Robert Wasserman, Kimberly Hoffmann, Robin Hallett, Judit Anido, Dorotea Maetzel, Patricia Giblin, Enda Moran, Adrianne Kelly, Joan Seoane, Daniel D. Von Hoff, Lillian Siu, Josep Tabernero. Phase 1 dose escalation of MSC-1, a humanized anti-LIF monoclonal antibody, in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT147.