Comparative biomarker analysis of PALOMA-2/3 trials for palbociclib.

While cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including palbociclib, combined with endocrine therapy (ET), are becoming the standard-of-care for hormone receptor-positive/human epidermal growth factor receptor 2‒negative metastatic breast cancer, further mechanistic insights are needed to maximize benefit from the treatment regimen. Herein, we conducted a systematic comparative analysis of gene expression/progression-free survival relationship from two phase 3 trials (PALOMA-2 [first-line] and PALOMA-3 [≥second-line]). In the ET-only arm, there was no inter-therapy line correlation. However, adding palbociclib resulted in concordant biomarkers independent of initial ET responsiveness, with shared sensitivity genes enriched in estrogen response and resistance genes over-represented by mTORC1 signaling and G2/M checkpoint. Biomarker patterns from the combination arm resembled patterns observed in ET in advanced treatment-naive patients, especially patients likely to be endocrine-responsive. Our findings suggest palbociclib may recondition endocrine-resistant tumors to ET, and may guide optimal therapeutic sequencing by partnering CDK4/6 inhibitors with different ETs. Pfizer (NCT01740427; NCT01942135)

Development of a Colon Cancer GEMM-Derived Orthotopic Transplant Model for Drug Discovery and Validation

Purpose: Effective therapies for KRAS-mutant colorectal cancer (CRC) are a critical unmet clinical need. Previously, we described genetically engineered mouse models (GEMM) for sporadic Kras-mutant and non-mutant CRC suitable for preclinical evaluation of experimental therapeutics. To accelerate drug discovery and validation, we sought to derive low-passage cell lines from GEMM Kras-mutant and wild-type tumors for in vitro screening and transplantation into the native colonic environment of immunocompetent mice for in vivo validation. Experimental Design: Cell lines were derived from Kras-mutant and non-mutant GEMM tumors under defined media conditions. Growth kinetics, phosphoproteomes, transcriptomes, drug sensitivity, and metabolism were examined. Cell lines were implanted in mice and monitored for in vivo tumor analysis. Results: Kras-mutant cell lines displayed increased proliferation, mitogen-activated protein kinase signaling, and phosphoinositide-3 kinase signaling. Microarray analysis identified significant overlap with human CRC-related gene signatures, including KRAS-mutant and metastatic CRC. Further analyses revealed enrichment for numerous disease-relevant biologic pathways, including glucose metabolism. Functional assessment in vitro and in vivo validated this finding and highlighted the dependence of Kras-mutant CRC on oncogenic signaling and on aerobic glycolysis. Conclusions: We have successfully characterized a novel GEMM-derived orthotopic transplant model of human KRAS-mutant CRC. This approach combines in vitro screening capability using low-passage cell lines that recapitulate human CRC and potential for rapid in vivo validation using cell line-derived tumors that develop in the colonic microenvironment of immunocompetent animals. Taken together, this platform is a clear advancement in preclinical CRC models for comprehensive drug discovery and validation efforts

Estimation and Mapping of Wet and Dry Mercury Deposition Across Northeastern North America

Whereas many ecosystem characteristics and processes influence mercury accumulation in higher trophic-level organisms, the mercury flux from the atmosphere to a lake and its watershed is a likely factor in potential risk to biota. Atmospheric deposition clearly affects mercury accumulation in soils and lake sediments. Thus, knowledge of spatial patterns in atmospheric deposition may provide information for assessing the relative risk for ecosystems to exhibit excessive biotic mercury contamination. Atmospheric mercury concentrations in aerosol, vapor, and liquid phases from four observation networks were used to estimate regional surface concentration fields. Statistical models were developed to relate sparsely measured mercury vapor and aerosol concentrations to the more commonly measured mercury concentration in precipitation. High spatial resolution deposition velocities for different phases (precipitation, cloud droplets, aerosols, and reactive gaseous mercury (RGM)) were computed using inferential models. An empirical model was developed to estimate gaseous elemental mercury (GEM) deposition. Spatial patterns of estimated total mercury deposition were complex. Generally, deposition was higher in the southwest and lower in the northeast. Elevation, land cover, and proximity to urban areas modified the general pattern. The estimated net GEM and RGM fluxes were each greater than or equal to wet deposition in many areas. Mercury assimilation by plant foliage may provide a substantial input of methyl-mercury (MeHg) to ecosystems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44443/1/10646_2004_Article_6259.pd