A5082885390- Cancer Genomics and Diagnostics
- Colorectal Cancer Treatments and Studies
- Cancer-related Molecular Pathways
- Advanced Breast Cancer Therapies
- Ubiquitin and proteasome pathways
- Epigenetics and DNA Methylation
- Ferroptosis and cancer prognosis
- Hippo pathway signaling and YAP/TAZ
- RNA modifications and cancer
- FOXO transcription factor regulation
- Cellular Mechanics and Interactions
- Histone Deacetylase Inhibitors Research
- Health and Medical Research Impacts
- RNA and protein synthesis mechanisms
- Photosynthetic Processes and Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Cell death mechanisms and regulation
- Pharmacogenetics and Drug Metabolism
- MicroRNA in disease regulation
- Pancreatic function and diabetes
- Cancer-related gene regulation
- Genetic factors in colorectal cancer
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- DNA Repair Mechanisms
Harvard University
2019-2024
Brigham and Women's Hospital
2022-2024
Dana-Farber Cancer Institute
2019-2021
Boston University
2020
Toxikon (United States)
2004
Triple-negative breast cancer (TNBC) is the most aggressive subtype and has highest rate of recurrence1. The predominant standard care for advanced TNBC systemic chemotherapy with or without immunotherapy; however, responses are typically short lived1,2. Thus, there an urgent need to develop more effective treatments. Components PI3K pathway represent plausible therapeutic targets; than 70% TNBCs have alterations in PIK3CA, AKT1 PTEN3–6. However, contrast hormone-receptor-positive tumours,...
Abstract Cell cycle gene expression occurs in two waves. The G1/S genes encode factors required for DNA synthesis and the G2/M contribute to mitosis. Retinoblastoma protein (RB) DREAM complex (DP, RB-like, E2F4 MuvB) cooperate repress all cell during G1 inhibit entry into cycle. damage activates p53 leading increased levels of p21 inhibition progression. Whether are differentially repressed by RB RB-like proteins p130 p107 response is not known. We performed profiling primary human...
Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers, and partial loss function contributes to cell transformation. Displacement regulatory B by the SV40 Small T antigen (ST) or mutation/deletion alters abundance types complexes cells, leading Here, we show that ST not only displaces common but also promotes A-C subunit interactions with alternative (B’’’, striatins) are components Striatin-interacting kinase (STRIPAK) complex. We found STRN4,...
To identify genes whose loss confers resistance to CHK1 inhibitors, we perform genome-wide CRISPR-Cas9 screens in non-small-cell lung cancer (NSCLC) cell lines treated with the inhibitor prexasertib (CHK1i). Five of top six hits screens, MYBL2 (B-MYB), LIN54, FOXM1, cyclin A2 (CCNA2), and CDC25B, are cell-cycle-regulated that contribute entry into mitosis. Knockout MMB-FOXM1 complex components LIN54 FOXM1 reduce CHK1i-induced DNA replication stress markers premature mitosis during Late S...
While screening and early detection have reduced mortality from prostate cancer, castration-resistant disease (CRPC) is still incurable. Here, we report that combined EZH2/HDAC inhibitors potently kill CRPCs cause dramatic tumor regression in aggressive human mouse CRPC models. Notably, EZH2 HDAC both transmit transcriptional repressive signals: regulating histone H3 methylation deacetylation, respectively. Accordingly, show suppression of are required to derepress/induce a subset targets,...
Despite the success of KRAS G12C inhibitors in non-small cell lung cancer (NSCLC), more effective treatments are needed. One preclinical strategy has been to co-target RAS and mTOR pathways, however toxicity due broad inhibition limited its utility. Therefore, we sought develop a refined means targeting cap-dependent translation identify most therapeutically important eIF4F-translated targets. Here show that an eIF4A inhibitor, which targets component eIF4F, dramatically enhances effects...
Abstract Current treatments for KRAS-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic oncogenic signals. Specifically, show inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway promote dramatic tumor regression in vivo. Together these agents cooperatively suppress Wingless Int-1 (WNT)-driven transcription drive...
Abstract Resistance to HER2 inhibitors remains a clinical challenge in HER2+ breast cancer. Therefore, there is an urgent need 1) understand the mechanisms that underlie resistance these current treatments and 2) develop improved, more importantly, curative combination therapies. We previously showed RasGAP DAB2IP tumor metastasis suppressor Interestingly, we have now generated robust data demonstrating loss of also mediates therapeutic First, genetically ablated multiple cancer cell lines...
<div>Abstract<p>Current treatments for <i>KRAS</i>-mutant colorectal cancers are often limited by cellular plasticity and rewiring responses. Here we describe a promising therapeutic strategy that simultaneously targets epigenetic oncogenic signals. Specifically, show inhibitors of histone methyltransferase, EZH2, synergize with various rat sarcoma virus (RAS) pathway promote dramatic tumor regression <i>in vivo</i>. Together these agents cooperatively...
<p>Extended data related to Figure 5.</p>
<p>Extended data related to Figure 1.</p>
<p>Extended data related to Figure 6.</p>
<p>Related to Figure 4.</p>
<p>Extended data related to Figure 7.</p>
<p>EZH2 and MEK inhibitors do not cause toxicity in vivo.</p>
<p>Extended data related to Figure 3.</p>
Abstract p53 activation results cell cycle arrest at the G1/S checkpoint and repression of early (G1/S) late (G2/M) gene expression in a p21 dependent manner. The mechanism how repress is unclear. known to CDK2 which key inhibitor pocket protein family members RB p130. During normal cycle, p130 as part DREAM complex (DP1, RB-like p130, E2F4, MuvB) cooperate expression. binds represses promoters through MuvB binding though repressor E2F binding. only able bind its interaction with activator...
Abstract Resistance to HER2 inhibitors remains a clinical challenge in HER2+ breast cancer. Therefore, there is an urgent need 1) understand the mechanisms that underlie resistance these current treatments and 2) develop improved, more importantly, curative combination therapies. We recently discovered two emerging tumor suppressor RasGAPs, DAB2IP RASAL2, cooperatively drive metastatic cancer when lost or inactivated. Interestingly, we have now generated robust data demonstrating loss of...
Abstract Triple negative breast cancer (TNBC) is the most aggressive subtype and has highest rate of recurrence. The predominant standard care for advanced TNBC systemic chemotherapy with or without immunotherapy, however responses are typically short-lived. Thus, there an urgent need to develop more effective treatments. PI3K pathway components represent plausible therapeutic targets, as approximately 40% TNBCs have PIK3CA/AKT1/PTEN alterations. However, unlike hormone receptor-positive...
Abstract Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers and partial loss function contributes to cell transformation. Displacement regulatory B by the SV40 Small T antigen (ST) or mutation/deletion alters abundance types complexes cells, leading Here we show that ST not only displaces common but also promotes A-C subunit interactions with alternative (B’’’, striatins) are components Striatin-interacting kinase (STRIPAK) complex. We found...