Pancreatic Ductal Adenocarcinoma (PDAC) is an expeditiously fatal malignancy with a five-year survival rate of 6–8%. Conventional chemotherapeutics fail in many cases due to inadequate primary response and rapidly developing resistance. This treatment failure is particularly challenging in pancreatic cancer because of the high molecular heterogeneity across tumors. Additionally, a rich fibro-inflammatory component within the tumor microenvironment (TME) limits the delivery and effectiveness of anticancer drugs, further contributing to the lack of response or developing resistance to conventional approaches in this cancer. As a result, there is an urgent need to model pancreatic cancer ex vivo to discover effective drug regimens, including those targeting the components of the TME on an individualized basis. Patient-derived three-dimensional (3D) organoid technology has provided a unique opportunity to study patient-specific cancerous epithelium. Patient-derived organoids cultured with the TME components can more accurately reflect the in vivo tumor environment. Here we present the advances in organoid technology and multicellular platforms that could allow for the development of “organ-on-a-chip” approaches to recapitulate the complex cellular interactions in PDAC tumors. We highlight the current advances of the organ-on-a-chip-based cancer models and discuss their potential for the preclinical selection of individualized treatment in PDAC.

HER2 amplification results in increased tumor growth and aggressiveness in breast cancer. Despite advancements in HER2-targeted therapy, treatment resistance, cancer recurrence, and metastasis remain significant obstacles in combating this deadly disease. PARP inhibitors, have emerged as a promising class of drugs targeting cancers deficient in homologous recombination repair. Recent preclinical evidence suggests that PARP inhibitors exhibit sensitivity in cancers with high replication stress and genomic instability, as well as some HER2 positive breast cancer cell lines. To investigate the relationship between HER2 amplification and PARP inhibitor sensitivity, we utilized isogenic models of HER2-positive breast cancer, whereby cells were either sensitive or resistant to lapatinib and treated with the PARP inhibitor olaparib used as a single agent, or in combination with HER2-targeted therapies. Our results show that HER2 overexpressing MCF-10A cells are highly sensitivity to single-agent olaparib. The addition of trastuzumab and lapatinib resulted in a synergistic increase in toxicity. To determine if olaparib could be used to overcome resistance to lapatinib, we obtained SKBR3 cells conditioned to be resistant to lapatinib. Despite resistance to lapatinib, these cells continue to exhibit sensitivity to olaparib. Reverse phase protein analysis revealed that lapatinib resistant clones exhibited a statistically-significant increase in protein expression of the apoptosis inhibitor MCL-1, which is decreased upon olaparib treatment resulting in apoptosis. Taken together, our findings suggest that HER2 overexpression may predict sensitivity to olaparib alone, or in combination with trastuzumab and lapatinib. Lapatinib resistant HER2-positive breast cancer cells are sensitive to olaparib, possibly through downregulation of MCL-1.

Routine maintenance and re-housing of the paleontological collections at the University of Colorado Museum of Natural History (UCM) permitted a brief examination of select mosasaur specimens. The majority of the examined material hails from the Sharon Springs Member of the Pierre Shale (early Campanian) at the Red Bird locality in Niobrara County, Wyoming, USA. The sample studied from this locality includes the mosasaurid taxa Clidastes sp., Latoplatecarpus willistoni, and cf. Plioplatecarpus. Also present within the collections were a pair of dentaries of Platecarpus tympaniticus from the upper Smoky Hill Chalk Member (late Santonian) of Kansas, USA, and a single large jaw section of Mosasaurus hoffmanni from the Fox Hills Formation (Maastrichtian).

While reporting on the mosasaurid fauna of the upper Demopolis Chalk of western Alabama and northeastern Mississippi, Derstler (1988) noted the presence of numerous remains of Plioplatecarpus sp. and Mosasaurus conodon, and a single isolated tooth of Prognathodon cf. Prognathodon solvayi. These remains are of Late Campanian age, originating from within a few meters of the lower boundary of the Bluffport Marl Member.