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Retinoids as Chemo-Preventive and Molecular-Targeted Anti-Cancer Therapies
Victoria O Hunsu1,2, Caroline O B Facey1, Jeremy Z Fields3
1Center for Translational Cancer Research, Helen F. Graham Cancer Center & Research Institute, Newark, DE 19713, USA.
Abstract:
Retinoic acid (RA) agents possess anti-tumor activity through their ability to induce cellular differentiation. However, retinoids have not yet been translated into effective systemic treatments for most solid tumors. RA signaling is mediated by the following two nuclear retinoic receptor subtypes: the retinoic acid receptor (RAR) and the retinoic X receptor (RXR), and their isoforms. The identification of mutations in retinoid receptors and other RA signaling pathway genes in human cancers offers opportunities for target discovery, drug design, and personalized medicine for distinct molecular retinoid subtypes. For example, chromosomal translocation involving RARA occurs in acute promyelocytic leukemia (APL), and all-trans retinoic acid (ATRA) is a highly effective and even curative therapeutic for APL patients. Thus, retinoid-based target discovery presents an important line of attack toward designing new, more effective strategies for treating other cancer types. Here, we review retinoid signaling, provide an update on retinoid agents and the current clinical research on retinoids in cancer, and discuss how the retinoid pathway genotype affects the ability of retinoid agents to inhibit the growth of colorectal cancer (CRC) cells. We also deliberate on why retinoid agents have not shown clinical efficacy against solid tumors and discuss alternative strategies that could overcome the lack of efficacy.
Insights
Retinoid agents show anti-tumor effects by inducing cell differentiation. Understanding retinoid receptor mutations can lead to targeted cancer therapies, though efficacy in solid tumors remains a challenge.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Retinoic acid (RA) agents exhibit anti-tumor properties by promoting cellular differentiation.
- Despite potential, retinoids are not yet effective systemic treatments for most solid tumors.
- RA signaling involves retinoic acid receptors (RARs) and retinoic X receptors (RXRs).
Purpose of the Study:
- To review retinoid signaling pathways in cancer.
- To update on retinoid agents and clinical research in oncology.
- To discuss the impact of retinoid pathway genotype on colorectal cancer (CRC) cell growth and explore strategies to overcome limited efficacy in solid tumors.
Main Methods:
- Literature review of retinoid signaling and cancer research.
- Analysis of retinoid receptor mutations and their role in cancer.
- Discussion of clinical trial data and therapeutic strategies for retinoid-based cancer treatment.
Main Results:
- Mutations in retinoid receptors and RA pathway genes present opportunities for targeted drug design and personalized medicine.
- All-trans retinoic acid (ATRA) is a curative therapy for acute promyelocytic leukemia (APL) due to specific RARA translocations.
- Retinoid agents' efficacy varies significantly based on the tumor's molecular profile, particularly in colorectal cancer (CRC).
Conclusions:
- Targeted discovery within the retinoid pathway is crucial for developing more effective cancer treatments.
- Understanding the molecular basis of retinoid response is key to improving their clinical utility in solid tumors.
- Alternative strategies are needed to enhance the efficacy of retinoid agents against solid malignancies.
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