Summary Previously, we reported on the anti-tumor activities of two designed calix[4]arene-based topomimetics (PTX008 and PTX009) of the amphipathic, angiostatic peptide Anginex. Here, we chemically modified the hydrophobic and hydrophilic faces of PTX008 and PTX009, and discovered new calixarene compounds that are more potent, cytotoxic anti-tumor agents. One of them, PTX013, is particularly effective at inhibiting the growth of several human cancer cell lines, as well as drug resistant cancer cells. Mechanistically, PTX013 induces cell cycle arrest in sub-G1 and G0/G1 phases of e.g. SQ20B cells, a radio-resistant human head and neck carcinoma model. In the syngeneic B16F10 melanoma tumor mouse model, PTX013 (0.5 mg/Kg) inhibits tumor growth by about 50-fold better than parent PTX008. A preliminary pharmacodynamics study strongly suggests that PTX013 exhibits good in vivo exposure and a relatively long half-life. Overall, this research contributes to the discovery of novel therapeutics as potentially useful agents against cancer in the clinic.
Background GammaTile® (GT) is a recent U.S. Food and Drug Administration (FDA) cleared brachytherapy platform. Here, we report clinical outcomes for recurrent glioblastoma patients after GT treatment following maximal safe resection. Methods We prospectively followed twenty-two consecutive Isocitrate Dehydrogenase (IDH) wild-type glioblastoma patients (6 O6-Methylguanine-DNA methyltransferase methylated (MGMTm); sixteen MGMT unmethylated (MGMTu)) who underwent maximal safe resection of recurrent tumor followed by GT placement. Results The cohort consisted of 14 second and eight third recurrences. In terms of procedural safety, there was one 30-day re-admission (4.5%) for an incisional cerebrospinal fluid leak, which resolved with lumbar drainage. No other wound complications were observed. Six patients (27.2%) declined in Karnofsky Performance Score (KPS) after surgery due to worsening existing deficits. One patient suffered a new-onset seizure post-surgery (4.5%). There was one (4.5%) 30-day mortality from intracranial hemorrhage secondary to heparinization for an ischemic limb. The mean follow-up was 733 days (range 279-1775) from the time of initial diagnosis. Six-month local control (LC6) and twelve-month local control (LC12) were 86 and 81%, respectively. Median progression-free survival (PFS) was comparable for MGMTu and MGMTm patients (~8.0 months). Median overall survival (OS) was 20.0 months for the MGMTu patients and 37.4 months for MGMTm patients. These outcomes compared favorably to data in the published literature and an independent glioblastoma cohort of comparable patients without GT treatment. Conclusions This clinical experience supports GT brachytherapy as a treatment option in a multi-modality treatment strategy for recurrent glioblastomas.
Anginex, a synthetic 33mer β-sheet-forming peptide, is a potent inhibitor of angiogenesis in vitro and in vivo. Previous studies demonstrate that Anginex, through binding to one of the hydrophobic faces of human galectin-1 (hGal-1), prevents endothelial cell adhesion to the extracellular matrix, induces apoptosis in angiogenically-activated endothelial cells (ECs), and suppresses tumor growth in animal models. Since small molecules have several pharmacologic advantages over therapeutic peptides, we sought to design a small molecule peptidomimetic of anginex. Calix[4]arene was chosen as the basic scaffold to mimic the approximate molecular dimensions, amphipathicity, and cationic topology of Anginex. Chemical modification of the hydrophobic (upper rim) and hydrophilic (lower rim) faces of calix[4]arene resulted in the discovery of a lead compound, 0118, possessing in vitro and in vivo activities similar to that of anginex. These studies reveal that small hydrophobic groups on the upper rim and dimethylaminoethylacetamide (DMAEA) moieties on the lower rim of 0118 are important for its biologic activity. Until now, structure-activity relationship (SAR) development of calixarene has focused on modifications of its hydrophobic and hydrophilic surfaces. Since the hGal-1-Anginex binding site is a hydrophobic surface, we hypothesize that a larger hydrophobic calixarene surface area will translate into enhanced bioactivity. We have chosen calix[6]arene and tetrathiacalix[4]arene as tools to explore the core-expanded SAR of our lead compound. A calix[6]arene analog of 0118 not only has a larger hydrophobic footprint, but also a greater intra-annular topoisomerization rate which should allow for greater conformational space sampling and, therefore, better inducible fit within its molecular receptor. The tetrathiacalix[4]arene derivative, with its longer C-S bonds (relative to the methylene bonds of calix[4]arene and calix[6]arene), should allow for a hydrophobic footprint larger than the parent 0118 but smaller than that of the calix[6]arene analog. The current studies focus on the synthesis and biologic activity of these 0118 core-expanded derivatives. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A141.
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