Abplatin(IV) Inhibited Tumor Growth On A Patient Derived Cancer Model of Hepatocellular Carcinoma And Its Comparative Multi-Omics Study With Cisplatin

Background: Cisplatin is the most common antitumor alkylating agent of platinum(II) (Pt(II)) in clinic, however it had many side effects. It is necessary to develop low toxicity platinum(IV) (Pt(IV)) drugs. Multi-omics was frequently used to help one understand the mechanism of a certain therapy at the molecular level. Little was known about the mechanism of Pt(IV) drugs, which may be benifical for clinical translation. Methods: We developed a Pt(IV) drug of cisplatin with two hydrophobic aliphatic chains and further encapsulated it with a drug carrier human serum albumin (HSA) to prepare Abplatin(IV). Transcriptomics, metabolomics and lipidomics were performed to clarify the mechanism of Pt(IV) drugs. T-test assay and fold change were used to find the differential substances.Results: We had further shown Abplatin(IV) had better tumor-targeting performance and greater tumor inhibtion rate than cisplatin. Lipidomics study showed that Abplatin(IV) might induce the changes of BEL-7404 cell membrane, and caused the disorder of glycerophospholipids and sphingolipids. In addition, transcriptomics and metabolomics study showed that Abplatin(IV) mainly disturbed more significant purine metabolism pathway than cisplatin.Conclusions: This research highlighted the development of Abplatin(IV) and the use of multi-omics to help one understand the mechanism of action of prodrugs and their DDS, which was the key to the clinical translation of them.

The rexinoid V-125 reduces tumor growth in preclinical models of breast and lung cancer

Rexinoids are ligands which activate retinoid X receptors (RXRs), regulating transcription of genes involved in cancer-relevant processes. Rexinoids have anti-neoplastic activity in multiple preclinical studies. Bexarotene, used to treat cutaneous T cell lymphoma, is the only FDA-approved rexinoid. Bexarotene has also been evaluated in clinical trials for lung and metastatic breast cancer, wherein subsets of patients responded despite advanced disease. By modifying structures of known rexinoids, we can improve potency and toxicity. We previously screened a series of novel rexinoids and selected V-125 as the lead based on performance in optimized in vitro assays. To validate our screening paradigm, we tested V-125 in clinically relevant mouse models of breast and lung cancer. V-125 significantly (p < 0.001) increased time to tumor development in the MMTV-Neu breast cancer model. Treatment of established mammary tumors with V-125 significantly (p < 0.05) increased overall survival. In the A/J lung cancer model, V-125 significantly (p < 0.01) decreased number, size, and burden of lung tumors. Although bexarotene elevated triglycerides and cholesterol in these models, V-125 demonstrated an improved safety profile. These studies provide evidence that our screening paradigm predicts novel rexinoid efficacy and suggest that V-125 could be developed into a new cancer therapeutic.

Oxaliplatin-Induced Peripheral Neuropathy Can Be Minimized By Pressurized Regional Intravascular Delivery In An Orthotopic Murine Pancreatic Cancer Model.

Purpose: There is a great need to reduce the toxicity of chemotherapy used in the management of pancreatic ductal adenocarcinoma (PDAC). Here we explore if regional pressurized delivery of oxaliplatin can minimize peripheral neuropathy in mice.Methods: We used an orthotopic PDAC mouse model and delivered a single dose of oxaliplatin through the portal vein using a pressure-enabled system (pancreatic retrograde venous infusion, PRVI). We analyzed the effects of PRVI on tumor burden and peripheral neuropathy using histopathological and functional assays.Results: Tumor weights in mice treated with 2 mg/Kg oxaliplatin using PRVI were significantly lower than in mice treated with the same dose systemically. This resulted in reduced peripheral neuropathy signatures in PRVI mice compared to the 20 mg/Kg systemic dose required to achieve similar tumor control.Conclusion: Regional delivery of highly cytotoxic agents using PRVI can reduce the therapeutic dose of these drugs, thereby lowering toxic side effects.

Bioprinted Cancer Model of Neuroblastoma in a Renal Microenvironment as an Efficiently Applicable Drug Testing Platform

Development of new anticancer drugs with currently available animal models is hampered by the fact that human cancer cells are embedded in an animal-derived environment. Neuroblastoma is the most common extracranial solid malignancy of childhood. Major obstacles include managing chemotherapy-resistant relapses and resistance to induction therapy, leading to early death in very-high-risk patients. Here, we present a three-dimensional (3D) model for neuroblastoma composed of IMR-32 cells with amplified genes of the myelocytomatosis viral related oncogene MYCN and the anaplastic lymphoma kinase (ALK) in a renal environment of exclusively human origin, made of human embryonic kidney 293 cells and primary human kidney fibroblasts. The model was produced with two pneumatic extrusion printheads using a commercially available bioprinter. Two drugs were exemplarily tested in this model: While the histone deacetylase inhibitor panobinostat selectively killed the cancer cells by apoptosis induction but did not affect renal cells in the therapeutically effective concentration range, the peptidyl nucleoside antibiotic blasticidin induced cell death in both cell types. Importantly, differences in sensitivity between two-dimensional (2D) and 3D cultures were cell-type specific, making the therapeutic window broader in the bioprinted model and demonstrating the value of studying anticancer drugs in human 3D models. Altogether, this cancer model allows testing cytotoxicity and tumor selectivity of new anticancer drugs, and the open scaffold design enables the free exchange of tumor and microenvironment by any cell type.