Research Techniques Made Simple: Preclinical Development of Combination Antitumor Targeted Therapies in Dermatology

Abstract

The identification and application of targeted therapies that inhibit critical pathways in malignant cells have shown tremendous promise for improving clinical outcomes for patients with advanced cutaneous malignancies. However, tumor cell heterogeneity, development of drug resistance, and risks of off-target effects remain barriers to prolonged remission and definitive cure. Herein, we describe the potential that combinations of antitumor targeted agents may offer in overcoming these challenges and detail techniques whereby promising combination regimens can be identified and further evaluated preclinically. Cancer cell lines and primary patient-derived malignant cells can be utilized to perform dose-response screenings in vitro for individual targeted agents before moving toward the evaluation of potential synergistic combinations. Mathematical analyses, including the Chou-Talalay method, determine combination indices and Hill slopes that permit relative comparisons among various drug combinations by quantification of synergistic activities. Further preclinical in vivo evaluation of promising single versus combination regimens may be studied in relevant mouse models of cutaneous malignancy. Ultimately, the formulation of combination targeted therapy regimens may be more broadly effective and less toxic, helping to better inform clinical trial design and prioritization.

The Research Techniques Made Simple Series: Lasting and Future Impact on Investigative Dermatology

“…The RTMS series has broached topics related to drug discovery, development, and delivery. "Molecular Docking in Dermatology e A Foray into In Silico Drug Discovery" (Issa et al, 2019) was downloaded 2,473 times, and we hope that the 2021 publication of "Preclinical Development of Combination Antitumor Targeted Therapies in Dermatology" (Yumeen et al, 2020) and "Skin-Targeted Drug and Vaccine Delivery Using Dissolvable Microneedle Arrays" (November 2021) will lead to new therapeutics for skin diseases. The RTMS series has also featured assessment of outcomes measures with an early article "'Validation' of Outcome Measures in Dermatology" (Viola et al, 2013), being followed this year by "Developing and Validating QOL Outcome Measures for Skin Diseases" (Braun et al, 2020).…”