Mimetic sHDL nanoparticles: A novel drug-delivery strategy to target triple-negative breast cancer.

BACKGROUND: Withanolides are naturally derived heat shock protein 90 inhibitors that are potent in preclinical models of triple negative breast cancers. Conjugation to synthetic high-density lipoprotein nanoparticles improves solubility and targets delivery to the scavenger receptor B1. Triple negative breast cancers highly overexpress the scavenger receptor B1, and we hypothesize that encapsulation of the novel withalongolide A 4,19,27-triacetate by synthetic high-density lipoprotein will have enhanced efficacy against triple negative breast cancers in vivo. METHODS: Validated human triple negative breast cancer cell lines were evaluated for the scavenger receptor B1 expression by quantitative polymerase chain reaction and Western blot. Withalongolide A 4,19,27-triacetate inhibitory concentration50 values were obtained using CellTiter-Glo assays (Promega, Madison, WI, USA). The scavenger receptor B1-mediated drug uptake was evaluated in vitro under fluorescence microscopy and in vivo with IVIS imaging of mouse xenografts (MD-MBA-468LN). To evaluate drug efficacy, mice were treated with synthetic high-density lipoprotein alone, withalongolide A 4,19,27-triacetate alone, withalongolide A 4,19,27-triacetate synthetic high-density lipoprotein, and chemotherapy or Prussian blue stain (control). RESULTS: Triple negative breast cancer cell lines had greater scavenger receptor B1 expression by quantitative polymerase chain reaction and Western blot versus controls. Fluorescent-labeled synthetic high-density lipoprotein uptake was scavenger receptor B1-mediated in vitro, and in vivo tumor uptake using IVIS imaging demonstrated significantly increased tumor radiant efficiency versus control. Inhibitory concentration50 for withalongolide A 4,19,27-triacetate-treated cells with or without synthetic high-density lipoprotein encapsulation were 70-fold to 200-fold more potent than synthetic high-density lipoprotein alone. In triple negative breast cancer mouse xenografts, treatment with synthetic high-density lipoprotein withalongolide A 4,19,27-triacetate resulted in a 54% decrease in tumor volume compared with the control or with synthetic high-density lipoprotein alone. CONCLUSION: The synthetic high-density lipoprotein withalongolide A 4,19,27-triacetate nanoconjugates are potent against triple negative breast cancers and show improved scavenger receptor B1-mediated targeting. Treatment with synthetic high-density lipoprotein-encapsulated withalongolide A 4,19,27-triacetate is able to significantly decrease the growth of tumor in mice compared with the control and has better efficacy than the current standard of care, warranting further evaluation as a novel therapeutic agent.

BRAF and MEK Inhibitors: Use and Resistance in BRAF-Mutated Cancers.

The mitogen activated protein kinase/extracellular signal-related kinase (MAPK/ERK) signaling pathway serves an integral role in growth, proliferation, differentiation, migration, and survival of all mammalian cells. Aberrant signaling of this pathway is often observed in several types of hematologic and solid malignancies. The most frequent insult to this signaling cascade, leading to its constitutive activation, is to the serine/threonine kinase rapidly accelerating fibrosarcoma (RAF). Considering this, the development and approval of various small-molecule inhibitors targeting the MAPK/ERK pathway has become a mainstay of treatment as either mono- or combination therapy in these cancers. Although effective initially, a major clinical barrier with these inhibitors is the relapse of patients due to drug resistance. Knowledge of the mechanisms of resistance to these drugs is still premature, highlighting the need for a more in-depth understanding of how patients become insensitive to these pharmacologic interventions. Herein, we will succinctly summarize the milestones in the approval of select MAPK/ERK pathway inhibitors, their use in patients, and major modes of resistance.