Co-regulator activity of Mediator of DNA Damage Checkpoint 1 (MDC1) is associated with DNA repair dysfunction and PARP inhibitor sensitivity in lobular carcinoma of the breast.

Invasive lobular carcinoma of the breast (ILC) are typically estrogen receptor α (ER)-positive and present with biomarkers of anti-estrogen sensitive disease, yet patients with ILC face uniquely poor long-term outcomes with increased recurrence risk, suggesting endocrine response and ER function are unique in ILC. We previously found specifically in ILC cells that ER is co-regulated by the DNA repair protein Mediator of DNA Damage Checkpoint 1 (MDC1). This novel MDC1 activity, however, was associated with dysfunction in the canonical DNA repair activity of MDC1, but absent typical features of DNA repair deficiency.

Simultaneous measurement of biochemical phenotypes and gene expression in single cells.

Methods to measure heterogeneity among cells are rapidly transforming our understanding of biology but are currently limited to molecular abundance measurements. We developed an approach to simultaneously measure biochemical activities and mRNA abundance in single cells to understand the heterogeneity of DNA repair activities across thousands of human lymphocytes, identifying known and novel cell-type-specific DNA repair phenotypes.

WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer.

G-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G-M checkpoint for adaptation to stress and DNA repair, making G-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G-M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of loss.

Genomic profiling toward precision medicine in non-small cell lung cancer: getting beyond EGFR.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The application of next-generation genomic technologies has offered a more comprehensive look at the mutational landscape across the different subtypes of non-small cell lung cancer (NSCLC). A number of recurrent mutations such as TP53, KRAS, and epidermal growth factor receptor (EGFR) have been identified in NSCLC.

A high-fat diet is associated with altered adipokine production and a more aggressive esophageal adenocarcinoma phenotype in vivo.

Objective: Obesity has been linked to esophageal adenocarcinoma (EAC). We hypothesize that adipokines, which are altered by obesity, could affect EAC growth rates and potentially serve as biomarkers of disease and targets for treatment. We have developed a potential murine model to investigate the effects of obesity-altered adipokines on EAC in vivo.

LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress.

Five-year survival rates for non-small cell lung cancer (NSCLC) have seen minimal improvement despite aggressive therapy with standard chemotherapeutic agents, indicating a need for new treatment approaches. Studies show inactivating mutations in the LKB1 tumor suppressor are common in NSCLC. Genetic and mechanistic analysis has defined LKB1-deficient NSCLC tumors as a phenotypically distinct subpopulation of NSCLC with potential avenues for therapeutic gain.

Dasatinib, a small molecule inhibitor of the Src kinase, reduces the growth and activates apoptosis in pre-neoplastic Barrett's esophagus cell lines: evidence for a noninvasive treatment of high-grade dysplasia.

Background: Only local ablation (radiofrequency ablation, cryotherapy) or esophagectomy currently is available to treat high-grade dysplasia in Barrett's esophagus. Alternative treatments, specifically chemopreventive strategies, are lacking. Our understanding of the molecular changes of high-grade dysplasia in Barrett's esophagus offers an opportunity to inhibit neoplastic progression of high-grade dysplasia in Barrett's esophagus.