ABSTRACT
Epigenetic therapies that cause genome-wide epigenetic alterations, could trigger local interplay between different histone marks, leading to a switch of transcriptional outcome and therapeutic responses of epigenetic treatment. However, in human cancers with diverse oncogenic activation, how oncogenic pathways cooperate with epigenetic modifiers to regulate the histone mark interplay is poorly understood. We herein discover that the hedgehog (Hh) pathway reprograms the histone methylation landscape in breast cancer, especially in triple-negative breast cancer (TNBC). This facilitates the histone acetylation caused by histone deacetylase (HDAC) inhibitors and gives rise to new therapeutic vulnerability of combination therapies. Specifically, overexpression of zinc finger protein of the cerebellum 1 (ZIC1) in breast cancer promotes Hh activation, facilitating the switch of H3K27 methylation (H3K27me) to acetylation (H3K27ac). The mutually exclusive relationship of H3K27me and H3K27ac allows their functional interplay at oncogenic gene locus and switches therapeutic outcomes. Using multiple in vivo breast cancer models including patient-derived TNBC xenograft, we show that Hh signaling-orchestrated H3K27me and H3K27ac interplay tailors combination epigenetic drugs in treating breast cancer. Together, this study reveals the new role of Hh signaling-regulated histone modifications interplay in responding to HDAC inhibitors and suggests new epigenetically-targeted therapeutic solutions for treating TNBC.
ABSTRACT
BCS Ⅱ drugs are characterized by low solubility and high permeability. Improving their solubility is considered an important approach to improve its oral absorption. Recent strategies to increase the solubility of poorly-soluble drugs may unexpectedly result in greatly depressed permeability, ultimately leading to failure in improving oral absorption. Based on the mathematics of membrane permeability coefficient of a drug, the membrane/aqueous partition coefficient is dependent on the drug's solubility in the gastrointestinal milieu, suggesting a unique interplay between the solubility and permeability of the drug, and treating the one irrespectively of the other may be insufficient. When we focus on the increase of drug solubility and overlook the efficacy of drug permeability, the positive effect of increased solubility to drug oral absorption might be traded off by depressed permeability. To provide rational formulary designs, by optimizing excipients and evaluation, this review summarizes solubility- permeability interplay for different types of solubilizing techniques, such as cyclodextrin, surfactants-based vehicle, cosolvent, amorphous solid dispersions, other infectors such as P-gp transporters and new techniques for simultaneous evaluation of drug solubility and permeability.
ABSTRACT
Proton beams have been used for cancer treatment for more than 28 years, and several technological advancements have been made to achieve improved clinical outcomes by delivering more accurate and conformal doses to the target cancer cells while minimizing the dose to normal tissues. The state-of-the-art intensity modulated proton therapy is now prevailing as a major treatment technique in proton facilities worldwide, but still faces many challenges in being applied to the lung. Thus, in this article, the current status of proton therapy technique is reviewed and issues regarding the relevant uncertainty in proton therapy in the lung are summarized.