A5051072215- Advanced Breast Cancer Therapies
- HER2/EGFR in Cancer Research
- PI3K/AKT/mTOR signaling in cancer
- Chronic Lymphocytic Leukemia Research
- Neuroendocrine Tumor Research Advances
- Sphingolipid Metabolism and Signaling
- Fibroblast Growth Factor Research
- Cancer-related Molecular Pathways
- Lung Cancer Research Studies
- Cancer Genomics and Diagnostics
- Cancer Immunotherapy and Biomarkers
- Cytokine Signaling Pathways and Interactions
- Lung Cancer Treatments and Mutations
- Monoclonal and Polyclonal Antibodies Research
- Renal cell carcinoma treatment
- Estrogen and related hormone effects
- PARP inhibition in cancer therapy
- Prostate Cancer Treatment and Research
- Breast Cancer Treatment Studies
- ATP Synthase and ATPases Research
- Cancer Mechanisms and Therapy
- Colorectal Cancer Treatments and Studies
- Cancer Treatment and Pharmacology
- Radiopharmaceutical Chemistry and Applications
- Epigenetics and DNA Methylation
University of Naples Federico II
2016-2025
Federico II University Hospital
2010-2025
Vanderbilt University Medical Center
2016-2020
The University of Texas Southwestern Medical Center
2017-2019
Vanderbilt-Ingram Cancer Center
2015-2019
Vanderbilt University
2015-2019
Fundación Instituto Valenciano de Oncología
2017-2018
Breast Cancer Research Foundation
2015-2018
Puma Biotechnology (United States)
2018
Centre for Cancer Biology
2018
Abstract Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer and transduced were resistant to fulvestrant ± or palbociclib. This resistance was abrogated by treatment FGFR tyrosine kinase (TKI) lucitanib. Addition TKI erdafitinib palbociclib/fulvestrant induced complete responses patient-derived-xenografts. Next generation sequencing circulating tumor...
Abstract Purpose: Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER+/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary in patients metastatic ER+ refractory to therapy. Experimental Design: Twenty-six received letrozole daily. Outcomes were assessed by standard solid-tumor methods. Tumor blocks collected...
Acquired resistance to cyclin-dependent kinases 4 and 6 (CDK4/6) small-molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen identify that, when downregulated, yield sensitivity the CDK4/6 inhibitor ribociclib. manner, identified 3-phosphoinositide-dependent protein kinase 1 (PDK1) as key modifier of ribociclib estrogen receptor-positive MCF-7 cells. Pharmacologic inhibition PDK1 with GSK2334470...
Genomic profiling of ER + /HER2 − breast tumors after short-term estrogen deprivation revealed alterations associated with intrinsic resistance and provided mechanistic insights.
Purpose:FGFR1 amplification occurs in approximately 15% of estrogen receptor-positive (ER+) human breast cancers. We investigated mechanisms by which FGFR1 confers antiestrogen resistance to ER+ cancer.Experimental Design: tumors from patients treated with letrozole before surgery were subjected Ki67 IHC, FISH, and RNA sequencing (RNA-seq). ER+/FGFR1-amplified cancer cells, patient-derived xenografts (PDX) siRNA or the FGFR tyrosine kinase inhibitor lucitanib. Endpoints cell/xenograft...
Abstract Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 is driven by cancer stem cell (CSC)-like populations could be targeted enhance the antitumor action these drugs. Therefore, we investigated mechanisms which inhibitors affect stem-like properties TNBC cells. Treatment established lines with a inhibitor or...
Abstract Purpose: We examined the role of ERBB2-activating mutations in endocrine therapy resistance estrogen receptor positive (ER+) breast cancer. Experimental Design: ERBB2 mutation frequency was determined from large genomic databases. Isogenic knock-in ER+ MCF7 cells and xenografts were used to investigate estrogen-independent growth. Structural analysis determine molecular interaction HERL755S with HER3. Small molecules siRNAs inhibit PI3Kα, TORC1, Results: Genomic data revealed a...
Several evidences suggest a marked angiogenic dependency in triple-negative breast cancer (TNBC) tumorigenesis and potential sensitivity to anti-angiogenic agents. Herein, the putative role of Hedgehog (Hh) pathway regulating TNBC-dependent angiogenesis was investigated.Expression regulation Hh transcription factor glioma-associated oncogene homolog1 protein (GLI1) were studied on endothelial compartment TNBC-initiated angiogenesis. To evaluate translational relevance our findings,...
Abstract Purpose: In hormone receptor–positive (HR+)/HER2− metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and discover therapeutic targets reverse this resistance. Non-luminal subtype high levels of CCNE1 are candidate biomarkers in setting, but further validation needed. Experimental Design: We performed mRNA gene expression profiling correlation with progression-free survival (PFS) on 455 tumor...
In patients with ER+ metastatic breast cancer (mBC), the first-line treatment involves combination of endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i). However, a significant group experiences disease progression, emphasizing urgent clinical need to identify novel anti-tumor therapies. We previously generated cells resistant fulvestrant (ER downregulator) abemaciclib (CDK4/6 inhibitor) from MCF7 T47D (MCF7-FAR T47D-FAR). RNA-seq-based Gene Set Enrichment Analysis (GSEA) revealed...
Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use limited by intrinsic or acquired resistance. Alterations "sphingolipid rheostat"-the balance between proapoptotic molecule ceramide and mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved resistance anticancer-targeted agents. Moreover, cross-talks SphK1 EGFR-dependent signaling pathways...
Cetuximab is the only targeted agent approved for treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates disease progression are frequently reported. As phosphoinositide 3-kinase (PI3K) mammalian target rapamycin (mTOR) pathways have an important role in pathogenesis HNSCC, we investigated their involvement cetuximab resistance. Different human cancer lines sensitive or resistant to were tested dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone combination,...
The urokinase-type plasminogen activator receptor (uPAR) is a GPI-anchored cell membrane that focuses urokinase (uPA) proteolytic activity on the surface. Its expression increased in many human cancers, including non-small lung cancer (NSCLC) and colorectal (CRC), correlates with poor prognosis early invasion metastasis. uPAR able to control, through cross-talk tyrosine kinase receptors, shift between tumor dormancy proliferation, usually precedes metastasis formation. Therefore, we...
Immunotherapies targeting programmed cell death protein 1 (PD-1) or its ligand, ligand (PD-L1), dramatically improve the survival of melanoma patients. However, only ∼40% treated patients demonstrate a clinical response to single-agent anti-PD-1 therapy. An intact tumor type-II interferon (i.e. IFN-γ) correlates with anti-PD-1, and de novo acquired resistance may harbor loss-of-function alterations in JAK/STAT pathway, which lies downstream gamma receptor (IFNGR1/2). In this study, we...
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...
Abstract Purpose: FGFR1 overexpression has been associated with endocrine resistance in ER+ breast cancer. We found localized the nucleus of cancer cells primary tumors resistant to estrogen suppression. investigated a role nuclear on gene transcription and antiestrogen resistance. Experimental Design: Tumors from patients treated letrozole were subjected Ki67 IHC. MCF7 transduced FGFR1(SP-)(NLS) promote overexpression. genomic activity ER+/FGFR1-amplified ± FOXA1 siRNA or FGFR tyrosine...
Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which overexpression sustains this resistance, we tested panel of cancer cell lines either sensitive or resistant lapatinib.To determine role lapatinib evaluated effects inhibition/silencing vitro on survival, migration, and invasion lapatinib-resistant cells. In vivo experiments were performed JIMT-1 cells...
Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in maintenance and progression different human cancers. Therefore, inhibition Hh pathway represents valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is Smoothened (Smo) antagonist induces dose-related Smo-dependent tumour growth. We assayed effects alone or combination with everolimus sunitinib on growth invasion RCC models both vitro vivo. To this aim, we used panel...