ABSTRACT
Background: The advent of immunotherapy has revolutionized non-small cell lung cancer (NSCLC) treatment. Anlotinib (AN), a multitargeted tyrosine kinase inhibitor, holds promise in combination with PD-1 monoclonal antibody therapy. Understanding the impact of optimal dosage is pivotal. Objective: This study aims to assess the comparative efficacy of high-dose AN versus low-dose AN when combined with PD-1 monoclonal antibody for the treatment of NSCLC. Methods: A total of 70 patients with NSCLC undergoing PD-1 monoclonal antibody therapy at our hospital from June 2020 to January 2022 were selected. The low-dose group (n=33) received AN at 8 mg and 10 mg. In comparison, the high-dose group (n=37) received AN at 12 mg. Comparative analyses included assessment of clinical efficacy, adverse reactions, prognosis, survival, changes in T lymphocyte subsets, inflammatory factors pre and post-chemotherapy, and treatment satisfaction. Results: No significant difference was observed in clinical efficacy and prognosis between the two groups (P > .05). The low-dose group exhibited fewer adverse reactions and inflammatory responses, along with improved immune function post-treatment (P < .05). Treatment satisfaction was higher in the low-dose group compared to the high-dose group (P < .05). Conclusions: Findings suggest that combining low-dose AN with PD-1 monoclonal antibody therapy is a safer approach in the treatment of advanced NSCLC. These findings advocate for the adoption of a tailored, lower-dose AN regimen, presenting a clinically sound and patient-centered strategy in the ongoing pursuit of optimized treatment modalities for advanced NSCLC.
ABSTRACT
Plasmodium falciparum and vivax are responsible for the majority of malaria infections worldwide, resulting in over a million deaths annually. Malaria parasites now show measured resistance to all currently utilized drugs. Novel antimalarial drugs are urgently needed. The Plasmodium Kinesin-5 mechanoenzyme is a suitable "next generation" target. Discovered via small molecule screen experiments, the human Kinesin-5 has multiple allosteric sites that are "druggable." One site in particular, unique in its sequence divergence across all homologs in the superfamily and even within the same family, exhibits exquisite drug specificity. We propose that Plasmodium Kinesin-5 shares this allosteric site and likewise can be targeted to uncover inhibitors with high specificity. To test this idea, we performed a screen for inhibitors selective for Plasmodium Kinesin-5 ATPase activity in parallel with human Kinesin-5. Our screen of nearly 2000 compounds successfully identified compounds that selectively inhibit both P. vivax and falciparum Kinesin-5 motor domains but, as anticipated, do not impact human Kinesin-5 activity. Of note is a candidate drug that did not biochemically compete with the ATP substrate for the conserved active site or disrupt the microtubule-binding site. Together, our experiments identified MMV666693 as a selective allosteric inhibitor of Plasmodium Kinesin-5; this is the first identified protein target for the Medicines of Malaria Venture validated collection of parasite proliferation inhibitors. This work demonstrates that chemical screens against human kinesins are adaptable to homologs in disease organisms and, as such, extendable to strategies to combat infectious disease.