Roadmap on plasticity and epigenetics in cancer.

The role of plasticity and epigenetics in shaping cancer evolution and response to therapy has taken center stage with recent technological advances including single cell sequencing. This roadmap article is focused on state-of-the-art mathematical and experimental approaches to interrogate plasticity in cancer, and addresses the following themes and questions: is there a formal overarching framework that encompasses both non-genetic plasticity and mutation-driven somatic evolution? How do we measure and model the role of the microenvironment in influencing/controlling non-genetic plasticity? How can we experimentally study non-genetic plasticity? Which mathematical techniques are required or best suited? What are the clinical and practical applications and implications of these concepts?

No association between chronic use of ranitidine, compared with omeprazole or famotidine, and gastrointestinal malignancies.

BACKGROUND: In 2019, the United States Food and Drug Administration detected above-regulation levels of the human carcinogen N-nitrosodimethylamine (NDMA) in ranitidine, resulting in a complete removal of the medication from the market. NDMA is known to cause gastrointestinal malignancies in animal models. AIM: To determine if patients who were receiving ranitidine have a higher risk of developing cancers of the digestive tract compared to patients taking other anti-reflux medications. METHODS: Using the nationwide database IBM Explorys, patients taking ranitidine were compared to patients on either famotidine or omeprazole. Incidence data of new malignancies of the oesophagus, stomach, liver, pancreas, and colon/rectum were obtained in 1-year intervals for up to 10 years. Two multivariable logistic regression models were used to calculate odds ratios (ORs), one adjusting for common risk factors for each cancer studied, and the other for demographic factors. RESULTS: Patients on ranitidine who were compared to patients on famotidine had ORs of 0.51(95% CI 0.43-0.60), 0.43(95% CI 0.36-0.51), 0.39(95% CI 0.36-0.41), 0.54(95% CI 0.49-0.62), and 0.46(95% CI 0.43-0.49) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers, respectively (P < 0.001). Patients on ranitidine compared to omeprazole had ORs of 0.62(95% CI 0.52-0.72), 0.58(95% CI 0.49-0.68), 0.81 (95% CI 0.76-0.86), 0.68(95% CI 0.60-0.76), and 0.66(95% CI 0.62-0.70) of developing oesophageal, gastric, hepatocellular, pancreatic, and colorectal cancers respectively (P < 0.001). CONCLUSIONS: Use of ranitidine was not associated with an increased odds of developing gastrointestinal malignancies compared to omeprazole or famotidine use.

Combined epigenetic and metabolic treatments overcome differentiation blockade in acute myeloid leukemia.

A hallmark of acute myeloid leukemia (AML) is the inability of self-renewing malignant cells to mature into a non-dividing terminally differentiated state. This differentiation block has been linked to dysregulation of multiple cellular processes, including transcriptional, chromatin, and metabolic regulation. The transcription factor HOXA9 and the histone demethylase LSD1 are examples of such regulators that promote differentiation blockade in AML. To identify metabolic targets that interact with LSD1 inhibition to promote myeloid maturation, we screened a small molecule library to identify druggable substrates. We found that differentiation caused by LSD1 inhibition is enhanced by combined perturbation of purine nucleotide salvage and de novo lipogenesis pathways, and identified multiple lines of evidence to support the specificity of these pathways and suggest a potential basis of how perturbation of these pathways may interact synergistically to promote myeloid differentiation. In sum, these findings suggest potential drug combination strategies in the treatment of AML.

Identification of optimal dosing schedules of dacomitinib and osimertinib for a phase I/II trial in advanced EGFR-mutant non-small cell lung cancer.

Despite the clinical success of the third-generation EGFR inhibitor osimertinib as a first-line treatment of EGFR-mutant non-small cell lung cancer (NSCLC), resistance arises due to the acquisition of EGFR second-site mutations and other mechanisms, which necessitates alternative therapies. Dacomitinib, a pan-HER inhibitor, is approved for first-line treatment and results in different acquired EGFR mutations than osimertinib that mediate on-target resistance. A combination of osimertinib and dacomitinib could therefore induce more durable responses by preventing the emergence of resistance. Here we present an integrated computational modeling and experimental approach to identify an optimal dosing schedule for osimertinib and dacomitinib combination therapy. We developed a predictive model that encompasses tumor heterogeneity and inter-subject pharmacokinetic variability to predict tumor evolution under different dosing schedules, parameterized using in vitro dose-response data. This model was validated using cell line data and used to identify an optimal combination dosing schedule. Our schedule was subsequently confirmed tolerable in an ongoing dose-escalation phase I clinical trial (NCT03810807), with some dose modifications, demonstrating that our rational modeling approach can be used to identify appropriate dosing for combination therapy in the clinical setting.

Demographics Predict Stage III/IV Colorectal Cancer in Individuals Under Age 50.

GOALS: The goal of this study was to quantify the association between demographic factors and advanced colorectal cancer (CRC) in patients under age 50. BACKGROUND: CRC incidence in the United States has declined in older individuals but increased in those under age 50 (early-onset). More than 60% of early-onset CRC patients present with advanced disease (stage III/IV), but predictors of stage in this population are poorly defined. STUDY: We analyzed CRC cases diagnosed between age 20 and 49 in the United States Surveillance, Epidemiology, and End Results (SEER) 18 database during 2004 to 2015. Logistic regression models were fit to assess the impact of age, sex, race, ethnicity, marital status, and cancer site on the probability of advanced disease. RESULTS: The analysis included 37,044 cases. On multivariable regression, age was inversely associated with advanced disease. Relative to 45 to 49-year-olds, 40 to 44-year-olds had 8% greater odds of having advanced CRC, and 20 to 24-year-olds had 53% greater odds. Asians, blacks, and Pacific Islanders had 10%, 12%, and 45% greater odds of advanced disease compared with whites. Compared with nonpartnered individuals, those with partners had 11% lower odds of advanced CRC. Both right-sided and left-sided colon cancer were more likely to be diagnosed at stage IV compared with rectal cancer. CONCLUSIONS: Among individuals with early-onset CRC, younger age, Asian, black, or Pacific Islander race, and being nonpartnered were predictors of advanced disease at presentation. Colon cancer was more likely to be diagnosed at stage IV than rectal cancer. Patient characteristics associated with advanced CRC may indicate both differences in tumor biology and disparities in health care access.

Drug Sensitivity and Allele Specificity of First-Line Osimertinib Resistance EGFR Mutations.

Osimertinib, a mutant-specific third-generation EGFR tyrosine kinase inhibitor, is emerging as the preferred first-line therapy for EGFR-mutant lung cancer, yet resistance inevitably develops in patients. We modeled acquired resistance to osimertinib in transgenic mouse models of EGFRL858R -induced lung adenocarcinoma and found that it is mediated largely through secondary mutations in EGFR-either C797S or L718V/Q. Analysis of circulating free DNA data from patients revealed that L718Q/V mutations almost always occur in the context of an L858R driver mutation. Therapeutic testing in mice revealed that both erlotinib and afatinib caused regression of osimertinib-resistant C797S-containing tumors, whereas only afatinib was effective on L718Q mutant tumors. Combination first-line osimertinib plus erlotinib treatment prevented the emergence of secondary mutations in EGFR. These findings highlight how knowledge of the specific characteristics of resistance mutations is important for determining potential subsequent treatment approaches and suggest strategies to overcome or prevent osimertinib resistance in vivo. SIGNIFICANCE: This study provides insight into the biological and molecular properties of osimertinib resistance EGFR mutations and evaluates therapeutic strategies to overcome resistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/10/2017/F1.large.jpg.