Immune checkpoint therapy—current perspectives and future directions

Predicting the clinical response to chemotherapeutic or targeted treatment in patients with locally advanced or metastatic lung cancer requires an accurate and affordable tool. Tumor organoids are a potential approach in precision medicine for predicting the clinical response to treatment. However, their clinical application in lung cancer has rarely been reported because of the difficulty in generating pure tumor organoids. In this study, we have generated 214 cancer organoids from 107 patients, of which 212 are lung cancer organoids (LCOs), primarily derived from malignant serous effusions. LCO-based drug sensitivity tests (LCO-DSTs) for chemotherapy and targeted therapy have been performed in a real-world study to predict the clinical response to the respective treatment. LCO-DSTs accurately predict the clinical response to treatment in this cohort of patients with advanced lung cancer. In conclusion, LCO-DST is a promising precision medicine tool in treating of advanced lung cancer. 

http://www.cell.com/article/S2666379122004906/pdf

Using patient-derived organoids to predict locally advanced or metastatic lung cancer tumor response: A real-world study

Introduction: Diseases caused by fungi and parasites are major illnesses in humans as well as in animals. Microtubule-targeted drugs are highly effective for the treatment of fungal and parasitic infections; however, several human parasitic infections such as malaria, trypanosomiasis and leishmaniasis do not have effective remedial drugs. In addition, the emergence of drug-resistant fungi and parasites makes the discovery of new drugs imperative. Areas covered: This article describes similarities and dissimilarities between parasitic, fungal and mammalian tubulins and focuses on microtubule-targeting agents and therapeutic approaches for the treatment of fungal and parasitic diseases. New microtubule-targeted antileishmanial, antimalarial and antifungal drugs, with structures, biological activities and related patents, are described. The potential of dsRNA against tubulin to inhibit proliferation of protozoan and helminthic parasites is also discussed. Patent documents up to 2010 have been searched on USP...

Microtubules as antifungal and antiparasitic drug targets.

http://www.umich.edu/~rnapeopl/WalterLabPub/Cline_et_al_Biomacromolecules_2013.pdf

Paclitaxel-conjugated PAMAM dendrimers adversely affect microtubule structure through two independent modes of action.

Decades of efforts in engineering in vitro cancer models have advanced drug discovery and the insight into cancer biology. However, the establishment of preclinical models that enable fully recapitulating the tumor microenvironment remains challenging owing to its intrinsic complexity. Recent progress in engineering techniques has allowed the development of a new generation of in vitro preclinical models that can recreate complex in vivo tumor microenvironments and accurately predict drug responses, including spheroids, organoids, and tumor‐on‐a‐chip. These biomimetic 3D tumor models are of particular interest as they pave the way for better understanding of cancer biology and accelerating the development of new anticancer therapeutics with reducing animal use. Here, the recent advances in developing these in vitro platforms for cancer modeling and preclinical drug screening, focusing on incorporating hydrogels are reviewed to reconstitute physiologically relevant microenvironments. The combination of spheroids/organoids with microfluidic technologies is also highlighted to better mimic in vivo tumors and discuss the challenges and future directions in the clinical translation of such models for drug screening and personalized medicine.

3D Biomimetic Models to Reconstitute Tumor Microenvironment In Vitro: Spheroids, Organoids, and Tumor‐on‐a‐Chip

Patient-derived micro-organospheres enable clinical precision oncology.

We developed tubulin purification strategies that allowed sufficient material to be produced for compound-screening projects. Tubulins were polymerized in the presence of compounds using either turbidometric or fluorescence polymerization assays. IC50 and EC50 values were calculated and used to determine ratios between host and target tubulin (TT) (e.g., IC50-neuronal tubulin/IC50-TT). This ratio can be compared between compounds to identify the ones which are most selective for a particular TT. We found ratios for different compounds ranged from 0.16 to 4.0 between neuronal and cancer cell tubulin indicating that the sequence and posttranslational heterogeneity between these tubulins are sufficient to identify selective ligands for the TT. Likewise, compounds compared between neuronal and fungal tubulin had ratios ranging from 0.03 to 0.60, and compounds compared between neuronal to plant tubulin had ratios ranging from 0.03 to 52. Considering these data, we believe cancer cell tubulin-targeted drugs could be obtained with ratios in excess of 20, herbicides with ratios in excess of 200, and fungicides in excess of 200.

A tubulin polymerization microassay used to compare ligand efficacy.

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Patient-derived micro-organospheres enable clinical precision oncology.

A tubulin polymerization microassay used to compare ligand efficacy.