Researchers at Kanazawa University report in the Journal of Thoracic Oncology a promising novel approach for a combined treatment of the most common type of lung cancer and associated secondary cancers in the central nervous system. The approach lies in combining two cancer drugs, with one compensating for a resistance side effect of the other.
In 20 – 40% of patients with cancer, metastasis (the development of secondary tumors) in the central nervous system (CNS) occurs. CNS metastatis impacts negatively on a patient’s quality of life, and is associated with a poor health prognosis. In a form of cancer known as ALK-rearranged non-small-cell lung cancer (NSCLC), CNS metastatis is known to persist when drugs targeting primary tumors are used. Now, Seiji Yano from Kanazawa University and colleagues have investigated the origins for the resistence to such drugs, and tested a new therapeutic strategy on a mouse model.
The researchers looked at the drug alectinib. Although used in standard treatments for advanced ALK-rearranged NSCLC, approximately 20 – 30% of patients treated with alectinib develop CNS metastatis, which is attributed to acquired resistance to the drug.
By treating mice first injected with tumor cells with alectinib daily for 16 weeks, the scientists obtained a mouse model displaying alectinib resistance. By biochemical analyses of the mouse brains, Yano and colleagues were able to link the resistance to the activation of a protein known as epidermal growth factor receptor (EGFR). This activation is, in turn, a result of an increase in production of amphiregulin (AREG), a protein that binds to EGFR and in doing so ‘activates’ it.
Based on this insight, the researchers tested the effect of administering drugs used for inhibiting the action of EGFR in combination with alectinib treatment. The experiments showed that a combination treatment of alctinib with either erlotinib or osimertinib — two existing EGFR-inibiting drugs — prevented the progression of CNS metastasis, controlling the condition for over 30 days.
The scientists conclude that the combined use of alectinib and EGFR-inhibitors could overcome alectinib resistance in the mouse model of leptomeningeal carcinomatosis (LMC), a particular type of CNS metastasis. Quoting Yano and colleagues: “Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC.”
[Background]
Nanopipettes
Nanopipettes are pipettes, usually made from quartz or glass, with a pore opening in the nanometer range. Today, nanopipettes are used for various nanotechnology applications, including molecular sensing, delivery of chemicals, and scanning-probe microscopy. The latter is a technique for imaging a material’s surface by scanning a probe over it; for the probe, a solution-filled nanopipette can be used.
The function of a nanopipette is usually to enable the transport, and their detection, of nanometer-sized objects (in solution) through the pipette pore.
Completely filling a nanopipette with a solution has been difficult: because of the capillary force, an ‘air bubble’ is nearly always present in the pipette’s tip. Removing the air bubble has proven to be problematic for nanopipettes with a pore opening of 10 nanometer or less.
Now, Shinji Watanabe and colleagues from Kanazawa University have found a way to achieve complete filling of a batch of many nanopipettes with a pore opening of about 10 nm. The method, based on the application of a temperature gradient to the nanopipettes, is simple and efficient.
Article
Osimertinib overcomes alectinib resistance caused by amphiregulin in a leptomeningeal carcinomatosis model of ALK-rearranged lung cancer
Journal: Journal of Thoracic Oncology
Authors: Sachiko Arai, Shinji Takeuchi, Koji Fukuda, Hirokazu Taniguchi, Akihiro Nishiyama, Azusa Tanimoto, Miyako Satouchi, Kaname Yamashita, Koshiro Ohtsubo, Shigeki Nanjo, Toru Kumagai, Ryohei Katayama, Makoto Nishio, Mei-mei Zheng, Yi-Long Wu, Hiroshi Nishihara, Takushi Yamamoto, Mitsutoshi Nakada, and Seiji Yano
DOI: 10.1016/j.jtho.2020.01.001
Funder
This work was supported by grants JSPS KAKENHI Grant Number, 16H05308 (to SY), AMED (the Project for Cancer Research and Therapeutic Evolution (P-CREATE)) under Grant Number 16cm0106513h0001 (to SY), Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University (to H. Taniguchi).
