A5025351031- Advanced Breast Cancer Therapies
- Cancer Treatment and Pharmacology
- Cancer Genomics and Diagnostics
- Breast Cancer Treatment Studies
- HER2/EGFR in Cancer Research
- Fibroblast Growth Factor Research
- Cancer Cells and Metastasis
- Cancer-related Molecular Pathways
- BRCA gene mutations in cancer
- Metastasis and carcinoma case studies
- PARP inhibition in cancer therapy
- Chronic Lymphocytic Leukemia Research
- Lung Cancer Treatments and Mutations
- Acute Myeloid Leukemia Research
- Lung Cancer Research Studies
- MicroRNA in disease regulation
- Neuroendocrine Tumor Research Advances
- Estrogen and related hormone effects
- DNA Repair Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Cytokine Signaling Pathways and Interactions
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Cancer-related cognitive impairment studies
Harvard University
2015-2025
Massachusetts General Hospital
2015-2025
Dana-Farber Cancer Institute
2017-2023
Dana-Farber/Harvard Cancer Center
2023
North Shore Community College
2023
Brigham and Women's Hospital
2017-2022
Dana-Farber Brigham Cancer Center
2017-2022
Sylvester Comprehensive Cancer Center
2009-2021
University of Miami
2009-2021
Foundation Medicine (United States)
2021
Mechanisms driving resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in hormone receptor-positive (HR+) breast cancer have not been clearly defined. Whole-exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate mechanisms including RB1 loss, activating alterations AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, loss estrogen receptor expression. In vitro experiments confirmed that these conferred resistance. Cancer cells cultured also acquired RB1, KRAS, or...
•We analyzed mechanisms of resistance to PARP inhibitor/platinum chemotherapy in BRCA1/2-mutant metastatic breast cancer.•Genomic reversion functional BRCA1/2 protein was identified one-half patients.•Up-regulation DNA end resection as a mechanism two additional patients.•RAD51 foci assessed by immunohistochemistry correlated with clinical response inhibitor/platinum.•RAD51 focus staining warrants further exploration biomarker for use. BackgroundLittle is known about poly(adenosine...
LBA1001 Background: The combination of CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET) is the standard first line treatment for HR+, HER2- advanced breast cancer (ABC). While disease progression occurs in nearly all patients (pts) with ABC, optimal pts who experience on a CDK4/6i ET remains uncertain. Real-world evidence suggests that use abemaciclib after prior prolongs progression-free survival (PFS) ABC; however, Phase 2 trials other have generated mixed results. Here we present...
Vepdegestrant (ARV-471) is an oral PROTAC ER degrader that binds E3 ubiquitin ligase and to directly trigger ubiquitination of its subsequent proteasomal degradation. In a first-in-human Phase I/II study, vepdegestrant monotherapy was well tolerated with clinical activity in pretreated patients ER+/HER2- advanced breast cancer. The global, randomized III VERITAC-2 study compares efficacy safety versus fulvestrant adults cancer after treatment CDK4/6 inhibitor plus endocrine therapy....
Abstract Consequences of the obesity epidemic on cancer morbidity and mortality are not fully appreciated. Obesity is a risk factor for many cancers, but mechanisms by which it contributes to development patient outcome have yet be elucidated. Here, we examined effects coculturing human-derived adipocytes with established primary breast cells tumorigenic potential. We found that interaction between increased secretion proinflammatory cytokines. Prolonged culture or cytokines proportion...
p90 ribosomal S6 kinase (RSK1) is an effector of both Ras/MEK/MAPK and PI3K/PDK1 pathways. We present evidence that RSK1 drives p27 phosphorylation at T198 to increase RhoA-p27 binding cell motility. activation p27pT198 in early G 1 . As for many kinase–substrate pairs, cellular coprecipitates with p27. siRNA inhibition rapidly reduce p27pT198. overexpression increases p27pT198, p27-cyclin D1-Cdk4 complexes, stability. Moreover, transfectants show mislocalization cytoplasm, increased...
To identify clinically relevant mechanisms of resistance to ER-directed therapies in ER+ breast cancer.We conducted a genome-scale functional screen spanning 10,135 genes investigate whose overexpression confer selective estrogen receptor degraders. In parallel, we performed whole-exome sequencing paired pretreatment and postresistance biopsies from 60 patients with metastatic cancer who had developed ER-targeted therapy. Furthermore, experiments validate genes/pathways drug combinations...
p27 restrains normal cell growth, but PI3K-dependent C-terminal phosphorylation of at threonine 157 (T157) and T198 promotes cancer invasion. Here, we describe an oncogenic feedforward loop in which p27pT157pT198 binds Janus kinase 2 (JAK2) promoting STAT3 (signal transducer activator transcription 3) recruitment activation. induces TWIST1 to drive a p27-dependent epithelial-mesenchymal transition (EMT) further activates AKT contributing acquisition maintenance metastatic potential....
CDK4/6 inhibition is now part of the standard armamentarium for patients with estrogen receptor-positive (ER+) breast cancer, so that defining mechanisms resistance a pressing issue. Here, we identify increased CDK6 expression as key determinant acquired after palbociclib treatment in ER+ cancer cells. critical cellular survival during exposure. The observed resistant cells dependent on TGF-β pathway suppression via miR-432-5p expression. Exosomal mediates transfer phenotype between...
Background: Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are widely used as first-line therapy for hormone receptor–positive metastatic breast cancer (HR+ MBC). Although abemaciclib monotherapy is also FDA-approved treatment disease progression on endocrine therapy, there limited insight into the clinical activity after prior CDK4/6i. Patients Methods: We identified patients with HR+ MBC from centers in United States who received CDK4/6i, abstracted features, outcomes, toxicity,...
TPS1122 Background: ARV-471 is an oral PROTAC ER degrader that binds to and degrades wild-type clinically relevant mutants. directly recruits the ubiquitin-proteasome system degrade ER, whereas selective degraders (SERDs) indirectly cause degradation. In a first-in-human phase 1/2 study, monotherapy was well tolerated showed clinical activity in heavily pretreated patients with ER+/HER2- advanced breast cancer. The 3 dose (200 mg once daily [QD]) chosen due comparable efficacy favorable...
1022 Background: Optimizing sequential use of Antibody Drug Conjugates (ADCs) is an area unmet need and rising clinical importance. With the recent approvals sacituzumab govitecan (SG) for HR+/HER2- triple negative metastatic breast cancer (MBC) as well trastuzumab deruxtecan (T-DXd) HER2-low MBC, many patients are now candidates multiple ADCs. However, given potential cross-resistance based on antibody target vs payload (Coates et al, Cancer Discov. 2021), optimal sequencing remains...
Abstract Background: Antibody-drug conjugates (ADCs) improve survival in patients with metastatic breast cancer (MBC) and offer the potential for targeted delivery of highly potent therapy. Many are now candidates multiple ADCs, but optimal strategies sequencing unknown. We previously reported on a single institution experience receiving ADCs MBC (Abelman, ASCO 2023). Here we report multi-institution update biomarker analysis. Methods: included all treated at three academic medical...
p27 is a key regulator of cell proliferation. While it opposes cycle progression by binding to and inhibiting cyclin E-Cdk2, T157/T198 phosphorylation promotes its assembly D-type cyclin-CDKs. In addition actions on the cycle, regulates CDK-independent cytoplasmic functions. human cancers, oncogenic activation PI3K signaling pathway often results in mislocalization p27. Cytoplasmic plays an important role motility migration; binds RhoA modulates RhoA/ROCK cascade. p27:RhoA facilitated at...
While FGFR1 amplification has been described in breast cancer, the optimal treatment approach for FGFR1-amplified (FGFR1+) metastatic cancer (MBC) remains undefined.Experimental Design: We evaluated clinical response to endocrine and targeted therapies a cohort of patients with hormone receptor-positive (HR+)/HER2- MBC validated functional role FGFR1-amplification mediating response/resistance therapy vitro.In (N = 110), we identified that FGFR1+ tumors were more likely have progesterone...