Profiling candidate therapeutics with limited cancer models during preclinical development hinders predictions of clinical efficacy and identifying factors that underlie heterogeneous patient responses for patient-selection strategies. We established ∼1,000 patient-derived tumor xenograft models (PDXs) with a diverse set of driver mutations. With these PDXs, we performed in vivo compound screens using a 1 × 1 × 1 experimental design (PDX clinical trial or PCT) to assess the population responses to 62 treatments across six indications. We demonstrate both the reproducibility and the clinical translatability of this approach by identifying associations between a genotype and drug response, and established mechanisms of resistance. In addition, our results suggest that PCTs may represent a more accurate approach than cell line models for assessing the clinical potential of some therapeutic modalities. We therefore propose that this experimental paradigm could potentially improve preclinical evaluation of treatment modalities and enhance our ability to predict clinical trial responses.
Nongrowing bacteria evade the bactericidal activity of beta-lactam antibiotics. We sought to determine if slow growth rate also alters bactericidal activity. The bactericidal activity of two beta-lactams on Escherichia coli grown in glucose limited chemostats was compared for generation times ranging from 0.7 to 12 h. The degree of killing varied with drug structure and with E. coli strain. However, all killing rates were a constant function of the bacterial generation time: slowly growing bacteria became progressively more phenotypically tolerant to beta-lactam antibiotics as the generation time was extended.
Somatic PIK3CA mutations are frequently found in solid tumors, raising the hypothesis that selective inhibition of PI3Ka may have robust efficacy in PIK3CA-mutant cancers while sparing patients the side-effects associated with broader inhibition of the class I phosphoinositide 3-kinase (PI3K) family. Here, we report the biologic properties of the 2-aminothiazole derivative NVP-BYL719, a selective inhibitor of PI3Ka and its most common oncogenic mutant forms. The compound selectivity combined with excellent drug-like properties translates to dose-and time-dependent inhibition of PI3Ka signaling in vivo, resulting in robust therapeutic efficacy and tolerability in PIK3CA-dependent tumors. Novel targeted therapeutics such as NVP-BYL719, designed to modulate aberrant functions elicited by cancer-specific genetic alterations upon which the disease depends, require well-defined patient stratification strategies in order to maximize their therapeutic impact and benefit for the patients. Here, we also describe the application of the Cancer Cell Line Encyclopedia as a preclinical platform to refine the patient stratification strategy for NVP-BYL719 and found that PIK3CA mutation was the foremost positive predictor of sensitivity while revealing additional positive and negative associations such as PIK3CA amplification and PTEN mutation, respectively. These patient selection determinants are being assayed in the ongoing NVP-BYL719 clinical trials.
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
Introduction Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the posttranslational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.
The bactericidal activity of 23 I-lactam antibiotics was compared in slowly growing bacteria cultured in a chemostat. In an attempt to mimic possible in vivo conditions, slowly growing cultures were produced by limitation of iron, glucose, phosphate, or magnesium. Only select antibiotics remained effectively bactericidal against slowly growing cells. For these compounds, the rate of antibiotic-induced loss of viability was a constant when killing was expressed per generation (in contrast to absolute time) in that slowly growing bacteria were killed proportionately more slowly. Individual antibiotics differed greatly, however, in their specific bactericidal activities against slowly growing cells, i.e., in the absolute degree of killing elicited during exposure of the bacteria to MIC equivalents of the drugs. Specific bactericidal activities varied not only with drug structure but also with the bacterial strains and, to a lesser extent, with the nature of the growth-limiting nutrient. In slowly growing cultures exposure to the low drug concentrations studied here (near MIC) caused killing without detectable lysis. Antibiotics with high specific bactericidal activities were capable of rapidly killing cultures of slowly growing pathogens despite extremely long generation times approaching those reported for in vivo growth rates.The in vitro bactericidal activity of an antibiotic does not always correlate with therapeutic efficacy. The reasons for this lack of correlation are likely to be multiple (35). One explanation which has received only recent attention is the probable phenotypic differences between bacteria growing in the nutritionally limited in vivo environment and those growing under optimum conditions in the laboratory. Phenotypically induced changes in microorganisms have been shown to alter markedly their susceptibility to the bactericidal activity of antimicrobial agents; these changes include alterations in drug permeability across the outer or cytoplasmic membranes (3,7,14), alterations in the structure of peptidoglycan such that it resists degradative enzymes (17,23,26,28), or alteration of penicillin-binding proteins (4,9,13,25).A slow growth rate (12,22,24) and a restricted availability of iron (5, 33) and possibly other nutrients appear to be characteristic of many infections in vivo. These two parameters could be major contributors to phenotypic tolerance (i.e., relative insensitivity to the bactericidal effect of drugs) in vivo (E. Tuomanen, Rev. Infect. Dis., in press). Since the earliest days of the antibiotic era it has been recognized that slowly growing bacteria are less susceptible to antibiotic action than those growing at optimum rates (16).The chemostat has already proved useful in studies of the effect of growth rate and nutritional status of microorganisms on their susceptibility to antimicrobial agents (8,14,19,20,29). The purpose of the study described here was to compare the bactericidal activity of a range of 1-lactam antibiotics on several species of bacteria growing at reduced ...
Dysregulated angiogenesis and high tumor vasculature permeability, two vascular endothelial growth factor (VEGF)-mediated processes and hallmarks of human tumors, are in part phosphatidylinositol 3-kinase (PI3K) dependent. NVP-BEZ235, a dual PI3K/mammalian target of rapamycin (mTOR) inhibitor, was found to potently inhibit VEGF-induced cell proliferation and survival in vitro and VEGF-induced angiogenesis in vivo as shown with s.c. VEGF-impregnated agar chambers. Moreover, the compound strongly inhibited microvessel permeability both in normal tissue and in BN472 mammary carcinoma grown orthotopically in syngeneic rats. Similarly, tumor interstitial fluid pressure, a phenomenon that is also dependent of tumor permeability, was significantly reduced by NVP-BEZ235 in a dose-dependent manner on p.o. administration. Because RAD001, a specific mTOR allosteric inhibitor, was ineffective in the preceding experiments, we concluded that the effects observed for NVP-BEZ235 are in part driven by PI3K target modulation. Hence, tumor vasculature reduction was correlated with full blockade of endothelial nitric oxide (NO) synthase, a PI3K/Akt-dependent but mTORC1-independent effector involved in tumor permeability through NO production. In the BN472 tumor model, early reduction of permeability, as detected by Ktrans quantification using the dynamic contrast-enhanced magnetic resonance imaging contrasting agent P792 (Vistarem), was found to be a predictive marker for late-stage antitumor activity by NVP-BEZ235. [Cancer Res 2008;68(16):6598–607]
On the basis of previously described X-ray studies of an enzyme/aza-dipeptide complex,8 aza-dipeptide analogues carrying N-(bis-aryl-methyl) substituents on the (hydroxethyl)hydrazine moiety have been designed and synthesized as HIV-1 protease inhibitors. By using either equally (12) or orthogonally (13) protected dipeptide isosteres, symmetrically and asymmetrically acylated aza-dipeptides can be synthesized. This approach led to the discovery of very potent inhibitors with antiviral activities (ED50) in the subnanomolar range. Acylation of the (hydroxethyl)hydrazine dipeptide isostere with the L-tert-leucine derivative 29 increased the oral bioavailability significantly when compared to the corresponding L-valine or L-isoleucine derivatives. The bis(L-tert-leucine) derivatives CGP 75355, CGP 73547, CGP 75136, and CGP 75176 combine excellent antiviral activity with high blood concentration after oral administration. Furthermore, they show no cross-resistance with saquinavir-resistant strains and maintain activity against indinavir-resistant ones. Consequently they qualify for further profiling as potential clinical candidates.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.