ABSTRACT
[This corrects the article DOI: 10.3389/fmed.2022.999004.].
ABSTRACT
Colorectal cancer (CRC) is the third most prevalent form of cancer in the United States and results in over 50,000 deaths per year. Treatments for metastatic CRC are limited, and therefore there is an unmet clinical need for more effective therapies. In our prior work, we coupled high-throughput chemical screens with patient-derived models of cancer to identify new potential therapeutic targets for CRC. However, this pipeline is limited by (1) the use of cell lines that do not appropriately recapitulate the tumor microenvironment, and (2) the use of patient-derived xenografts (PDXs), which are time-consuming and costly for validation of drug efficacy. To overcome these limitations, we have turned to patient-derived organoids. Organoids are increasingly being accepted as a "standard" preclinical model that recapitulates tumor microenvironment cross-talk in a rapid, cost-effective platform. In the present work, we employed a library of natural products, intermediates, and drug-like compounds for which full synthesis has been demonstrated. Using this compound library, we performed a high-throughput screen on multiple low-passage cancer cell lines to identify potential treatments. The top candidate, psymberin, was further validated, with a focus on CRC cell lines and organoids. Mechanistic and genomics analyses pinpointed protein translation inhibition as a mechanism of action of psymberin. These findings suggest the potential of psymberin as a novel therapy for the treatment of CRC.
ABSTRACT
Colorectal cancer is the third most common cancer in the United States and responsible for over 50,000 deaths each year. Therapeutic options for advanced colorectal cancer are limited, and there remains an unmet clinical need to identify new treatments for this deadly disease. To address this need, we developed a precision medicine pipeline that integrates high-throughput chemical screens with matched patient-derived cell lines and patient-derived xenografts (PDX) to identify new treatments for colorectal cancer. High-throughput screens of 2,100 compounds were performed across six low-passage, patient-derived colorectal cancer cell lines. These screens identified the CDK inhibitor drug class among the most effective cytotoxic compounds across six colorectal cancer lines. Among this class, combined targeting of CDK1, 2, and 9 was the most effective, with IC50s ranging from 110 nmol/L to 1.2 µmol/L. Knockdown of CDK9 in the presence of a CDK2 inhibitor (CVT-313) showed that CDK9 knockdown acted synergistically with CDK2 inhibition. Mechanistically, dual CDK2/9 inhibition induced significant G2-M arrest and anaphase catastrophe. Combined CDK2/9 inhibition in vivo synergistically reduced PDX tumor growth. Our precision medicine pipeline provides a robust screening and validation platform to identify promising new cancer therapies. Application of this platform to colorectal cancer pinpointed CDK2/9 dual inhibition as a novel combinatorial therapy to treat colorectal cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Drug Screening Assays, Antitumor , Precision Medicine , Protein Kinase Inhibitors/pharmacology , Animals , Biomarkers, Tumor , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/etiology , Colorectal Neoplasms/metabolism , Cyclin-Dependent Kinase 2/antagonists & inhibitors , Cyclin-Dependent Kinase 9/antagonists & inhibitors , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery/methods , Drug Screening Assays, Antitumor/methods , Drug Synergism , Female , High-Throughput Screening Assays , Humans , Male , Mice , Mutation , Precision Medicine/methods , Xenograft Model Antitumor AssaysABSTRACT
Background: Quality of disease is improved in patients with pancreatic cancer via endoscopic placement of a biliary stent. Since the role of non-cover metal stent inside the biliary duct is not definitely clear, the aim of this study was to evaluate the recurrence of obstructive symptoms and quality of life after insertion of non-cover metal stent inside the biliary duct in patients with pancreatic cancer. Methods: This retrospective descriptive-analytical study was conducted on 81 patients with pancreatic cancer who were referred to Mortaz and Shahaid Sadoughi Hospital. Factors such as pruritus, jaundice, appetite, stomachache and general situation were measured. Quality of life assessment was performed using the Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire (version 4). Then, the quality of life score was classified in terms of median score (more and less than 18). Results: Patients had a mean age of 72±12.15 years. The most complete recovery among them was related to jaundice (54.3%) and pruritus (47.4%). Subjects had a mean quality of life score of 21.60±6.24. Moreover, the mean quality of life score of 37.2% and 62.8% of patients was less and more than the median value, respectively. In addition, there was no significant difference between frequency of recurrence in terms of variables including sex, age, death, chemotherapy, surgery, and quality of life (p>0.05). The mean recurrence time was 6.9±5.03 months. Conclusion: According to our findings, the quality of life score of most patients using metal stent is higher than 18. Therefore, it seems that the use of metal stent can improve the quality of life score in these patients. Stenting also improves jaundice and pruritus in these subjects. In addition, because there is no significant relation between the frequency of recurrence with age, mortality, chemotherapy, and quality of life, it can be concluded that none of the above factors affects the frequency of recurrence among patients with pancreatic cancer.
