Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99099/1/bjh12382.pd

Phase II study of the farnesyltransferase inhibitor R115777 in advanced melanoma (CALGB 500104)

BACKGROUND: Multiple farnesylated proteins are involved in signal transduction in cancer. Farnesyltransferase inhibitors (FTIs) have been developed as a strategy to inhibit the function of these proteins. As FTIs inhibit proliferation of melanoma cell lines, we undertook a study to assess the impact of a FTI in advanced melanoma. As farnesylated proteins are also important for T cell activation, measurement of effects on T cell function was also pursued. METHODS: A 3-stage trial design was developed with a maximum of 40 patients and early stopping if there were no responders in the first 14, or fewer than 2 responders in the first 28 patients. Eligibility included performance status of 0–1, no prior chemotherapy, at most 1 prior immunotherapy, no brain metastases, and presence of at least 2 cutaneous lesions amenable to biopsy. R115777 was administered twice per day for 21 days of a 28-day cycle. Patients were evaluated every 2 cycles by RECIST. Blood and tumor were analyzed pre-treatment and during week 7. RESULTS: Fourteen patients were enrolled. Two patients had grade 3 toxicities, which included myelosuppression, nausea/vomiting, elevated BUN, and anorexia. There were no clinical responses. All patients analyzed showed potent inhibition of FT activity (85-98%) in tumor tissue; inhibition of phosphorylated ERK and Akt was also observed. T cells showed evidence of FT inhibition and diminished IFN-γ production. CONCLUSIONS: Despite potent target inhibition, R115777 showed no evidence of clinical activity in this cohort of melanoma patients. Inhibition of T cell function by FTIs has potential clinical implications. Clinicaltrials.gov number NCT0006012

Heterodimerization of Glycosylated Insulin-Like Growth Factor-1 Receptors and Insulin Receptors in Cancer Cells Sensitive to Anti-IGF1R Antibody

Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer.In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity.The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells

Carbon nanotubes in liquid crystals as versatile functional materials

Liquid crystals can be easily aligned in desired directions by treated surfaces or by external fields. The least ordered liquid crystal phase, the nematic, exhibits orientational order that can be easily transferred onto carbon nanotubes dispersed in it. The alignment of the carbon nanotubes can be demonstrated by po- larized Raman spectroscopy. Carbon nanotubes not only well integrate in the matrix but also, even at very low concentration, have a detectable effect on the liquid crystal properties that can be very attractive for display applications. The presence of big aggregates of carbon nanotubes, on the other hand, interfere strongly with the switching behaviour of the liquid crystal, as we can show following the local switching of liquid crystal molecules with Raman spectroscopy

Nanotube alignment using lyotropic liquid crystals

A new method for the successful alignment of carbon nanotubes is presented. An aqueous lyotropic nematic liquid-crystal phase acts as a self-organizing template to align and disperse the nonfunctionalized nanotubes simultaneously, and the success of the method is confirmed through Raman spectroscopy analysis (see figure). This work could be extended to allow tailoring of the alignment for specific purposes and properties, using different lyotropic liquid crystals

Effect of phenyl rings in liquid crystal molecules on swcnts studied by raman spectroscopy

Carbon nanotubes can be aligned by dispersing them in a liquid crystalline matrix. To control and opti- mize the obtained alignment it is important to understand the interactions between the molecules of the liquid crystal host phase and the carbon nanotubes. To this end we have carried out resonant Raman spec- troscopy investigations of dispersions of single-wall carbon nanotubes (SWCNTs) in a liquid crystal com- pound comprising molecules with a biphenyl rigid core structure. We detect a distinct wavenumber shift of the radial breathing modes, confirming that the carbon nanotubes interact with the surrounding liquid crystal molecules, most likely through aromatic interactions (π-stacking). The interactions between liquid crystal host and nanotube guests are also evident from a polarizing microscopy study of the liquid crys- tal – isotropic phase transition in the proximity of bundles of nanotubes. The ordered liquid crystal phase is stable up to higher temperatures around the bundles than in areas without visible signs of CNTs. Con- versely, the transition from the disordered isotropic phase to the liquid crystal phase on cooling always nucleates at the carbon nanotube bundles