Anaplastic thyroid cancer: genome-based search for new targeted therapy options

Abstract

Objective: Anaplastic thyroid cancer (ATC) is one of the most lethal human cancers with meager treatment options. We aimed to identify targeted drugs already approved by the FDA for solid cancer in general, which could be effective in ATC. Design: Database mining. Methods: FDA-approved drugs for targeted therapy were identified by screening databases of MyCancerGenome and National Cancer Institute. Drugs were linked to target genes by querying Drugbank. Subsequently, MyCancerGenome, CIViC, TARGET and OncoKB were mined for genetic alterations which are predicted to lead to drug sensitivity or resistance. We searched the Cancer Genome Atlas database (TCGA) for patients with ATC and probed their sequencing data for genetic alterations which predict a drug response. Results: 155 FDA-approved drugs with 136 potentially targetable genes were identified. 17 (52%) of 33 patients found in TCGA had at least one genetic alteration in targetable genes. The point mutation BRAF V600E was seen in 45% patients. PIK3CA occurred in 18 % of cases. Amplifications of ALK and SRC were detected in 3% of cases, respectively. 15% of patients displayed a co-mutation of BRAF and PIK3CA. Besides BRAF-inhibitors, the PIK3CA-inhibitor copanlisib showed a genetically predicted response. The 146 (94%) remaining drugs showed no or low (under 4% cases) genetically predicted drug response. Conclusions: While ATC carrying BRAF mutations can benefit from BRAF-inhibitors and this effect might be enhanced by a combined strategy including PIK3CA-inhibitors in some of the patients, alterations in BRAF wild-type ATC are not directly targeted by currently FDA approved options.

Targeted Therapy for Adrenocortical Carcinoma: A Genomic-Based Search for Available and Emerging Options

“…For this reason, we decided to create a theoretical framework for planning future clinical studies based on available genomic data and drug response prediction, as described previously for other tumors [ 27 , 36 ]. A systematic in silico preclinical analysis including available and emerging options might help save time and costs and optimize treatments since most of the potential targets screened do not need to be validated experimentally.…”

“…FDA-approved drugs for any cancer therapy were identified by searching the databases of the National Cancer Institute [ 26 ] My Cancer Genome [ 24 ] and linked to their genetic target(s), as previously described [ 27 ].…”

“…Mutation variants and CNVs directly or indirectly affecting genes of potentially targeted treatments were identified by querying My Cancer Genome [ 24 ], CIVIC [ 25 ], TARGET [ 32 ] and OncoKB [ 23 ]), as previously described [ 27 ].…”

“…This study was conducted in accordance with the provisions of the Declaration of Helsinki and local laws, as previously described [ 27 ].…”

Targeting Tumor Microenvironment Akt Signaling Represents a Potential Therapeutic Strategy for Aggressive Thyroid Cancer

“…Activations of such signaling in cancer cells often cause unresponsiveness to treatments commonly used for thyroid cancer, including radiation and chemotherapy [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Currently, the success of targeted therapeutic strategies for advanced thyroid cancers is still limited [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. The increasing thyroid cancer incidences, combined with the relative lack of effective therapies in treating advanced disease, underscore the need for the identification of mechanisms underlying thyroid cancer progression and for the development of novel therapeutics targeting aggressive disease.…”