A5041961484- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- Estrogen and related hormone effects
- PI3K/AKT/mTOR signaling in cancer
- Cancer Genomics and Diagnostics
- Cancer Treatment and Pharmacology
- RNA modifications and cancer
- Breast Cancer Treatment Studies
- Lung Cancer Treatments and Mutations
- RNA Research and Splicing
- Monoclonal and Polyclonal Antibodies Research
- Computational Drug Discovery Methods
- FOXO transcription factor regulation
- Cancer-related Molecular Pathways
- Synthesis and biological activity
- DNA and Nucleic Acid Chemistry
- Epigenetics and DNA Methylation
- DNA Repair Mechanisms
- Protein Degradation and Inhibitors
- BRCA gene mutations in cancer
- Radiopharmaceutical Chemistry and Applications
- Cancer Cells and Metastasis
- PARP inhibition in cancer therapy
- Lung Cancer Research Studies
- Chronic Lymphocytic Leukemia Research
Memorial Sloan Kettering Cancer Center
2016-2025
Kettering University
2015-2025
Cornell University
2016-2025
Tennessee Oncology
2023
Queen Mary University of London
2023
Weill Cornell Medicine
2021-2022
New York University
2022
Icahn School of Medicine at Mount Sinai
2020
Eli Lilly (United States)
2020
ORCID
2020
With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for support tool that distills the implications associated with specific mutation events into standardized and easily interpretable format. To this end, we developed OncoKB, expert-guided precision oncology knowledge base.
There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it highly deregulated this disease and also mediates resistance anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors mTORC1, have resulted limited clinical efficacy probably due release negative regulatory feedback loop that triggers AKT ERK signaling. Since activation occurs via PI3K, we...
ESR1 mutations evolve during the treatment of metastatic breast cancer.
Estrogen receptor α (ESR1) mutations found in metastatic breast cancer (MBC) promote ligand-independent activation and resistance to estrogen-deprivation therapy laboratory models. The prevalence of these their potential impact on clinical outcomes has not been established.To determine the ESR1 (Y537S D538G) estrogen (ER)-positive MBC whether mutation is associated with inferior outcomes.From December 16, 2014, August 26, 2015, we analyzed cell-free DNA (cfDNA) from baseline plasma samples...
Abstract mTOR kinase inhibitors block mTORC1 and mTORC2 thus do not cause the activation of AKT observed with rapamycin. We now show, however, that these drugs have a biphasic effect on AKT. Inhibition leads to serine 473 (S473) dephosphorylation rapid but transient inhibition T308 phosphorylation signaling. However, also relieves feedback receptor tyrosine kinases (RTK), leading subsequent phosphoinositide 3-kinase rephosphorylation sufficient reactivate activity Thus, catalytic new steady...
HSP90 is a chaperone protein required for the stability of variety client proteins. 17-Demethoxygeldanamycin (17-AAG) natural product that binds to and inhibits its activity, thereby inducing degradation these clients. In preclinical studies, HER2 one most sensitive known proteins 17-AAG. On basis data activity in phase I study, we conducted II study 17-AAG (tanespimycin) with trastuzumab advanced trastuzumab-refractory HER2-positive breast cancer.We enrolled patients metastatic HER2(+)...
Inhibition of the PI3K/AKT pathway results in induction ER-dependent transcriptional activity and susceptibility to anti-estrogen therapy ER-positive breast cancer.
Dysregulated activation of the CDK4/6 kinases is a hallmark most mammary-derived carcinomas. ATP-competitive inhibitors against this complex have been recently advanced in clinic and shown significant activity, particularly tumors driven by estrogen receptor (ER). However, resistance to these compounds has begun emerge often months years after their initiation. We investigated potential mechanisms using cell line models that are highly sensitive class drugs. After prolonged exposure...
Abstract Most mutations in cancer are rare, which complicates the identification of therapeutically significant and thus limits clinical impact genomic profiling patients with cancer. Here, we analyzed 24,592 cancers including 10,336 prospectively sequenced advanced disease to identify mutant residues arising more frequently than expected absence selection. We identified 1,165 statistically hotspot 80% arose 1 1,000 or fewer patients. Of 55 recurrent in-frame indels, validated that novel...
Abstract Recent studies have identified somatic ESR1 mutations in patients with metastatic breast cancer and found some of them to promote estrogen-independent activation the receptor. The degree which all recurrent mutants can drive activities reduced sensitivity ER antagonists like fulvestrant is not established. In this report, we characterize spectrum from more than 900 patients. were detected 10%, D538G being most frequent (36%), followed by Y537S (14%). Several novel, activating also...
Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant cells chronic exposure to treatment. Genomewide copy-number variation analyses the resistant compared parental revealed a focal amplification genomic DNA containing cyclin E gene. In cohort 34 + treated trastuzumab-based therapy, found that...
Dysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was determine the role Akt activation cancer as a function mechanism whether inhibition feasible approach therapy.A selective allosteric inhibitor kinase used interrogate panel cell lines characterized for genetic lesions that activate signaling: amplification mutations order biochemical biologic consequences pathway. A variety...
Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity AKT inhibition AKT-mutant cancers. Patients Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary points progression-free survival (PFS) response according Response Evaluation Criteria Solid Tumors (RECIST)....
Somatic mutations in the estrogen receptor alpha (ERα) gene ( ESR1 ), especially Y537S and D538G, have been linked to acquired resistance endocrine therapies. Cell-based studies demonstrated that these mutants confer ERα constitutive activity antiestrogen suggest ligand-binding domain dysfunction leads therapy resistance. Here, we integrate biophysical structural biology data reveal how lead a constitutively active antiestrogen-resistant ERα. We show mutant ERs recruit coactivator absence of...
Seeing double can be a good thing Many human breast cancers harbor activating mutations in PIK3CA , the gene coding for catalytic subunit of phosphoinositide 3-kinase (PI3K). Clinical trials are underway to evaluate efficacy PI3K inhibitors cancer patients. Vasan et al. found unexpectedly that subset not one—but two— mutations, and occur on same allele (see Perspective by Toker). In model systems, hyperactivate signaling enhance tumor growth. Preliminary analysis clinical trial data suggests...